No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities
Allergy
Abstract
Histamine intolerance (HIT) is associated with an excess of histamine because of an impaired function of the histamine-degrading enzyme diamine oxidase (DAO). The genetic background of HIT is unknown yet.
Case-control association study of all haplotype tagging and four previously reported DAO SNPs and one HNMT Single nucleotide polymorphism with symptoms of HIT and DAO serum activity in 484 German individuals including 285 patients with clinical symptoms of HIT and 199 controls.
Diamine oxidase serum activity was significantly associated with seven SNPs within the DAO gene. The minor allele at rs2052129, rs2268999, rs10156191 and rs1049742 increased the risk for a reduced DAO activity whereas showing a moderate protective effect at rs2071514, rs1049748 and rs2071517 in the genotypic (P = 2.1 × 10(-8) , 7.6 × 10(-10) , 8.3 × 10(-10) , 0.009, 0.005, 0.00001, 0.006, respectively) and allelic genetic model (P = 2.5 × 10(-11) , 5.4 × 10(-13) , 8.9 × 10(-13) , 0.00002, 0.006, 0.0003, 0.005, respectively). Reporter gene assays at rs2052129 revealed a lower promoter activity (P = 0.016) of the minor allele. DAO mRNA expression in peripheral blood mononuclear cells of homozygous carriers of the minor allele at rs2052129, rs2268999, rs10156191 was lower (P = 0.002) than homozygous carriers of the major allele. Diamine oxidase variants were not associated with the HIT phenotype per se, only with DAO activity alone and the subgroup of HIT patients displaying a reduced DAO activity.
DAO gene variants strongly influence DAO expression and activity but alone are not sufficient to fully effectuate the potentially associated disease state of HIT, suggesting an interplay of genetic and environmental factors.
... DAO deficiency may also have a genetic origin [10][11][12]. To date, more than 50 nonsynonymous Single Nucleotide Variation (SNVs) have been identified in the coding sequence of the DAO-encoding gene (AOC1/ABP1) located in chromosome 7 (7q34-q36) [11][12][13][14][15]. Among them, rs10156191, rs1049742 and rs1049793 are reported to be the SNVs that most affect DAO functionality in Caucasian individuals [6,12,15,16]. ...
... To date, more than 50 nonsynonymous Single Nucleotide Variation (SNVs) have been identified in the coding sequence of the DAO-encoding gene (AOC1/ABP1) located in chromosome 7 (7q34-q36) [11][12][13][14][15]. Among them, rs10156191, rs1049742 and rs1049793 are reported to be the SNVs that most affect DAO functionality in Caucasian individuals [6,12,15,16]. Moreover, a SNV in the promoter region of the DAO-encoding gene (rs2052129) is associated with reduced transcriptional activity [16]. ...
... Ayuso et al. (2007) observed that carriers of the variant rs1049793, whether heterozygous or homozygous, displayed a lower serum DAO activity than non-carriers [6]. Similarly, Maintz et al. (2011), found that reduced DAO activity was associated with certain AOC1 variants, especially in those individuals who were carrying the T allele in variant rs2052129 [15]. However, limited existing literature delves into the examination of the association between these SNVs and the clinical manifestations of histamine intolerance. ...
A retrospective pilot study was carried out to investigate the prevalence of four variants of the diamine oxidase (DAO) encoding gene (AOC1) in Caucasian adults with symptoms of histamine intolerance. In a cohort of 100 patients and 100 healthy individuals, DAO-encoding gene non-synonymous Single Nucleotide Variations (SNVs) were genotyped by multiplex single-nucleotide primer extension (SNPE) and capillary electrophoresis, and serum DAO activity was analyzed with a radio-extraction assay. The study found that 79% of individuals with symptoms of histamine intolerance harbored one or more of the four SNVs associated with reduced DAO activity. No significant differences were found in the prevalence of any variant between the group of patients and healthy controls. However, when considering the status of the alleles associated with DAO deficiency, more homozygous alleles were observed in histamine-intolerant patients. Moreover, a slightly but statistically higher percentage of patients had a high genetic risk score, reflecting the cumulative effect of carrying multiple DAO deficiency-associated gene variants and a high load of risk alleles (homozygous). A relationship between serum DAO activity and the genetic load of one specific SNV was observed, with DAO activity being significantly lower in patients homozygous for rs2052129. These results potentially support that carrying multiple DAO deficiency-associated gene variants and a high load of risk alleles (homozygous) is more relevant than the mere presence of one or more SNVs. Further studies are needed to determine the predictive value of these DAO-encoding gene variants.
... DAO is an enzyme encoded by the amine oxidase copper-containing 1 (AOC1) gene and responsible for extracellular degradation of histamine at the intestinal level [9][10][11]. It has been seen that the presence of minor alleles in some single nucleotide polymorphisms (SNPs) is associated with lower enzymatic activity of DAO and a greater expression of HIT symptoms [12][13][14]. The three most relevant SNPs in Caucasian individuals leading to a reduction in DAO enzyme activity are c.47C>T (rs10156191), c.995C>T (rs1049742), and c.1990C>G (rs1049793) [12,13]. ...
... [12]. In addition, another SNP in the promoter region of the AOC1 gene has been identified, with a frequency of 41.7%, which has been associated with a decrease in DAO transcriptional activity: c.-691G>T (rs2052129) [14]. ...
... Also, patients with LUTS presented a very high prevalence (88%) of at least one altered variant (presence of a minor allele associated with DAO deficiency) in the SNP of the AOC1 gene. Although HIT has been commonly associated as a syndrome that predominantly affects women [14,35,36], our sample included 46% of men, suggesting that genetic DAO deficiency can affect both sexes. The studied alleles were consistent with Hardy-Weinberg equilibrium, but considering the database of SNF (dbSNP) that included NCBI Allele Frequency Aggregator (ALFA) data as a reference (https://www.ncbi.nlm.nih.gov/snp/docs/gsr/alfa/, ...
Lower urinary tract symptoms (LUTS) are highly prevalent, and their treatment is mainly focused on the control of symptoms. Histamine intolerance (HIT) has been related to a variety of systemic symptoms. DAO deficiency has been identified as a significant factor contributing to histamine intolerance (HIT). Preclinical evidence indicates the involvement of histamine in the lower urinary tract. This study aimed to assess the prevalence of diamine oxidase deficiency (DAO) in a prospective cohort of 100 patients with at least moderate LUTS. A genetic study of four single nucleotide polymorphisms (SNPs) (c.-691G>T, c.47C>T, c.995C>T, and c.1990C>G) was performed. HIT was found in 85.9% of patients. The prevalence of at least one minor allele in the SNPs analyzed was 88%, without gender differences. Storage symptoms were more intense in the presence of HIT as well as asthenia and neurological and musculoskeletal symptoms. The presence of minor alleles of the AOC1 gene was associated with a higher intensity of symptoms. Minor alleles from c.-691G>T and c.47C>T SNPs were also associated with a greater severity of obstructive symptoms. Thirty-one percent of patients presented the four SNPS with at least one associated minor allele. The relationship between HIT and LUTS in a mixed population of men and women found in this study supports further investigations to define the pathophysiology of histamine in LUTS.
... In order to avoid potential intoxication or the deleterious effects of excessive histamine in the body, histamine is metabolized by two main enzymes: the DAO enzyme and histamine-N-methyltransferase (HNMT) [11,12]. HNMT is responsible for the degradation of intracellular histamine, whereas DAO metabolizes histamine extracellularly [10]. ...
... There are several candidate tests to detect genetic DAO deficiency. However, their informative value is questionable, as the DAO expression and activity depend on the interplay between genes and the environment [12]. Furthermore, DAO has a higher expression than HNMT, being the main barrier for the intestinal absorption of histamine [32]. ...
... Furthermore, DAO has a higher expression than HNMT, being the main barrier for the intestinal absorption of histamine [32]. At least in the Caucasian population, the SNPs that can most directly cause DAO deficiency are rs10156191, rs1049742, rs2052129, and rs1049793 [12,31]. ...
Speer allergic tension-fatigue syndrome (SATFS) is a classic allergy syndrome characterized by allergy-like symptoms, muscle tension, headaches, chronic fatigue, and other particular behaviors that were initially described in the fifties. The particular behaviors displayed include symptoms such as hyperkinesis, hyperesthesia (i.e., insomnia), restlessness, and distractibility, among others. Interestingly, these symptoms are very similar to descriptions of attention deficit hyperactivity disorder (ADHD), the most prevalent neurodevelopmental disorder worldwide, which is characterized by inattention, hyperactivity, and impulsivity. The clinical description of SATFS precedes the nomination of ADHD in 1960 by Stella Chess. In this conceptual paper, we stress that there is a gap in the research on the relationship between ADHD and allergic pathologies. The hypotheses of this conceptual paper are (1) SATFS is probably one of the first and best historical descriptions of ADHD alongside a common comorbidity (allergy) displayed by these patients; (2) SATFS (ADHD) is a systemic disease that includes both somatic and behavioral manifestations that may influence each other in a bidirectional manner; (3) The role of neuroinflammation and histamine is key for understanding the pathophysiology of ADHD and its frequent somatic comorbidities; (4) The deficiency of the diamine oxidase (DAO) enzyme, which metabolizes histamine extracellularly, may play a role in the pathophysiology of ADHD. Decreased DAO activity may lead to an accumulation of histamine, which could contribute to core ADHD symptoms and comorbid disorders. Further empirical studies are needed to confirm our hypotheses.
... The DAO enzyme is encoded by amine oxidase copper-containing 1 (AOC1), which is expressed in intestinal and renal epithelial cells, where it is primarily stored in vesicles in the basolateral plasma membrane (Barbry et al., 1990;Schwelberger, 2004). The AOC1 gene is located on chromosome 7q36, and its most relevant nonsynonymous polymorphisms in Caucasian individuals include rs10156191 (p.Thr16Met), rs1049742 (p.Ser332Phe), and rs1049793 (p.His645Asp), which affect enzyme production of DAO (Ayuso et al., 2007), including rs2052129 (G4586T), which is found in the promoter region of the gene and produces lower transcriptional activity (Maintz et al., 2011). Noninvasive genetic analyses that identify SNPs associated with reduced DAO activity have been performed for years (Comas-Basté et al., 2020). ...
... Despite the low number of symptoms associated with the four AOC1 gene variants, evidence suggests that reduced levels of the Frontiers in Genetics frontiersin.org 06 enzyme DAO, and thus high accumulation of extracellular histamine, are associated with symptoms of atopic dermatitis (Maintz et al., 2006;Maintz et al., 2011;Mušič et al., 2013;Schnedl et al., 2019), migraine (Maintz et al., 2006;Maintz et al., 2011;Schnedl et al., 2019), GI disorders (Raithel et al., 1999;Maintz et al., 2006;Maintz et al., 2011;Mušič et al., 2013;Schnedl et al., 2019), and food or drug allergies (Raithel et al., 1999;Maintz et al., 2006;Maintz et al., 2011;Schnedl et al., 2019), and that these symptoms may occur concurrently in many cases. It was demonstrated that administering 75 mg of pure liquid oral histamine under experimental conditions provoke immediate as well as delayed symptoms in 50% of healthy females without a history of food intolerance, including diarrhea, flatulence, and headache (Wöhrl et al., 2004). ...
... Despite the low number of symptoms associated with the four AOC1 gene variants, evidence suggests that reduced levels of the Frontiers in Genetics frontiersin.org 06 enzyme DAO, and thus high accumulation of extracellular histamine, are associated with symptoms of atopic dermatitis (Maintz et al., 2006;Maintz et al., 2011;Mušič et al., 2013;Schnedl et al., 2019), migraine (Maintz et al., 2006;Maintz et al., 2011;Schnedl et al., 2019), GI disorders (Raithel et al., 1999;Maintz et al., 2006;Maintz et al., 2011;Mušič et al., 2013;Schnedl et al., 2019), and food or drug allergies (Raithel et al., 1999;Maintz et al., 2006;Maintz et al., 2011;Schnedl et al., 2019), and that these symptoms may occur concurrently in many cases. It was demonstrated that administering 75 mg of pure liquid oral histamine under experimental conditions provoke immediate as well as delayed symptoms in 50% of healthy females without a history of food intolerance, including diarrhea, flatulence, and headache (Wöhrl et al., 2004). ...
Introduction: The amine oxidase copper-containing 1 (AOC1) gene encodes for the diamine oxidase (DAO) enzyme. DAO is an enzyme that catabolizes some molecules, including histamine, and is the degradative enzyme in the polyamine catabolic pathway that is active in intestinal mucosal cells. Variants of AOC1 are associated with reduced DAO activity, resulting in accumulation of high levels of histamine and causing a wide range of neurological, gastrointestinal, and epidermal disorders, which are present in people with fibromyalgia. This study aimed to evaluate the impact of four AOC1 gene variants, namely, rs10156191, rs1049742, rs1049793, and rs2052129, on fibromyalgia symptoms measured by the Fibromyalgia Impact Questionnaire (FIQ), such as sleep disorders, atopic dermatitis, migraine, gastrointestinal (GI) disorders, allergies, and intolerances, in adult women with fibromyalgia.
Methods: The sample consisted of 100 unrelated women with fibromyalgia between 33 and 60 years of age (48.48 years ±7.35), whose were diagnosed by a rheumatologist based on symptoms such as pain, stiffness, and fatigue. Single-nucleotide polymorphisms (SNPs) of AOC1 were identified using oral mucosa samples collected following a standard hygiene protocol. DNA was extracted, and gene variants of interest were analyzed using multiplex single-nucleotide primer extension (SNPE). Clinical data were collected using the FIQ and a series of variables that quantified the intensity and frequency of the symptoms.
Results: The minor allele frequencies of rs10156191, rs1049742, rs1049793, and rs2052129 were 31.5, 10, 32.5, and 27%, respectively. Each variant was found to be in Hardy–Weinberg equilibrium, but partial linkage disequilibrium between AOC1 SNPs is suspected. The results show that fibromyalgia symptoms measured using the FIQ tend to increase with the number of risk alleles and that the intensity of dry skin and low stool consistency may be associated with an increase in the number of these alleles.
Conclusion: This study constitutes the first step in investigating associations between fibromyalgia symptoms and candidate variants of the AOC1 gene in DAO enzyme activity. Identification of reduced DAO activity may improve the quality of life and treatment of symptoms in fibromyalgia patients.
... In order to avoid a potential intoxication or the deleterious effects of excessive histamine in the body, histamine is metabolized by two main enzymes: diamine oxidase (DAO), and histamine-N-methyltransferase (HNMT) [9,10]. HNMT is responsible for the degradation of intracellular histamine, whereas DAO metabolizes histamine extracellularly [8]. ...
... There are several candidate tests to detect DAO deficiency. However, their informative value is questionable, as the DAO expression and activity depends on the interplay between genes and environment [10]. Furthermore, DAO has a higher expression than HNMT, being the main barrier for the intestinal absorption of histamine [31]. ...
... Furthermore, DAO has a higher expression than HNMT, being the main barrier for the intestinal absorption of histamine [31]. At least in the Caucasian population, the SNPs that can most directly cause DAO deficiency are rs10156191, rs1049742, rs2052129, and rs1049793 [10,30]. ...
The Speer allergic tension-fatigue syndrome (SATFS) is a classic syndrome characterized by allergy-like symptoms, muscle tension, headache, chronic fatigue, and a particular behavior. The particular behavior displayed includes symptoms such as hyperkinesis, hyperesthesia (i.e., insomnia), restlessness, and distractibility, among others. Interestingly, these symptoms are very similar to recent descriptions of attention deficit hyperactivity disorder (ADHD), the most prevalent neurodevelopmental disorder worldwide, which is characterized by inattention, hyperactivity and impulsivity. Although the exact cause of ADHD remains unknown, it has been proposed that deficiency of the enzyme diamine oxidase (DAO), which metabolizes histamine, may be involved in the development of ADHD. Our conceptual paper suggests that DAO enzyme deficiency may be involved in the development and severity of ADHD. Histamine, which is metabolized by DAO, plays an important role in the regulation of attention, memory and cognition. Therefore, decreased DAO activity could lead to an accumulation of histamine, which could contribute to ADHD symptoms. This study provides a theoretical framework for the relationship between DAO deficiency and ADHD, which could have important implications for the diagnosis and treatment of the disorder. Further empirical studies are needed to confirm our hypothesis and explore the clinical implications of the relationship between DAO deficiency, histamine, and ADHD.
... Food intolerance is receiving increasing attention both from research [3,4] and in routine allergy clinical practice possibly due to the many and heterogenous overlapping symptoms with other clinical conditions. The term histamine intolerance (HIT) refers to a complex disorder of controversial definition [4][5][6][7], characterized by pseudo-allergic symptoms encompassing post-prandial malaise, diarrhea, and meteorism along with cutaneous manifestations, such as urticaria and itch, as well as vasomotor disturbances leading to hypotension, tachycardia, flushing, rhino-conjunctival symptoms, and headache [8][9][10][11][12][13]. HIT is supposed to be caused by an imbalance between histamine intake and catabolism [14]. ...
... A quantitative and/or functional deficit of diamine oxidase (DAO), the main extracellular enzyme devoted to histamine catabolism along the digestive tract, might also contribute to the pathogenesis of HIT [8][9][10][11], while the heterogeneous distribution of histamine receptors might account for clinical phenotype variability among subjects. The diagnostic work-up of HIT still remains challenging, uncertain, and time-consuming as well as frequently leading to misdiagnosis. ...
... As per the local practice protocols, patients with suspected HIT underwent a complete allergy work-up, including clinical interview, skinprick tests, and total and specific Immunoglobulin E (IgE) when needed (Supplementary Materials Table S1). Serum DAO activity was also measured in all patients with suspected HIT through a commercially available radio extraction assay (DAO-REA ® ; Sciotec Diagnostic Technologies GmbH, Tulln, Austria) used in previous studies [9,30]. All patients with a confirmed new HIT diagnosis were prescribed a low-histamine diet trial and/or DAO supplementation (Daosin ® , Sciotec Diagnostic Technologies GmbH, Tulln, Austria: one tablet before each meal or as needed) according to the physician's evaluation of HIT severity (Supplementary Materials Figure S1). ...
Background:
Histamine Intolerance (HIT) is a multifaceted pseudoallergic disorder possibly due to defective histamine metabolism. Diamine oxidase (DAO) contributes to histamine degradation and can be measured in the serum. The role of DAO measurement in the diagnostic work-up of HIT still remains unclear, and conflicting results have been reported in the literature. Therefore, we aimed to evaluate the possible clinical usefulness and consistency of DAO value ranges as provided by the assay manufacturer and verify whether they could predict the response to treatment.
Methods:
We retrospectively analyzed 192 outpatients with HIT symptoms and measured serum DAO values at baseline. Patients were prescribed either with low-histamine diet and/or enzymatic supplementation according to symptom severity and re-evaluated six to eight months later. Patients were stratified into three groups according to DAO levels: <3 U/mL, 3-10 U/mL, and >10 U/mL. HIT severity was assessed on a scale of 1 to 5 before and after treatment.
Results:
A total of 146 patients completed the study. Gastrointestinal and cutaneous symptoms, often associated with headache, were more frequent in subjects with DAO < 10 U/mL. Symptom severity and DAO ranges were correlated. Patients with intermediate DAO levels (3-10 U/mL) showed a more complex clinical phenotype but also a more significant improvement in symptom severity (score reduction 50%, interquartile range (IQR) = 33-60%) when compared to patients with low DAO (40%, IQR = 20-60%; p = 0.045) or high DAO (33%, IQR = 0-50%; p < 0.001). Complex clinical phenotypes were also more frequent in patients with intermediate DAO levels.
Conclusions:
HIT is characterized by typical symptoms and low levels of DAO activity. Symptom severity was associated with the degree of DAO deficiency. Patients with DAO values between 3 and 10 U/mL show the best response to treatment (low-histamine diet and/or DAO supplementation). DAO value could arguably be considered as a predictor of clinical response to treatment. Prospective studies are needed to confirm these data.
... Regarding the genetic background of histamine intolerance, several studies have analyzed in depth the polymorphisms in genes encoding the enzymes L-histidine decarboxylase, DAO and HNMT, as well as the different histamine receptors. More than 50 non-synonymous single-nucleotide polymorphisms (SNPs) in the DAO-encoding gene have been identified, some of which can produce a protein with altered activity and lead to symptoms of histamine intolerance [67][68][69][70][71][72]. Specifically, the most relevant SNPs affecting DAO enzyme functionality in Caucasian individuals are rs10156191, rs1049742, rs2268999, and especially rs1049793 [69,71]. ...
... Specifically, the most relevant SNPs affecting DAO enzyme functionality in Caucasian individuals are rs10156191, rs1049742, rs2268999, and especially rs1049793 [69,71]. On the other hand, it has also been identified an SNP in the promoter region of the gene that causes a lower transcriptional activity of the DAO-encoding gene (rs2052129), as well as several genetic variations responsible for enzyme deficiency in people of Asian or African origin (rs45558339 and rs35070995, respectively) [67,72]. In most cases, the effect of these genetic variations on DAO functionality is through changes in enzyme kinetics, the resulting increase in KM causing a reduction in the rate of histamine degradation [69]. ...
... In most cases, the effect of these genetic variations on DAO functionality is through changes in enzyme kinetics, the resulting increase in KM causing a reduction in the rate of histamine degradation [69]. In parallel, three SNPs have been identified as responsible for enhanced DAO enzyme activity (rs2071514, rs1049748 and rs2071517) [72]. There is also evidence of DAO mutations in patients with certain cardiovascular, gastrointestinal and nervous system pathologies, although with contradictory results regarding positive/negative effects [68]. ...
... Regarding the genetic background of histamine intolerance, several studies have analyzed in depth the polymorphisms in genes encoding the enzymes L-histidine decarboxylase, DAO and HNMT, as well as the different histamine receptors. More than 50 nonsynonymous single-nucleotide polymorphisms (SNPs) in the DAO-encoding gene have been identified, some of which can produce a protein with altered activity and lead to symptoms of histamine intolerance [67][68][69][70][71][72]. Specifically, the most relevant SNPs affecting DAO enzyme functionality in Caucasian individuals are rs10156191, rs1049742, rs2268999 and especially rs1049793 [69,71]. ...
... Specifically, the most relevant SNPs affecting DAO enzyme functionality in Caucasian individuals are rs10156191, rs1049742, rs2268999 and especially rs1049793 [69,71]. On the other hand, an SNP in the promoter region of the gene has also been identified that causes a lower transcriptional activity of the DAO-encoding gene (rs2052129), as well as several genetic variations responsible for enzyme deficiency in people of Asian or African origin (rs45558339 and rs35070995, respectively) [67,72]. In most cases, the effect of these genetic variations on DAO functionality is through changes in enzyme kinetics, the resulting increase in K M causing a reduction in the rate of histamine degradation [69]. ...
... In most cases, the effect of these genetic variations on DAO functionality is through changes in enzyme kinetics, the resulting increase in K M causing a reduction in the rate of histamine degradation [69]. In parallel, three SNPs have been identified as being responsible for enhanced DAO enzyme activity (rs2071514, rs1049748 and rs2071517) [72]. There is also evidence of DAO mutations in patients with certain cardiovascular, gastrointestinal and nervous system pathologies, although with contradictory results regarding positive/negative effects [68]. ...
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century. Although interest in histamine intolerance has considerably grown in recent years, more scientific evidence is still required to help define, diagnose and clinically manage this condition. This article will provide an updated review on histamine intolerance, mainly focusing on its etiology and the existing diagnostic and treatment strategies. In this work, a glance on histamine intoxication will also be provided, as well as the analysis of some uncertainties historically associated to histamine intoxication outbreaks that may be better explained by the existence of interindividual susceptibility to ingested histamine.
... DAO enzyme has three common non-synonymous single nucleotide polymorphisms (SNPs) that are: rs10156191 (Thr16Met), rs1049742 (Ser332Phe) and rs1049793 (His645Asp) which can reduce protein's activity by altering its form Garcia-Martin et al., 2007). Another SNP rs2052129 (G4586 T), present in promoter region of gene, has been related with decreased transcriptional activity of DAO (Maintz et al., 2011). Various studies have reported that the patients with minor alleles of rs1049793, rs10156191 and rs2052129 SNPs have lower serum DAO activity on comparison with controls (Garcia-Martin et al., 2015). ...
... Similarly our results revealed association of these SNPs with migraine in gender analysis. These results were also similar to Maintz et al. (2011)who reported the risk for a lower DAO activity with increased frequencies of minor alleles in rs2052129, rs10156191, rs2268999 and rs1049742 SNPs. They found that reporter gene assays at rs2052129 showed a lower promoter activity (p = .016) of the minor allele. ...
... Both the SNPs taken in present study are reported to alter DAO enzyme activity in vivo . Rs10156191T allele encodes a protein with amino acid substitution in the position 16 as Met instead of Thr in wild type protein and reduces intrinsic activity of enzyme and its ability to metabolize circulating histamine (Maintz et al., 2011). As frequency of T allele is more in female migraineurs, it can be expected that decreased clearance of circulating histamine could be the reason for developing migraine. ...
Background
Migraine is a common neurovascular disorder affected by various levels of neurotransmitters. Low histamine metabolism is also related with pathophysiology of migraine. As diamine oxidase (DAO) gene variants are linked with higher levels of histamine in migraine patients, we investigated the possible relationship of two variants rs2052129 and rs10156191of this gene with migraine risk in North Indian population.
Methods
A case-control study for 250 migraine patients and 250 matched healthy controls was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Results
We found statistically significant differences in allelic frequencies of rs2052129 (p = .009, OR = 1.462; 95% CI: 1.098–1.947) and rs10156191 (p = .019, OR = 1.430; 95% CI: 1.060–1.928) variants in DAO gene. For rs1015691, we were able to show statistically significant association at all genotypic, dominant and allelic levels in both MA (for T allele, p = .020; OR = 1.662, 95% CI: 1.083–2.551) as well as in female subgroup (for T allele, p = .025, OR = 1.460; 95% CI: 1.049–2.033). But no such significant association was found in clinical sub grouping of migraine in rs2052129 as p > .05. However in gender analysis, protective effect of T allele in male migraine patients for rs2052129 (OR < 1) was found.
Conclusions
Our findings clearly indicated that a female patient with rs10156191T allele and in MA subgroup showed an increased risk for migraine. Our data also indicated that rs2052129T variant showed a significant role in migraine susceptibility of this population.
... Endogenous and exogenous environmental factors, health status. Habitat peculiarities and lifestyle of individuals also have a modifying effect on the functioning of the histamine metabolic network [5,29,58,85,109,110]. Thus, it was demonstrated that DAO (AOC1) deficiency is common in patients with migraine, but a low level of this enzyme was also registered in healthy individuals (in 87 and 44% of individuals, respectively) [103], which indicates the presence of other factors contributing to the manifestation of adverse effects of alleles. ...
... Habitat peculiarities and lifestyle of individuals also have a modifying effect on the functioning of the histamine metabolic network [5,29,58,85,109,110]. Thus, it was demonstrated that DAO (AOC1) deficiency is common in patients with migraine, but a low level of this enzyme was also registered in healthy individuals (in 87 and 44% of individuals, respectively) [103], which indicates the presence of other factors contributing to the manifestation of adverse effects of alleles. In another study, evidence that DAO (AOC1) activity can depend on variants of the gene encoding this enzyme are given [58], but the authors concluded not only unfavorable allelic variants but also the effect of additional (ecological) factors is required for the manifestation of pathological symptoms in histamine intolerance. Indeed, it was established that, if patients with histamine intolerance followed a diet with a low level of this amine, not only symptoms of the disease decreased in them, but also the activity of the AOC1 enzyme increased [5,85]. ...
... Compiled according to databases[11,12, 18] and publications[26,34,46,[56][57][58][59][60]. SNP ID, polymorphism identification number. ...
Histamine is a biologically active substance of local effect, but is involved in the regulation of different processes in the body, including the pathogenesis of diseases. In the present review, molecular genetic, clinical, and experimental studies on the role of histamine and key genes of its metabolism in the pathogenesis of diseases are summarized. Data on associated polymorphic variants (30 SNPs, 1 CNV) of key histamine metabolism genes with multifactorial diseases are given, including HDC (involved in the synthesis of histamine), HNMT, AOC1, MAOB, ALDH7A1 (involved in the processes of histamine degradation), and HRH1, HRH2, HRH3, HRH4 (histamine receptors): associations were established with allergic and oncological diseases, diseases of nervous and cardiovascular systems, gastrointestinal tract, metabolic disorders, etc. A nonrandomness of established associations of histamine metabolic pathway genes with pathological conditions is supported by clinical observations and experimental studies performed on model objects and cell lines. Moreover, according to clinical and experimental data, a wider range of pathological conditions in which risk structural and functional peculiarities of key histamine metabolic pathway genes will make a certain contribution can be expected. The questions of the complexity of determining the significance of histamine level and structural and functional peculiarities of histamine metabolic pathway genes in terms of a positive/negative effect on the body, as well as some possible reasons for inconsistency of association studies performed in different ethnoterritorial groups, are discussed.
... Seven of these SNPs produce an amino acid substitution, serving as candidates that cause alterations in the metabolic capacity of the enzyme. Of the polymorphisms found in the AOC1 gene sequence, four have been associated with a low enzymatic activity in the metabolism of histamine [13,14]. This relationship has been explained by symptoms due to ingested histamine; however, it has not been proven with a specific diagnosis. ...
... In this study, four variants of the AOC1 gene were evaluated: p.Thr16Met (rs10156191), p.Ser332Phe (rs1049742), p.His664Asp (rs1049793), and c.691G > T (rs2052129), whose minor allele is associated with lower levels of DAO activity and therefore a lower capacity for histamine degradation [13,14]. In this sense, our results revealed that 74.5% of the women with fibromyalgia had a genetic DAO deficiency, that is, they had at least one risk allele in one of the four variants analyzed. ...
Diamine oxidase (DAO) is an enzyme that metabolizes intestinal histamine. Single nucleotide polymorphisms (SNPs) of the Amine Oxidase Copper Containing 1 (AOC1) gene can lead to low enzymatic activity or functionality in histamine metabolism. This study aimed to determine the prevalence of DAO deficiency for four variants of the AOC1 gene, p.Thr16Met (rs10156191), p.Ser332Phe (rs1049742), p.His664Asp (rs1049793), and c.691G > T (rs2052129), in 98 Spanish women with fibromyalgia between the ages of 33 and 60 years, and compare the distribution of allelic and genotypic frequencies with those of European population samples in Hardy–Weinberg equilibrium extracted from the Allele Frequency Aggregator (ALFA) database. The patients’ DNA was extracted, and analyzed using SNPE Multiplex (Single Nucleotide Primer Extension). The prevalence of genetic DAO deficiency was 74.5% based on the four variants of the AOC1 gene. SNP deficits were found at frequencies of 53.1% for p.Thr16Met, 49% for c.691G > T, 48% for p.His664Asp, and 19.4% for p.Ser332Phe. The allele and genotypic frequencies of the women with fibromyalgia did not differ from the European population. Variants of the AOC1 gene that are associated with genetic DAO deficiency could serve as a disruptive biomarker in patients with fibromyalgia. This study was registered in ClinicalTrials.gov Identifier: NCT05389761.
... DAO deficiency has been linked to single-nucleotide polymorphisms that encode a protein with decreased histamine breakdown capacity and may have hereditary roots. [19] On the other hand, impaired DAO activity can also be transient and reversible and can result from a side effect of several commonly used pharmaceuticals, such as clavulanic acid or acetylcysteine might be a secondary sign of digestive issues. Due to these digestive issues, the DAO might be a significant factor that cause gut bacterial dysbiosis, which could alter the structural and composition of bacterial diversity in the gut. ...
... In the small intestine, this is achieved primarily by PRRs, antimicrobial peptides and secreted IgA, and an immune milieu consisting of a cytokine environment that includes IL-33, IL-10 and transforming growth factor-β (TGFβ). [19,20] Parasutterella affects the immune response in the gut. Ju T et.al shows Parasutterella colonization did not alter the level of detected colonic cytokines except for a tendency to reduce the IL-1β expression, which indicates that the colonization of Parasutterella did not induce the host innate immune responses and further supports the role of Parasutterella as commensal or symbiotic gut microbe. ...
The present study aimed to explore gut microbiota alterations and host cytokine responses in a population with elevated serum diamine oxidase (DAO) disorder. A total of 53 study participants were included in this study, segregated into 2 groups: subjects with high-level DAO (DAO-H, n = 22) subjects with normal DAO level (DAO-N, n = 31). We investigated the clinical and demographic parameters of study participants. The fecal bacterial communities and serum cytokines in 2 groups were assessed by 16S ribosomal RNA gene sequencing and immunoassay. High-pressure liquid chromatography was used to determine hemoglobin Alc. Flow cytometry was used to find the cytokine level in the blood serum. There is no difference in age, total cholesterol (TCHO), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), hemoglobin Alc, fasting plasma glucose (FPG) and homocysteine between the 2 groups. No significant difference were found in α-diversity between the 2 groups, however, the gut microbiota of subjects in DAO-H were characterized by marked interindividual differences, decreased abundance of Phocaeicola, Lachnospira, Bacteroides, Alistipes, Agathobacter, Lachnospira and Bactetoides and increased abundances of Mediterraneibacter, Blautia, Faecallibacterium, Agathobacter, and Parasutterella. Furthermore, the cytokines were no related to the DAO level in both groups and exhibited no significant differences between DAO-H and DAO-N. This study adds a new dimension to our understanding of the DAO and gut microbiota, and revealed that an increase in the DAO level in the intestinal mucosa could alter the gut microbiota composition, which can cause gut-related complications. Research is needed to extensively evaluate downstream pathways and provide possible protective or treatment measures pertaining to relevant disorders.
... Seven of these SNPs produce an amino acid substitution, being candidates to cause alterations in the metabolic capacity of the enzyme. From all polymorphisms found in the AOC1 gene sequence, 4 of these polymorphisms have been associated to a low enzymatic activity in the metabolism of histamine Maintz et al. 2011). Studies indicate that this type of polymorphism occurs with an approximate global frequency of 10-13%, especially in women (International Society of DAO De ciency 2018). ...
... In this study, four variants of the AOC1 gene were examined in the scienti c literature that have been associated with lower levels of DAO activity with a lower capacity for histamine degradation Maintz et al. 2011). For all variants, the CC result has been associated to a normal production of the DAO enzyme, while the CT, CG, TT or GG result has been associated to an abnormal production of the enzyme and therefore an increased risk of DAO de ciency. ...
Diamine oxidase (DAO) is the enzyme responsible for the metabolism of intestinal histamine. Single nucleotide polymorphisms (SNPs) of the AOC1 gene are associated with low enzymatic activity or functionality in the metabolism of histamine.
The objectives of the present study were to determine the prevalence of DAO deficiency for four variants of the AOC1 gene, p.Thr16Met (rs10156191), p.Ser332Phe (rs1049742), p.His664Asp (rs1049793) and c.691G > T (rs2052129) in Spanish women with fibromyalgia, as well as to compare the distribution of allelic and genotypic frequencies with European population samples in Hardy-Weinberg equilibrium (HWE) extracted from the ALFA (Allele Frequency Aggregator) database.
The sample consisted of 98 Spanish women with fibromyalgia between 33 and 60 years old (48.5 years ± 7.5) DAO enzyme activity was determined by a sample of oral mucosa and a standard hygiene protocol was followed. The patients' DNA was extracted and the analysis of gene variants of interest was performed using SNPE Multiplex (Single Nucleotide Primer Extension).
The prevalence of genetic DAO deficiency was 74.5% by the four variants of the AOC1 gene. The deficit for each SNP followed the following frequencies: p.Thr16Met (53.1%), c.691G > T (49%), p.His664Asp (48%) and p.Ser332Phe (19.4%). The allelic and genotypic prevalence of the variants had similar distributions of European population except for p.Ser332Phe.
Variants of the AOC1 gene could be associated with genetic DAO deficiency and potential disruptive biomarker in fibromyalgia patients.
... Still, an increase in histamine is due to the release of nitrogen monoxide upon stimulation by provoking hypothalamic activity of H1R in the intracranial arteries [22]. This non-synonymous single nucleotide polymorphism (SNP) which codes for altered DAO activity, was decoded on the AOC1 gene [23]. Schematic representation of histamine causing migraine was shown in Figure 1. ...
... These SNPs can cause amino-acid substitutions that are relevant to enzyme activity or kinetic properties. Alleles (rs2268999, rs2052129, rs1049742 and rs10156191) have been reported to increase the risk of decreased DAO activity [23]. In another study done in peripheral blood of migraine patients, DAO mRNA expression of homozygous minor allele carriers such as (rs2052129, rs10156191, and rs2268999) is significant (p-value = 0.002) than the major allele reported in the German population [41]. ...
Migraine is a common neurovascular multifactorial disease with biochemical abnormalities in the central nervous system (CNS). It is characterized by episodes of frequent headaches, affecting about 14% of the world's population. Trace elements are essential to play an important role in neurotransmission and causing oxidative stress in patients with migraine. Also, it is hypothesized that Histamine (biogenic amine), catabolized by Diamine oxidase (DAO), induces a vascular headache. DAO contains Copper as a cofactor and is coded by the Amine oxidase copper containing 1 (AOC1) gene. This study aims to determine the level of serum copper (Cu), an association of the AOC1 gene and antioxidant capacity in migraine patients. In this study, a total number of 200 individuals (patients and controls) were equally distributed in each group according to demographic details obtained. The results obtained from this study were found to be significant to migraine. The frequency of T allele (rs10156191) in exon 4 AOC1 was 7.5% in migraineurs OR of 16.13; 95% CI- 0.63 to 47.97, and the p-value was observed to be 0.074. The mean concentration of Cu was found to be 0.09 ± 0.02 mg/L and 0.22 ± 0.10 mg/L in patients and controls, respectively. Antioxidant capacity of serum was found to be lower in patients (3 ± 1.2 μM ascorbic acid equivalents) when compared to controls (7 ± 0.9 μM ascorbic acid equivalents). Decreased Cu and a nonsynonymous of rs10156191 are associated with migraine, which may decrease in DAO activity. Further research, needs to be focused on the DAO activity that can determine the migraine-inducing effect.
... It is believed that ineffective scavenging of dietary histamine by DAO is to blame for histamine intolerance due to reduced activity of this enzyme in susceptible individuals. Single-nucleotide polymorphisms (SNPs) of the gene coding for DAO occur resulting in reduced DAO levels and increases in food allergies (Maintz et al., 2011) and other inflammatory and neoplastic gastrointestinal diseases (Petersen et al., 2002). Schwelberger (2004) found a subpopulation of individuals with a genetic predisposition to gastrointestinal diseases with SNPs of the gene coding for DAO in the gut, and so intestinal DAO may be responsible for both differences in degree of histamine intolerance and susceptibility to SFP. ...
... An often-cited theory postulated for the mechanism of SFP, inhibition-potentiation of histamine toxicity, invokes inhibition of DAO and HNMT by inhibitors of these metabolic enzymes (Taylor and Lieber, 1979;Lyons et al., 1983;Hui and Taylor, 1985). Just as reductions in DAO due to polymorphisms (Maintz et al., 2011) lead to histamine intolerance (Maintz and Novak, 2007) inhibition of DAO is postulated to lead to SFP. Since intestinal DAO is the first barrier to ingested histamine (Wantke, 2015) inhibition of DAO leads to increased histamine absorption in the gut. ...
Histamine intoxications result when histamine-metabolizing enzymes are compromised or overwhelmed by dietary histamine in the human body. This can occur either due to metabolic enzyme deficiencies, such as in histamine intolerance to wines, aged cheese and other foods or from high concentrations of histamine following ingestion of decomposed fish. The presence of histamine in decomposed fish and fish products results from bacterial decarboxylation of free L-histidine following product mishandling. Consequently, histamine intoxications from mishandled fish, commonly referred to as scombrotoxin fish poisoning (SFP) or scombroid poisoning, require high levels of free L-histidine only found in certain species of pelagic fish. Differential diagnosis is required of clinicians since dietary histamine intoxications produce the same symptoms typical of release of endogenous histamine due to IgE -mediated seafood allergies or anisakiasis. Although high levels of dietary histamine are responsible for SFP, histamine has important physiological functions and tends to exert toxic effects only at doses beyond the physiological range. Endogenous histamine is essential to local immune responses, regulation of gastric acid secretion in the gut, and neurotransmission in the central nervous system. Scombrotoxins, postulated to explain histamine’s augmented toxicity in scombrotoxic fish, are a milieu of histamine and other bioactives. Since time-and-temperature abuse is required to produce high levels of histamine in fish, management consists of ensuring proper handling by identifying hazards and critical control points (HACCP) and maintaining a “cold chain” from catch to consumption. Reference methods for detecting histamine have received increased attention and the European Commission has validated a popular precolumn dansylation-based HPLC method through inter-laboratory collaboration and studied method equivalence with the AOAC fluorescence method 977.13 recognized by Codex Alimentarius. Much progress has been made during the last decade in the development and validation of rapid screening methods for detecting histamine in food and especially in fish products. These include many innovative sensors and several validated commercial test kits, many of them based on a recombinant form of the enzyme histamine dehydrogenase (HD).
... Störungen der enzymatischen Funktion der DAO können genetisch bedingt oder erworben sein (Maintz und Novak, 2007). Einerseits sind verschiedene Single Nucleotid Polymorphismen (SNPs) bekannt, die zu signifikant verminderter DAO-Aktivität im Serum führen (Maintz et al., 2011). Diese Polymorphismen tragen zur Entwicklung einer Histaminintoleranz bei, sind alleine aber nicht ausreichend, um das volle Krankheitsbild auszulösen (Maintz et al., 2011). ...
... Einerseits sind verschiedene Single Nucleotid Polymorphismen (SNPs) bekannt, die zu signifikant verminderter DAO-Aktivität im Serum führen (Maintz et al., 2011). Diese Polymorphismen tragen zur Entwicklung einer Histaminintoleranz bei, sind alleine aber nicht ausreichend, um das volle Krankheitsbild auszulösen (Maintz et al., 2011). Andererseits können die geschädigten Enterozyten bei gastrointestinalen Erkrankungen, beispielsweise Nahrungsmittelallergien (Kuefner et al., 2004), Kolonadenomen (Kuefner et al., 2008) und entzündlichen Darmerkrankungen wie ...
Hintergrund und Ziele: Unverträglichkeitsreaktionen gegen Nahrungsmittel sind häufig und umfassen alle nahrungsabhängigen Beschwerden. Dabei werden immunologisch bedingte Nahrungsmittelallergien von nicht immunologisch bedingten Nahrungsmittelintoleranzen differenziert. Kohlenhydratverwertungsstörungen wie die Laktose-, Fruktose- und Sorbitmalabsorption zählen zu den häufigsten nicht immunologischen Unverträglichkeiten von Nahrungsmitteln, während die Histaminintoleranz mit einer Prävalenz von etwa 1 bis 3 % der Gesamtbevölkerung deutlich seltener ist. Diese basiert auf einer Abbaustörung von überwiegend exogen aufgenommenem Histamin (histaminreiche Lebensmittel, u.a. Fleisch, Käse und Alkohol). Als Pathomechanismus wird eine verminderte Aktivität des intestinalen Enzyms Diaminoxidase (DAO) vermutet, welche Histamin abbaut. Die Symptomatik der Histaminintoleranz ist sehr vielfältig und kann sich an fast allen Organsystemen manifestieren. Die Beschwerden umfassen gastrointestinale (Bauchschmerzen, Diarrhoe, Meteorismus), kutane (Urtikaria, Pruritus, Flush), respiratorische (Asthmaanfälle, Rhinorrhoe) sowie kardiale (Hypotonie, Arrhythmien) Symptome und Kopfschmerzen. Der Nachweis dieser Erkrankung ist aufgrund der eingeschränkten labortechnischen Möglichkeiten erschwert. Die aktuelle S1-Leitlinie der DGAKI, der GPA, des AeDA und der SGAI empfiehlt bei Verdacht auf Unverträglichkeit gegenüber oral aufgenommenem Histamin eine orale Provokation mit Histamindihydrochlorid in aufsteigender Dosierung zur Festlegung einer individuellen Toleranzdosis durchzuführen. Laborchemisch kann eine erniedrigte DAO-Aktivität auf eine Histaminintoleranz hinweisen. Aufgrund der noch etwas niedrigen Sensitivität wurde der Test wiederholt kontrovers diskutiert. In der vorliegenden Studie sollten daher Tagesprofile der DAO und des Histamins erstellt werden, um dieses Diagnostikum innerhalb von Patientengruppen mit Verdacht auf Histaminintoleranz, Nahrungsmittelallergikern und Gesunden zu vergleichen. Methoden: In dieser prospektiven Kohortenstudie wurden 65 Patientin eingeschlossen und drei Gruppen zugeordnet. Eine Woche vor und während der Untersuchungen nahmen alle Probanden normale Mischkost zu sich. Neben einer Ernährungsanalyse wurde eine detaillierte Anamnese inklusive eines Fragebogens zu den vorliegenden Beschwerden erhoben. Allen Teilnehmern wurden Blutproben entnommen und zur Abklärung einer IgE- induzierten Allergie auf Gesamt-IgE und spezifische IgE gegen Nahrungsmittelallergene untersucht. Probanden mit positiven spezifischen IgE wurden als Nahrungsmittelallergiker eingestuft. Probanden mit Beschwerden, aber mit negativen spezifischen IgE und niedrigen Gesamt-IgE, wurden der Gruppe mit Verdacht auf Histaminintoleranz zugeordnet. Gesunde Kontrollprobanden zeigten keine nahrungsabhängigen Beschwerden und unauffällige Blutparameter. Anschließend wurden bei allen Probanden wiederholt Blutentnahmen über einen Zeitraum von 24 Stunden durchgeführt, um die Schwankungen der DAO-Aktivität im Serum (gemessen mit REA) und des Histaminspiegels im Plasma (gemessen mit ELISA) zu erfassen und somit ein Tagesprofil dieser beiden Parameter zu erstellen. Ergebnisse und Beobachtungen: Insgesamt wurden 64 Probanden in die Studie eingeschlossen, davon 10 Gesunde. 21 Patienten wurden aufgrund deutlich erhöhter Gesamt-IgE sowie positiver spezifischer IgE gegen Nussmischung, Weizen- und Roggenmehl, Sellerie, Tomate, Sojabohne und Milcheiweiß als Nahrungsmittelallergiker kategorisiert. Bei 33 Patienten wurde eine Histaminintoleranz vermutet. Tatsächlich lag bei 24 % (8 von 33) dieser Patienten eine Abbaustörung des exogen aufgenommenen Histamins vor, charakterisiert durch erhöhte Histaminspiegel und eine signifikant erniedrigte DAO-Aktivität im Tagesverlauf. Trotz typischer klinischer Symptome wiesen die restlichen 25 Probanden mit Verdacht auf Histaminintoleranz normale Histaminspiegel und DAO-Aktivitäten auf, die daher im weiteren Verlauf als „Patienten mit Nahrungsmittelhypersensitivität“ bezeichnet wurden. Bei diesen Probanden zeigten sich im Rahmen der Untersuchungen eher Nahrungsmittelintoleranzen gegen Fruktose, Laktose und Sorbit. Ebenso zeigte sich in dieser Gruppe häufiger ein Diarrhö-dominante Reizdarmsyndrom-Kategorisierung. Die klinische Symptomatik der Patienten mit Histaminabbaustörung, Nahrungsmittelhypersensitivität und Nahrungsmittelallergien reichte von typischen gastrointestinalen Beschwerden (Übelkeit, Erbrechen, Bauchschmerzen, Diarrhoe), kutanen Reaktionen (Pruritus, Urtikaria), respiratorischen Beschwerden (nasale Obstruktion, Rhinorrhoe, Asthmaanfälle) bis zu Kopfschmerzen und unterschied sich nicht wesentlich zwischen den Gruppen. Auch die Analyse sowohl der Tageszufuhr an Makronährstoffen, des Alkohol- und Nikotinkonsums sowie weiterer Parameter im Blut ergab keine signifikanten Unterschiede. Schlussfolgerungen: Bei einem relevanten Anteil der Patienten mit Verdacht auf Histaminintoleranz geht eine verminderte DAO-Aktivität mit erhöhten Histaminspiegeln im Blut einher und weist somit auf das Vorliegen einer Histaminintoleranz hin. Allein anhand der klinischen Symptomatik kann die Histaminintoleranz nicht von anderen Nahrungsmittelintoleranzen und Nahrungsmittelallergien differenziert werden. Dies wird zusätzlich durch die fehlende Korrelation zwischen subjektiven Beschwerden und den im Blut gemessenen Histaminparametern erschwert. Weitere Untersuchungen sind essentiell, um das Nachweisverfahren der Histaminintoleranz zu verbessern. Hierbei sollte möglicherweise die wiederholte Bestimmung des Histaminspiegels im Plasma und der DAO-Aktivität im Serum berücksichtig werden.
... Snížená degradace histaminu může nastat v důsledku snížené aktivity DAO (Manzotti et al., 2016;Mušič et al., 2013), která je primární či sekundární. Primárně snížená aktivita DAO je genetického původu (Ayuso et al., 2007;Maintz et al., 2011). Sekundárně snížená aktivita DAO vzniká v důsledku 1. poškození střevního epitelu při celiakii, laktázové intoleranci, Crohnově chorobě; 2. sníženého vstřebávání či karence mědi a zinku, vitaminu B6 a vitaminu C nebo je inhibována alkoholem (Wantke et al., 1994;Zimatkin et al., 1999) či některými léky (tab. ...
... Gen pro DAO je umístěn na chromozomu 7q35 a je exprimován ve střevě, ledvinách a placentě (Schwelberger 2004). Jsou popsány 4 polymorfismy DAO genu, které jsou spojeny s nižší aktivitou DAO (rs 10156191, rs 1049742, rs 2052129, rs 2268999) a 1 spojený s vyšší aktivitou (rs 1049748) (Ayuso et al., 2007;Maintz et al., 2011). Byly popsány jednonukleotidové polymorfismy (SNP) v genu DAO, které jsou spojeny se zánětlivými (García-Martin et al., 2006) a nádorovými onemocněními střeva (Petersen et al., 2005), migrenózní bolestí hlavy (García-Martín et al., 2015) či hypersenzitivní reakcí na nesteroidní antirevmatika (Agúndez et al., 2012). ...
The case study describes young man suffering with gastrointestinal, skin and psychiatric symptoms. This symptoms were associated with histamine intolerance (HIT) that was induced by low serum activity of diamine oxidase (DAO) and due to 3 mutations in AOC1/
DAO gene. DAO is the enzyme produced by the intestines that breaks down histamine. These mutations decrease effectivity of DAO and break down of histamine, which is toxic for body. The symptoms of HIT have large symptomatic overlap with psychosomatic disorders or allergies. Our patient did fulfilled diagnostic criteria for mild depressive disorder. The intensity of depressive symptoms measured by self-evaluation scales was clinically significant as well as intensity of anxiety symptoms. The patient fulfilled diagnostic criteria for Somatoform autonomic dysfunction – lower intestinal tract and irritable bowel syndrome before the proof of histamine intolerance (HIT). It is possible that some patients with HIT who are not recognized by somatic doctors may enter psychiatric care with suspicion of psychosomatic disease, which is in fact of organic origin and can be specifically treated. Questions on HIT, and if suspected, then the
identification of HIT biomarkers, should become part of the medical practice of so-called psychosomatic disorders that have symptomatic overlap with HIT. The presented case report is an example how we would deconstruct the phenomenological diagnosis of functional disorder to genetically determined clinical unit.
... Just as researchers identified genetic polymorphisms that inhibit DAO activity, studies have shown several other genetic variations that enhance the enzyme's activity [13]. Although the presented results are inconclusive, it is worth mentioning that the literature indicates that patients suffering from diseases affecting the gastrointestinal, cardiovascular, and nervous systems, among others, have been found to have mutations influencing DAO activity in their bodies [6,10]. ...
Histamine intolerance is a condition characterized by the accumulation of histamine to a point that exceeds the body’s capacity to eliminate it. Researchers have attributed several reasons to this condition, such as genetic factors, alcohol, and dietary deficiencies, among other elements. Symptoms of histamine intolerance have been found to extend beyond the gastrointestinal tract and to the whole body, with these symptoms being sporadic and non-specific. This review will explore various aspects related to histamine intolerance, such as its causes, symptoms, diagnosis, and information related to management.
... In contrast, DAO may be involved in the pathogenic cascade leading to skin rashes, and DAO supplementation may be effective in relieving symptoms [19]. Furthermore, several studies showed that reduced DAO levels were associated with symptoms typical of atopic dermatitis [26][27][28][29]. ...
Fibromyalgia (FM) is characterized by chronic musculoskeletal pain, muscle tension, joint mobility loss, and several psychological symptoms severely affecting patient well-being. Histamine is naturally degraded in the small intestine by diamine oxidase (DAO). Hereditary or acquired DAO deficiency causes extracellular histamine accumulation, leading to symptoms similar to those of individuals diagnosed with FM. Thus, this study aimed to assess the efficacy of adding DAO supplementation for 8 weeks to their standard therapy. We randomly assigned 100 women with FM (age: 33–61 years) to the supplementation and control groups. The Fibromyalgia Impact Questionnaire (FIQ), the Pain Catastrophizing Scale (PCS), and intensity scales were applied for a series of clinical symptoms together with the Bristol scale to assess the added value of DAO supplementation. Patients in both groups were receiving complete pharmacological support but some differences in the number of subjects receiving analgesics, antidepressants, and anxiolytics was noted. Patients in both study groups experienced favorable changes during the evaluation period as indicated by their final FIQ and PCS scores, particularly in the DAO group in the latter questionnaire. Qualitatively, the patients assigned to the DAO treatment group had lower scores for fatigue, anxiety, depression, burning and for rumination, magnification, and helplessness.
... One may speculate that this happens because, like many other enzymes, DAO can be affected by mutations that reduce its activity while preserving or not the epitopes that are recognized by monoclonal antibodies used in ELISA tests. However, if a lower DAO activity as a result of these mutations correlates with a clinical outcome in the form of histamine intolerance (HIT), it is still yet to be proven [16,17]. Hence, we can probably draw the conclusion that an ELISA test will detect most of the cases of DAO deficiency in order to support the diagnosis of HIT, but we cannot exclude for sure the possibility of losing some HIT cases if only ELISA is performed. ...
Histamine intolerance (HIT) is a common adverse reaction to food where elimination and reintroduction of histamine-rich food is part of the investigation. Analysis of the enzyme diamine oxidase (DAO) is sometimes used as an additional tool for diagnosis. This study aimed to describe the distribution of DAO in a large representative cohort of adults and to determine the association between DAO activity and possible associated factors. The study is based on the population-based West Sweden Asthma Study and includes 1051 subjects. Subjects underwent structured interviews including questions on demography, asthma, allergy symptoms, and lifestyle factors. Subjects were assessed for specific-IgE-antibodies and measurement of DAO activity in serum. Previously suggested cut-off levels for low values (<3 U/mL), normal values (>10 U/mL), and median levels of DAO were used. In the group of 1051 subjects, only a few presented reactions upon histamine intake, whereas 44% presented DAO levels below the suggested normal cut-off levels. BMI and age were shown to have an impact on DAO activity among women with increasing activity of DAO with increasing BMI and age. Among men, only increasing age was seen to have an impact on DAO levels. There was no difference in DAO levels with different sensitization status to common foods or airborne allergens. No association between DAO levels and reported symptoms to histamine-rich foods could be found. In conclusion, the determination of the DAO enzyme needs to be re-evaluated and may not be used as a valuable tool for histamine intolerance using current cut-off values. Further studies are needed to improve the use of DAO as a biomarker for histamine intolerance.
... HIT is a disturbance in histamine homeostasis caused by reduced intestinal degradation of histamine due to DAO deficiency [51]. DAO deficiency may be a major cause of HIT, in which alterations in histamine homeostasis lead to a decrease in intestinal degradation and a subsequent increase in plasma [52]. DAO deficiency may be congenitally caused by genetic mutations in DAO genes or alterations in protein coding resulting in decreased DAO levels; it may also be acquired from lesions that reduce DAO secretion, particularly in inflammatory or degenerative bowel diseases [53]. ...
The serum level of diamine oxidase (DAO) reflects the integrity and maturation of the small intestinal mucosa. This measure is important in diagnosing various diseases, including chronic urticaria tachyphylaxis, multiple organ dysfunction syndrome, preterm abortion, and migraine. This review aimed to summarize the findings of previous studies on the changes in DAO levels in diverse diseases and the application of this enzyme in the clinical setting, as well as the roles of this enzyme under physiological and pathological conditions. The advances in the mechanism and clinical application of DAO presented in this review will contribute to a better understanding of this enzyme and open up new and broader perspectives for future basic research and clinical applications.
... DAO deficiency may have a genetic origin and has been associated with singlenucleotide polymorphisms encoding a protein with reduced histamine degradation capacity [16,17]. On the other hand, impaired DAO activity can also be temporary and reversible, arising as a side effect of some widely used pharmacological drugs, such as clavulanic acid or acetylcysteine, or a secondary symptom of gastrointestinal disorders [18]. ...
An underlying cause of histamine intolerance is diamine oxidase (DAO) deficiency, which leads to defective homeostasis and a higher systemic absorption of histamine. Impaired DAO activity may have a genetic, pharmacological or pathological origin. A recent proposal also suggests it can arise from an alteration in the gut microbiota, although only one study has explored this hypothesis to date. A greater abundance of histamine-secreting bacteria in the gut could lead to the development of histamine intolerance. Thus, the aim of this study was to characterize the composition of the intestinal microbiota of patients with histamine intolerance symptoms and compare it with that of healthy individuals. The study was performed by sequencing bacterial 16S rRNA genes (V3-V4 region) and analyzing the data using the EzBioCloud Database. Dysbiosis of the gut microbiota was observed in the histamine intolerance group who, in comparison with the healthy individuals, had a significantly lower proportion of Prevotellaceae, Ruminococcus, Faecalibacterium and Faecablibacterium prausnitzii, which are bacteria related to gut health. They also had a significantly higher abundance of histamine-secreting bacteria, including the genera Staphylococcus and Proteus, several unidentified genera belonging to the family Enterobacteriaceae and the species Clostridium perfringens and Enterococcus faecalis. A greater abundance of histaminogenic bacteria would favor the accumulation of high levels of histamine in the gut, its subsequent absorption in plasma and the appearance of adverse effects, even in individuals without DAO deficiency.
... As a result, patients with HIT are often accompanied by many GI symptoms, including diffuse stomachache, GI colic, flatulence, diarrhea, and so on [3]. Elevated histamine concentrations and decreased DAO activity have been found in a variety of inflammatory and neoplastic bowel diseases [73]. Decreased HNMT and impaired total-histamine degradation were detected in colonic mucus from patients with food allergies. ...
Histamine intolerance (HIT) is a common disorder associated with impaired histamine metabolism. Notwithstanding, it is often misdiagnosed as other diseases because of its lack of specific clinical manifestations. HIT did not gain traction until the early 21st century. In this review, we will focus on the latest research and elaborate on the clinical manifestations of HIT, including its manifestations in special populations such as atopic dermatitis (AD) and chronic urticaria (CU), as well as the latest understanding of its etiology and pathogenesis. In addition, we will explore the latest treatment strategies for HIT and the treatment of specific cases.
... Our patient was a heterozygotic carrier of DAO SNPs rs2052129 (GT), rs2268999 (AT), and rs10156191 (CT). These can result in reduced serum DAO activity [9]. ...
Patient: Male, 36-year-old
Final Diagnosis: Adverse reaction to histamine in food and beverages
Symptoms: Abdominal pain • cough • emesis • fatigue • fever • headache • loose stools • malaise • nausea • rash • rhinorrea • sore throat
Medication: —
Clinical Procedure: Abdominal ultrasound • colonoscopy • gastroscopy • genetic analysis • histamine oral provocation test • laboratory checkup • MRI
Specialty: Allergology • Dermatology • Family Medicine • Gastroenterology and Hepatology • General and Internal Medicine • Nutrition and Dietetics
Objective
Unknown etiology
Background
Adverse reaction to histamine found in food and beverages is still a debated entity. It presents with a diverse, multisystemic clinical picture and lacks objective diagnostic criteria.
Case Report
We report a case of severe adverse reaction to histamine in food and beverages. The 36-year-old White man had diet-dependent problems for 17 years that involved periodic erythematous rash, fever, headaches, nausea, and upper respiratory symptoms. The symptoms developed in the same chronologic order each time. The course of the disease could be divided into a first (prodromal, gastrointestinal), a second (acute, dermal), and a third (subacute, respiratory) phase. The symptoms occurred every 3–6 weeks and lasted for 10–14 days. The differential diagnosis was time-consuming and very detailed. Family history, genetic testing, and oral hista-mine provocation testing supported the diagnosis of an adverse reaction to histamine in food and beverages. A low-histamine diet resulted in a symptom-free state. Follow-up lasted longer than 24 months.
Conclusions
This presentation of an adverse reaction to histamine in food and beverages can serve as a textbook example where a chronological, syndrome-like order of symptom appearance is described. To the best of our knowledge, this is the first report of a severe adverse reaction to histamine in food and beverages, where symptoms are described in 3 distinct recurring phases.
... Serum DAO activity has been found to be lower in carriers of the minor allele of rs1049742, 4 rs10156191 4 and rs2521929. 5 Several clinical-epidemiological, biochemical, experimental and pharmacological data give support to the hypothesis of a possible contribution of histamine in the etiopathogenesis or in the clinical presentation of migraine. 3 In addition, headache is a usual symptom of histamine intolerance, which has been related to DAO deficiency, [6][7][8][9] and low-or free-histamine diet has shown an important improvement of symptoms of histamine intolerance, including headache. ...
Background/objectives:
Histamine has shown a possible role in the etiopathogenesis of migraine. It has been reported an association between some polymorphisms in the diamine oxidase (DAO) gene and migraine (specially in women). Two studies addressing DAO activity in migraine patients showed conflicting results. We investigated the possible relationship of serum DAO activity and histamine levels and 3 polymorphisms in the DAO gene with the risk for migraine.
Methods:
We studied the frequencies of DAO rs10156191, rs1049742, and rs1049793 genotypes and allelic variants in 298 migraine patients and 360 healthy controls (using a TaqMan-based qPCR assay), and serum DAO activity and histamine levels in a subset of 99 migraine patients and 115 controls with strict exclusion criteria, and analyzed the relationship of these variables with several clinical features of migraine.
Results:
The frequencies of the DAO genotypes and allelic variants analyzed were similar in migraine patients and controls. Serum DAO activity was significantly higher in migraine patients (Vmax/Km 4.24 ± 2.93 vs. 3.60 ± 7.64, p<0.001), specially in females (Vmax/Km 4.63 ± 2.96 vs. 3.18 ± 2.32, p<0.0001) while serum histamine was similar in both study groups.
Conclusion:
Serum DAO activity was increased in patients with migraine, specially in females, while serum histamine levels were normal. None of the studied polymorphisms was associated with the risk for migraine.
... DAO activity also depends on the phase of the menstrual cycle [24]. Polymorphisms in the coding gene may cause congenital deficiency (in particular, rs10156191, rs1049742, and rs2268999), or in contrast may cause an increase of DAO activity (rs2071514, rs1049748, and rs2071517) [78]. ...
Histamine is a natural amine derived from L-histidine. Although it seems that our knowledge about this molecule is wide and diverse, the importance of histamine in many regulatory processes is still enigmatic. The interplay between different types of histamine receptors and the compound may cause ample effects, including histamine intoxication and so-called histamine intolerance or non-allergic food intolerance, leading to disturbances in immune regulation, manifestation of gastroenterological symptoms, and neurological diseases. Most cases of clinical manifestations of histamine intolerance are non-specific due to tissue-specific distribution of different histamine receptors and the lack of reproducible and reliable diagnostic markers. The diagnosis of histamine intolerance is fraught with difficulties, in addition to challenges related to the selection of a proper treatment strategy, the regular course of recovery, and reduced amelioration of chronic symptoms due to inappropriate treatment prescription. Here, we reviewed a history of histamine uptake starting from the current knowledge about its degradation and the prevalence of histamine precursors in daily food, and continuing with the receptor interactions after entering and the impacts on the immune, central nervous, and gastrointestinal systems. The purpose of this review is to build an extraordinarily specific method of histamine cycle assessment in regard to non-allergic intolerance and its possible dire consequences that can be suffered.
... With these results, and as it was suggested in previous studies, the clinical course of AR might be altered in patients with impaired histamine metabolism [17]. There are many causes of malfunction or decrease in DAO activity [5,11,31,32,33] For example, carriers of DAO C2029G mutated allele tend to develop more severe symptoms of rhinitis and other histamine intolerance-related symptoms [17,18,34]. Therefore, in future studies this fact must be corroborated. ...
Aim:
To analyze the diamine oxidase (DAO), the main catabolic enzyme of histamine, degradation activity and its relation with symptoms of persistent allergic rhinitis.
Methods:
In this descriptive and analytical observational study, we collected DAO activity levels and the nasal peak inspiratory flow.
Results:
Enzymatic activity deficit in 108 patients was 46.3% (95% CI, 0.44 - 0.63), 33.33% in mild and 47.92% in moderate/severe rhinitis (p = 0.376). The nasal peak inspiratory flow in patients with a deficit in DAO activity was 76.30 ± 28.40 L/min compared to 93.62 ± 37.50 L/min in patients with normal enzymatic activity (p = 0.010).
Conclusions:
It seems that the lower the catabolic activity of DAO, the lower the nasal peak inspiratory flow observed. Although DAO activity levels could be a severity biomarker in allergic rhinitis, a cause-effect association cannot be concluded. The enzyme could be another actor in the pathophysiology of allergic rhinitis.
... DAO, synthesized by intestinal enterocytes, is released for digestion, and into the circulation [11]. There are known genetic polymorphisms in the genes coding for DAO [12] and the histamine receptors [13], which apparently influence the clinical appearance of HIT. Impairment of the GI mucosa function by diseases and/or medications may also reduce DAO activity. ...
Background and pilot study: Celiac disease (CD) or gluten malabsorption is a well-defined autoimmune disorder
characterized by mucosal gastrointestinal reaction to ingested gluten proteins. The necessary treatment for CD is
a gluten-free diet. However, up to 30% of celiac patients experience persistent or recurring abdominal complaints
despite following an exact gluten-free diet. This condition was named refractory, non-responsive celiac disease.
Other food ingredients, such as carbohydrates and biogenic amines, also influence and impair digestion, and may
cause these abdominal symptoms. In this retrospective pilot study, we have reported on 20 non-responsive, celiac
disease patients, with persistent abdominal complaints, for longer than 6 months. These patients were evaluated
for extra food intolerance/malabsorption, including fructose malabsorption, histamine-, lactose intolerance, and
Helicobacter pylori (H.p.) infection.
Results and conclusions: The results demonstrate that 18 of the 20 refractory, non-responsive celiac disease patients
presented various, additional food intolerance/malabsorption and/or H.p. infection. Seven NRCD patients
demonstrated lactose intolerance, 7 showed fructose malabsorption, 11 had additional histamine intolerance and
6 had signs of H.p. infection or combinations thereof. If present, then eradication of H.p. was performed. Histamine
intolerance, was found in more than 50% of patients, and it seems to play an important role in nonresponsive
celiac disease. A registered dietician continued to help with, and to improve, the patients’ glutenfree
diet. Furthermore, additional food intolerance/malabsorption considerations were included in the individual,
dietary recommendations.
... Although the specificity is lower, the serum DAO activity (functional) analysis established that approximately one third of false negatives established by measuring the concentration of DAO in serum had probability of histamine intolerance, being a good complementary method in order to reduce false negatives, since patients with normal DAO levels could present a dysfunction in the activity of this enzyme for example due to single nucleotide polymorphisms. 13 By way of projection, we expect to evaluate these techniques by comparing the functional DAO data obtained by using a commercial KIT that uses Histamine as a substrate (D-HIT, Sciotec, Austria), which has been used to correlate DAO activity in serum as a diagnostic test of HI. 14 Also, an uncomplicated pregnancy is believed to be dependent on the balance between DAO and histamine in the placenta, 15 and low serum DAO Activity has been correlated to gastrointestinal toxicity and malnutrition due to anticancer drugs. 16 For this reason, it would be worth evaluating the relevance of these techniques for monitoring the functioning of DAO in pregnancy and in oncologic treatments. ...
Background
Diamine Oxidase (DAO) has an essential role for degradation of exogenous histamine in the intestine; thus, histamine intolerance (HI) mainly has been correlated to a low concentration and/or activity of this enzyme. The objective of the study was to standardize a colorimetric technique to measure the enzymatic activity (function) of hDAO to then apply it to a series of 22 patients with a clinical diagnosis of HI.
Methods
For the standardization variables such as volume and type of sample, incubation time, wavelength of maximum absorption, types of substrates, and concentration of oxidized ascorbate were evaluated. Then the activity and concentration of DAO was determined in 22 patients diagnosed with HI and 22 healthy subjects.
Results
The mean of serum DAO concentration in the 22 patients was of 9.268 ± 1.124 U/mL. The mean of serum DAO concentration in the 22 controls was of 20.710 ± 2.509 U/mL, being significantly higher (P value 0.0002) the mean of the samples. The mean of serum DAO activity of the patients was of 1.143 ± 0.085 U/L and the controls was 1.533 ± 0.119 U/L, significantly greater than the patients (P value 0.011). In addition, the sensitivity of both techniques was 0.63. In the measuring of DAO concentration the specificity was 0.9, constituting a good diagnostic test, especially to rule out the true negatives. The determination of DAO activity had a specificity of 0.68.
Conclusions
Although we used a small number of patients and controls and the absorbance values were lower than expected, statistically significant differences were found in the levels of concentration and DAO activity between the patients with histamine intolerance and the controls. Therefore, the measuring of DAO concentration and DAO activity is a good diagnostic strategy for study suspect cases of HI. The simultaneous use of both assays allows to reduce positive and negative false results, for example, patients with normal DAO levels that could present a dysfunction in the activity of this enzyme.
... The latter are low-cost, easyaccess, non-invasive tests. [16][17] OBJECTIVE: Describe the clinical characteristics of patients with HIT, apply an ELISA assay to determine serum DAO concentration, and analyze the proportion of patients with a diagnosis of HIT with a de cit of this enzyme in comparison with healthy individuals. ...
Introduction. Histamine intolerance (HIT) is a pathology with an estimated prevalence of 1% in which there is an imbalance between the intake of histamine via the digestive tract and the body's ability to degrade it. This results in an excessive accumulation of histamine that determines the appearance of gastrointestinal, skin, respiratory and neurological symptoms. The enzyme responsible for degrading histamine in the extracellular space is diamine oxidase (DAO); therefore, HIT is caused due to a deficit in the concentration and/or in the activity of this enzyme. Because histamine is the main mediator of the classic symptoms of IgE-mediated allergic reactions, it is difficult to differentiate a true allergy from HIT since it has basically the same clinical manifestations.
Objectives. The objective of this study was to perform a clinical characterization of patients with HIT and to determine the usefulness of quantifying serum DAO concentration in the diagnosis of HIT.
Method: Twenty-two patients over the age of 18 with a history of histamine intolerance were recruited, in whom IgE-mediated food allergy was ruled out, and 22 healthy patients. Both groups were surveyed and serum DAO concentration was determined.
Results: Middle-aged women predominated in the population with HIT. They described a wide variety of symptoms, with a dominance of abdominal pain, bloating, diarrhea, flushing, urticaria, itching, headache and dysmenorrhea. When comparing the average serum DAO concentration in the population with HIT (10.686 U/ml) with the average obtained in the control population (20.664 U/ml), there was a significant difference (p < 0.003).
Conclusion. The determination of serum DAO concentration is a useful tool for the diagnosis of HIT.
... There are known genetic polymorphisms for lactase (J€ arvel€ a, Torniainen, and Kolho 2009), celiac disease (Hunt and van Heel 2009), and a genetic background might also be a factor in fructose malabsorption (Patel et al. 2015). Additionally, polymorphisms in the genes coding for DAO (Maintz et al. 2011;Petersen, Raithel, and Schwelberger 2005) and the histamine receptors (Sadek and Stark 2016) have been identified. The polymorphisms of the four known histamine receptors and polymorphisms of DAO seem associated with multiple clinical symptoms and hundreds of symptom combinations in HIT. ...
In westernized countries, adverse reactions to ingested foods are reported to affect up to 20% of the population. Functional, nonspecific, non-allergic gastrointestinal complaints are mainly due to the intolerance/malabsorption of carbohydrates (lactose and fructose), proteins (gluten), and biogenic amines (histamine). Food intolerance/malabsorption is defined by one or several of the above mentioned food components not being degraded and/or absorbed properly within the gastrointestinal tract. Food intolerance/malabsorption causes variable, functional, nonspecific, non-allergic gastrointestinal and extra-intestinal complaints, and a detailed diagnostic workup for all possible etiologic factors in individual patients is essential. Usually, evaluation for histamine intolerance is not included in differential diagnoses of patients with functional, nonspecific, non-allergic gastrointestinal complaints. A targeted dietary intervention for single or possibly combined intolerance/malabsorption is required. In this article, we review currently discussed differential diagnoses and available tests for intolerance/malabsorption. Accordingly, we aim to outline why including histamine and, histamine intolerance, should be considered in differential diagnoses of patients with functional, nonspecific, non-allergic gastrointestinal complaints.
... A tünetek kialakulásához az enzim csökkent működésű genetikai variánsai is vezethetnek. A diamino-oxidáz aktivitását az alkohol, valamint bizonyos gyógyszerek (verapamil, propafenon, cefuroxim, klavulánsav, metamizol, amitriptilin, diazepam, furosemid) is csökkenthetik (11,12). ...
Histamine is a biogenic amine that presents in the human body and in a variety of foods. Biogenic amine intolerance results from an imbalance between the exogenic or accumulated endogenic histamine and the capacity for its degradation. The signs and symptoms are variable, typically affecting the skin and the gastrointestinal tract. The authors reviewed the data of 165 adults diagnosed with histamine/biogenic amine intolerance in a first Hungarian non-questionnaire-based, physician-confirmed study at the
Allergology Outpatient Unit of the Department of Dermatology, Venereology, and Dermato-oncology of the Semmelweis University. Patients were typically referred by general practitioners (50.3%) and dermatologists (32.7%), with a high proportion of women (75.8%), and with a mean age of 44.1 years. Among the clinically confirmed dermatological diagnoses, urticaria was the most common (56.4%). The most frequently reported gastroenterological comorbidity
was reflux/gastroesophageal reflux disease and antrum/corpus gastritis with a frequency of 7.9% in both groups. Among the group of biogenic amine-containing foods that provoked symptoms, cocoa/chocolate with a frequency of 18.8%, eggs (9.1%), smoked meat (7.9%), banana (7.9%) and cheese (6.7%) should be highlighted.
... Due to its intestinal location, DAO is the key enzyme in the degradation of ingested histamine and its deficit has been suggested to be the main cause of histamine intolerance (Kovacova-Hanuskova, Buday, Gavliakova, & Plevkova, 2015;Tuck et al., 2019;Kaur et al., 2019). Impaired DAO activity may be of genetic or acquired origin, with several causes capable to permanently or punctually compromise either the expression or the activity of DAO (Table 1) (Maintz et al., 2011;García-Martín et al., 2015;Kaur et al., 2019;Wagner, Buczyłko, Zielińska-Bliźniewska, & Wagner, 2019). ...
Diamine oxidase (DAO) is one of the key enzymes involved in the degradation of dietary histamine. An imbalance of histamine scavenging systems leads to histamine intolerance, a diet-related disorder that may be tackled by following a low-histamine diet. Recently, the supplementation with exogenous DAO enzyme of animal origin has received the green light as a novel food to enhance intestinal degradation of histamine. This work performed a screening for histamine-degrading capacity of Leguminosae species in order to explore its potential suitability as plant-derived active ingredient of enzymatic supplements. In vitro DAO activity was determined both in raw pulses and lyophilised sprouts by an enzymatic assay coupled to UHPLC-FLD and several germination and storage conditions were assessed. The sprouts of edible legumes showed an in vitro histamine-degrading capacity ranging from 36.0 to 408.3 mU g⁻¹, much higher than that found for the non-germinated seeds (0.14–1.95 mU g⁻¹). The germination of legume seeds for 6 days in darkness provided the maximum DAO activity. Only the freezing storage of the lyophilised sprouts kept the enzymatic activity intact for at least 12 months. These results demonstrate that certain edible legumes could be suitable for the formulation of DAO supplements for the treatment of histamine intolerance.
... A disturbed or slowed histamine degradation due to reduced DAO activity and the resulting histamine excess may cause the symptoms mentioned above, particularly in cases of high intakes of dietary histamine. Genetic variants may also play a role [60]. ...
Food intolerances are estimated to affect up to 20% of the population but complete understanding of diagnosis and management is complicated, given presentation and non-immunological mechanisms associated vary greatly. This review aims to provide a scientific update on common food intolerances resulting in gastrointestinal and/or extra-intestinal symptoms. FODMAP sensitivity has strong evidence supporting its mechanisms of increased osmotic activity and fermentation with the resulting distention leading to symptoms in those with visceral hypersensitivity. For many of the other food intolerances reviewed including non-coeliac gluten/wheat sensitivity, food additives and bioactive food chemicals, the findings show that there is a shortage of reproducible well-designed double-blind, placebo-controlled studies, making understanding of the mechanisms, diagnosis and management difficult. Enzyme deficiencies have been proposed to result in other food sensitivities including low amine oxidase activity resulting in histamine intolerance and sucrase-isomaltase deficiency resulting in reduced tolerance to sugars and starch. Lack of reliable diagnostic biomarkers for all food intolerances result in an inability to target specific foods in the individual. As such, a trial-and-error approach is used, whereby suspected food constituents are reduced for a short-period and then re-challenged to assess response. Future studies should aim to identify biomarkers to predict response to dietary therapies.
... Polymorphisms identified for the genes coding for DAO and for histamine receptors may help explain these symptoms. 7,8 Complex symptom combinations may influence disease expression and the individual response to diets or treatments. Disorders such as IBS are one of the main reasons for consultation in primary care and IBS is associated with high symptom burden causing a reduced quality of life. ...
Background/aims:
Food intolerance/malabsorption, particularly histamine intolerance (HIT), may cause nonspecific functional gastrointestinal and extraintestinal symptoms. We evaluated gastrointestinal and extraintestinal symptoms in patients with HIT.
Methods:
In an analysis of outpatients' charts we identified 133 patients, who presented with recurring nonspecific functional gastrointestinal, extraintestinal symptoms, and a diamine oxidase value <10 U/mL, indicative of HIT. A standardized anonymous questionnaire with symptoms of HIT based on known symptoms and the 4 histamine receptors including gastrointestinal, cardiovascular, respiratory and skin complaints was developed, and sent by mail to the patients.
Results:
In the 62 patients that completed the questionnaire bloating was the most common and most serious symptom. Other commonly reported gastrointestinal symptoms were postprandial fullness, diarrhea, abdominal pain, and constipation. The presence of 2 from a list of 24 symptoms resulted in 276 various symptom combinations. From calculated 2.024 possible combinations of 3 symptoms the patients with HIT presented 1.975 combinations.
Conclusions:
The knowledge of this wide variability of symptoms and complex symptom combinations in patients with HIT may help to clinically recognize and diagnose HIT.
... A significant relationship has been found between lower DAO activity and the presence of different single-nucleotide polymorphisms (SNPs) in the AOC1 gene located on chromosome 7 (7q36.1) that encodes this enzyme [29,30]. The secretion of DAO may also be inhibited by certain pathologies, especially inflammatory bowel diseases, and also by the action of drugs (acetylcysteine, clavulanic acid, metoclopramide, verapamil, etc.) [15,19]. ...
Histamine is a biogenic amine involved in important physiological activities in the organism, but its ingestion through food is associated with the onset of health disorders. Histamine intoxication, previously known as scombroid fish poisoning, is caused by the intake of foods with high levels of histamine. According to official European Union reports, more than 90% of the outbreaks registered in the last years were caused by the consumption of fish and seafood products. Histamine intolerance, on the other hand, arises when histamine degradation is impaired, mainly by a lower diamine oxidase (DAO) activity. Some of the uncertainties classically associated with histamine intoxication may be explained by this enzymatic deficit in a sensitive population. This chapter reviews the adverse effects of histamine from food within a risk analysis framework, focusing specifically on the components of risk assessment and management.
... With these results, and as it was suggested in previous studies, the clinical course of AR might be altered in patients with impaired histamine metabolism [17]. There are many causes of malfunction or decrease in DAO activity [5,11,31,32,33] For example, carriers of DAO C2029G mutated allele tend to develop more severe symptoms of rhinitis and other histamine intolerance-related symptoms [17,18,34]. Therefore, in future studies this fact must be corroborated. ...
Introducción: La rinitis es una inflamación del revestimiento mucoso de la nariz que se caracteriza por rinorrea, estornudos, prurito nasal y congestión. La fisiopatología del prurito sigue sin conocerse con exactitud. Muchos mediadores han sido puestos en relación, siendo la histamina uno de los persistentes candidatos y el más estudiado a lo largo de décadas. La diamino oxidasa es la enzima más importante en el metabolismo de la histamina ingerida. La intolerancia a la histamina resulta de un desequilibrio de la histamina acumulada y la capacidad para su degradación causado por un fallo en la función enzimática de la diamino oxidasa. Este hecho podría ser el causante de un agravamiento de la rinitis. El objetivo de este estudio es identificar la prevalencia de déficit en la actividad de la enzima diamino oxidasa en pacientes con rinitis alérgica.
Material y métodos: Estudio observacional de tipo transversal en el que a pacientes diagnosticados de rinitis alérgica se les realizó una extracción sanguínea para estimar la actividad de la enzima diamino oxidasa, así como medir el peak flow nasal inspiratorio y la calidad de vida mediante el test SPRINT-15.
Resultados: 38 pacientes fueron reclutados. El 55,26% presentaban déficit de actividad enzimática. El peak flow nasal inspiratorio obtuvo una media de 95,92 L/min, siendo de 86,42 L/min para los pacientes con déficit frente a 107,64 L/min para los que tenían una actividad enzimática normal (p =0,02).
Discusión: El déficit de actividad diamino oxidasa se asocia a una menor capacidad nasal inspiratoria.
... With these results, and as it was suggested in previous studies, the clinical course of AR might be altered in patients with impaired histamine metabolism [17]. There are many causes of malfunction or decrease in DAO activity [5,11,31,32,33] For example, carriers of DAO C2029G mutated allele tend to develop more severe symptoms of rhinitis and other histamine intolerance-related symptoms [17,18,34]. Therefore, in future studies this fact must be corroborated. ...
Introducción: La rinitis es una inflamación del revestimiento mucoso de la nariz que
se define por su presentación clínica, caracterizada por cinco síntomas cardinales:
rinorrea, estornudos, prurito nasal y congestión. La fisiopatología del prurito sigue sin
conocerse con exactitud. Muchos mediadores han sido puestos en relación, siendo la
histamina uno de los persistentes candidatos y el más estudiado a lo largo de décadas.
La diamino oxidasa es la enzima más importante en el metabolismo de la histamina
ingerida. La intolerancia a la histamina pertenece al grupo de reacciones de hipersensibilidad no IgE-mediadas que resulta de un desequilibrio de la histamina acumulada y la capacidad para su degradación causado por un fallo en la función enzimática de la DAO. Este hecho podría ser el causante de un agravamiento de la rinitis. El objetivo
de este estudio es identificar la prevalencia de déficit en la actividad de la enzima
diamino oxidasa en pacientes con rinitis.
Material y métodos: Fase de reclutamiento del estudio “Tratamiento con diamino-oxidasa
en pacientes con rinitis: un ensayo clínico aleatorizado, controlado y doble ciego
para comprobar la eficacia y seguridad (Estudio DAO-RIN)”. Se reclutaron pacientes
diagnosticados de rinitis alérgica y no alérgica con pruebas cutáneas realizadas y se
realizó estimación de actividad de la diamino oxidasa.
Resultados: 45 pacientes fueron reclutados, 24 con rinitis no alérgica y 21 con rinitis
alérgica.El peak fl ow nasal inspiratorio en rinitis no alérgica obtuvo una media de
92,08 L/min y de 96,19 L/min para rinitis alérgica. Los valores de diamino oxidasa
fueron 107,63 HDU/L frente 82,95 HDU/L.
Discusión: Parece existir una menor actividad de la enzima diamino oxidasa en pacientes
con rinitis alérgica, coincidiendo esto a su con un menor valor de peak flow nasal inspiratorio.
... This enzymatic deficit may have its origins in genetic mutations. Different polymorphisms of a single nucleotide in the gene that encodes this enzyme (AOC1 on chromosome 7) have been associated with lower DAO activity [14][15][16]. The deficit may also be due to acquired causes such as inflammatory bowel diseases that block the secretion of DAO [1,3,12], or to the inhibitory action of drugs, some of them with a very widespread use (e.g., acetylcysteine, clavulanic acid, metoclopramide, verapamil) [1,17]. ...
Low-histamine diets are currently used to reduce symptoms of histamine intolerance, a disorder in histamine homeostasis that increases plasma levels, mainly due to reduced diamine-oxidase (DAO) activity. These diets exclude foods, many of them of plant origin, which patients associate with the onset of the symptomatology. This study aimed to review the existing data on histamine and other biogenic amine contents in nonfermented plant-origin foods, as well as on their origin and evolution during the storage or culinary process. The only plant-origin products with significant levels of histamine were eggplant, spinach, tomato, and avocado, each showing a great variability in content. Putrescine has been found in practically all plant-origin foods, probably due to its physiological origin. The high contents of putrescine in certain products could also be related to the triggering of the symptomatology by enzymatic competition with histamine. Additionally, high spermidine contents found in some foods should also be taken into account in these diets, because it can also be metabolized by DAO, albeit with a lower affinity. It is recommended to consume plant-origin foods that are boiled or are of maximum freshness to reduce biogenic amine intake.
... The change His645Asp in DAO due to a polymorphism +8956C>G is responsible for decreased activity of DAO in serum samples [48]. In addition, the minor allele of DAO at rs2052129, rs2268999, Thr16Met and Ser332Phe has been associated with a decrease in DAO serum activity in patients with histamine intolerance in a German population [49]. DAO also presents differences according to gender in a healthy population, with higher levels in woman being described in comparison to men [50]. ...
Nonsteroidal anti-inflammatory drugs are the medications most frequently involved in hypersensitivity reactions to drugs. These can be induced by specific immunological and nonimmunological mechanisms, being the latter the most frequent. The nonimmunological mechanism is related to an imbalance of inflammatory mediators, which is aggravated by the cyclooxygenase inhibition. Genetic studies suggest that multiples genes and additional mechanisms might be involved. The proposals of this review is summarize the contribution of variations in genes involved in the arachidonic acid, inflammatory and immune pathways as well as the recent genome-wide association studies findings related to cross-intolerant nonsteroidal anti-inflammatory drugs hypersensitivity reactions. In addition, using integration of different genetic studies, we propose new target genes. This will help to understand the underlying mechanism of these reactions.
... Impaired degradation of histamine can follow a genetic or acquired impairment of the enzymatic function of DAO. The genes coding for DAO and HNMT enzymes are polymorphic and 7 diverse SNPs (single nucleotide polymorphisms) for DAO were significantly related with DAO serum activity [2]. The minor allele at rs2052129 was associated with a lower DAO mRNA expression for the homozygous minor allele, lower promoter activity and subsequently the increased risk of a reduced DAO activity [3]. ...
Introduction: Histamine is the major mediator of IgE- and non-IgE-mediated allergic reactions upon allergen or
hapten contact. Reduced histamine degradation capacity was associated with atopic eczema as well as with nonimmunological
histamine intolerance. Higher blood serum histamine level concomitant with decreased intestinal
diamine oxidase activity were observed in patients with food allergy.
Aim: To evaluate the relationship between patients’ blood diamine oxidase (DAO) activity/histamine status and
their reactivity to time-resolved histamine skin prick test in respect to vulnerability to allergic diseases.
Material and methods: Fifty-three patients were examined with skin prick tests (SPT) and patch tests for suspected
presence of either IgE- or non-IgE-mediated allergy. All individuals were skin prick tested with histamine and the
resolution of the wheal was monitored for 50 min. Blood DAO activity and histamine concentration were measured
with a radio-extraction radioimmunoassay.
Results: Time-resolved histamine skin prick testing revealed presence of wheals which were 35% larger in diameter
in 47% of examined subjects at 20 min of the test. These patients exhibited significantly compromised time-course
wheal resolution (wheal ≥ 3 mm at 50 min) compared to a group of patients with the normal-rate of wheal resolution
(wheal = 0 mm at 50 min). Within a group of subjects exhibiting impaired wheal resolution, 61% of patients
were diagnosed allergic compared to 50% in a group of patients with a normal rate of wheal resolution. Finally,
allergic patients were characterized by a significantly lower DAO activity and higher histamine content compared
to healthy subjects.
Conclusions: The results of this study indicate that patients with IgE- or non-IgE-mediated allergy are likely to
have low DAO blood activity and may concomitantly suffer from histamine intolerance. Furthermore, our results
suggest that allergic patients are more likely to develop an excessive SPT reaction. Our results emphasize caution
in interpretation of the SPT results in allergic patients with diagnosed histamine intolerance or histamine/DAO
activity imbalance.
Besin intoleransları, bazı besinlere veya bileşenlerine karşı immünolojik olmayan anormal organizma cevabıdır. Histamin intoleransı, histaminin metabolize edilememesi ve semptom yaratması ile gelişen besin intoleranslarından biridir. Diamin oksidaz (DAO) ve Histamin N metil transferaz (HNMT) enzimleri histamin metabolizmasında görev alan iki enzimdir. Çeşitli faktörlerin etkisiyle enzim üretimi veya aktivasyonlarının azalması ve histaminin parçalanamaması sonucu vücutta birikmesi ile histamin intoleransı patogenezinin geliştiği tahmin edilmektedir. Semptomlar arasında bireye göre değişmekle beraber abdominal distansiyon, karın ağrısı, kaşıntı, egzama, ürtiker, baş ağrısı, burun tıkanıklığı, rinit yer almaktadır. Özellikle sebebi bilinmeyen semptomlara sahip bireylerde DAO enzim aktivasyonun azaldığını gösteren çalışmalar mevcuttur. Farklı organları etkileyen semptomlarının olması, ayırıcı bir tanı testinin bulunmaması ve aynı histamin kaynağının farklı bireylerde farklı reaksiyonlara sebep olması histamin intoleransı tanısını zorlaştırmaktadır. Günümüzde tanı ve tedavi yaklaşımlarında histamin kısıtlı diyetler en güvenilir yöntem olarak kabul edilmektedir. Aynı semptomlarla seyredebilecek diğer hastalıkların varlığının dışlanması ve histamin kısıtlı diyete olumlu cevap, histamin intoleransı tanısını desteklemektedir. Tedavi, histamin eliminasyon diyetlerinin belirli bir süre uygulanmasını, histamin kaynaklarına beslenmede yeniden yer verilmesini ve semptomların takibini içerir. Bu derleme çalışmasında mevcut verilerle histaminin diyetsel kaynakları, metabolizması, histamin intoleransı ve ilişkili sağlık sorunları ile histamin eliminasyon diyetlerine yer verilmiştir. Besinlerde histaminin belirlenmesi ve histamin intoleransı, oldukça yeni bir kavram olduğundan, histamin intoleransı epidemiyolojisini belirlemek, tanı algoritmalarını ve olası tedavi seçeneklerini doğrulamak için daha fazla araştırmaya ihtiyaç vardır.
Background: Histamine intolerance manifests when there is an imbalance between the production of histamine and the body’s capacity to metabolise it. Within the gastrointestinal tract, diamine oxidase (DAO) plays a pivotal role in breaking down ingested histamine. Insufficient levels of DAO have been linked to various diseases affecting the respiratory, cardiovascular, nervous, muscular, and digestive systems; some of these symptoms are evidenced in fibromyalgia syndrome. This underscores the crucial role of DAO in maintaining the histamine balance and highlights its association with diverse physiological systems and health conditions. The management of fibromyalgia commonly involves the use of psychotropic medications; however, their potential interactions with DAO remain not fully elucidated. Methods: This study delved into the influence of various psychotropic medications on DAO activity through in vitro experiments. Additionally, we explored their impact on the human intestinal cell line Caco-2, examining alterations in DAO expression at both the mRNA and protein levels along with DAO activity. Results: Notably, the examined drugs—sertraline, pregabalin, paroxetine, alprazolam, and lorazepam—did not exhibit inhibitory effects on DAO activity or lead to reductions in DAO levels. In contrast, citalopram demonstrated a decrease in DAO activity in in vitro assays without influencing DAO levels and activity in human enterocytes. Conclusions: These findings imply that a collaborative approach involving psychotropic medications and DAO enzyme supplementation for individuals with fibromyalgia and a DAO deficiency could offer potential benefits for healthcare professionals in their routine clinical practice.
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century. Although interest in histamine intolerance has considerably grown in recent years, more scientific evidence is still required to help define, diagnose and clinically manage this condition. This article will provide an updated review on histamine intolerance, mainly focusing on its etiology and the existing diagnostic, differential diagnoses and treatment strategies.
This study aimed to investigate the effect of N-acetylcysteine (NAC) on indomethacin (IDMT)-induced intestinal injury in a piglet model and explore the underlying molecular mechanisms. Piglets were randomly divided into 3 treatment groups: (1) control group; (2) IDMT group; (3) NAC+IDMT group. The results showed that NAC administration significantly increased the average daily gain of piglets, attenuated the intestine hyperemia, and restored normal jejunal morphology. Further studies indicated that NAC administration significantly increased plasma citrulline concentration and jejunal villin expression, but decreased the content of proinflammatory cytokines in plasma and jejunum of IDMT-stimulated piglets. NAC administration selectively decreased the proportion of eosinophils but not neutrophils in plasma. Furthermore, NAC administration significantly increased the activities of superoxide dismutase and catalase in plasma but decreased the concentrations of hydrogen peroxide (plasma) and malondialdehyde (plasma and jejunum), as well as the activity of myeloperoxidase (jejunum) when comparing NAC+IDMT group with IDMT group. Gene Ontology analysis showed that the significantly enriched molecular function term was "ubiquitin-like protein ligase binding" for NAC+IDMT versus IDMT differentially regulated genes. In the biological process category, differentially regulated genes of NAC+IDMT versus IDMT were mainly enriched in immune-related terms. The major enrichments for differentially regulated proteins (DRPs) of NAC+IDMT versus IDMT were terms involved in lipid metabolism and immune response. KEGG pathway enrichment analysis showed that "arginine biosynthesis" was a significant enrichment term for the DRPs of NAC+IDMT versus IDMT. Further studies demonstrated that NAC administration up-regulated argininosuccinate synthase 1 mRNA expression and down-regulated arginase mRNA expression in the jejunum of IDMT-stimulated piglets. Moreover, the content of nitric oxide was restored to a normal level with the reduction of nitric oxide synthase activity. NAC administration ameliorated intestinal injury in IDMT-challenged piglets by enhancing antioxidant and anti-inflammatory functions and modulating arginine metabolism in the small intestine.
Restrictive diets for the treatment of different gastrointestinal disorders are reported to change the composition of intestinal microbiota. Recently, it has been proposed that individuals with histamine intolerance suffer from intestinal dysbiosis, having an overabundance of histamine-secreting bacteria, but how it is still unknown this state is affected by the usual dietary treatment of histamine intolerance [i.e., low-histamine diet and the supplementation with diamine oxidase (DAO) enzyme]. Thus, a preliminary study was carried out aiming to evaluate the potential changes on the composition of the intestinal microbiota in a group of five women diagnosed with histamine intolerance undergoing 9 months of the dietary treatment of histamine intolerance. After sequencing bacterial 16S rRNA genes (V3-V4 region) and analyzing the data using the EzBioCloud Database, we observed a reduction in certain histamine-secreting bacteria, including the genera Proteus and Raoultella and the specie Proteus mirabilis. Moreover, it was also observed an increase in Roseburia spp., a bacterial group frequently related to gut health. These changes could help to explain the clinical improvement experienced by histamine intolerant women underwent a dietary treatment.
The new pandemic disease COVID-19 has wreaked havoc worldwide. Its infectious agent, SARS-CoV-2, uses two key human enzymes called angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) to invade body cells. The first one is encoded by the ACE2 gene and the second by the TMPRSS2 gene. Both have an outstanding expression of RNA and proteins in the small intestine compared with other tissues. This prominent location may be related to the main entry route of SARS-CoV-2 into the organism. In the process of infection, two other genes can play a fundamental role: NOS2, which expresses inducible nitric oxide synthase (iNOS), and AOC1, which encodes diamine oxidase (DAO). Both also highlight in the small intestine and are involved in polyamine metabolism. These biogenic amines are important for viral replication, being enhanced when NOS2 and AOC1 genes are downregulated. In addition, NOS2 shows a negative correlation with ACE2 and TMPRSS2, while nondegraded histamine by DAO can lead to an upregulation of both genes on which the virus depends. Taken together, these data suggest that inhibition or underexpression of NOS2 and AOC1 determines the susceptibility to get sick, increasing the risk of infection. On the other hand, a therapeutic approach to the disease could be made with homeopathic medicines. Experiments show the remedies' ability to stimulate gene and protein expression, but a correlation between the symptoms of each drug and these expressions has not yet been established. Here an analysis of the pathogenesis of Silicea terra and Arsenicum album supported on the scientific literature is done. The objective is to propose a theory about their relationship with key genes whose protein expressed in deficiency can give rise to the chain of events that imbalance the internal environment (homeostasis) and allow the development of symptoms. Silicea seems to be related to NOS2 (gene)/iNOS (protein) and Arsenicum with AOC1 (gene)/DAO (protein), being necessary to carry out studies to corroborate these links. Therefore, the aim of this article is to show the importance of NOS2 and AOC1 genes in the development of COVID-19 and to propose a line of investigation to evaluate if homeopathy can improve their protein expression.
Histamine – biogenic amine that is synthesized in the human body and acts as a mediator of a number of biological reactions. The extracellular histamine pathway involving enzymes diamine oxidase. Lack activity of this enzyme leads to a syndrome of histamine intolerance and out comes related to the pleiotropic effects of histamine. The article presents the main causes of decreased activity diamine oxidase, typical clinical symptoms that characterize this syndrome, diagnostical go rithm and characteristics of patients. Described as analternative, safe for patient test for diagnosing the syndrome of histamine intolerance – «Histamin 50-Skin- Prick Test». Based on the clinical cases shows modern diagnostic capabilities in specifi c patients with manifestations of allergic pathology. Understanding the pathogenesis of the syndrome of histamine intolerance, research in to the diagnosis of failure diamine oxidase gives opportunities to the choice of effective approaches in the treatment of patients so requires a deep knowledge of physicians of differents pecialties.
The chromosome conformation capture (3C) technique and its genome-wide applications ('4C') have identified a plethora of distal DNA sequences that are frequently in close spatial proximity. In many cases, these have been correlated with transcriptional regulation of the interacting genes, but the functional significance of many of the extreme long-range and interchromosomal interactions remains unclear. This review summarises our current understanding of how chromatin conformation can impinge on gene expression, the major questions that need to be addressed to understand this more fully, and how these questions may be answered in the near future.
Nuala Sheehan and colleagues describe how Mendelian randomization provides an alternative way of dealing with the problems of observational studies, especially confounding.
The amiloride binding protein (ABP) is detected in many epithelium-rich and/or hematopoietic tissues (Lingueglia, E., Renard, S., Voilley, N., Waldmann, R., Chassande, O., Lazdunski, M., and Barbry, P. (1993) Eur. J. Biochem. 216, 679-687). The protein binds amiloride and some of its derivatives, such as phenamil, benzamil, and ethylpropylamiloride. These properties have previously suggested that ABP might be associated with an amiloride-sensitive Na+ channel. It corresponds in fact to an amiloride-sensitive diamine oxidase (DAO) that catalyzes the degradation of compounds such as putrescine or histamine. The analysis of the organization of the sequence of the human ABP/DAO gene reveals that the 2.4-kilobase messenger RNA is transcribed from two close origins identifying the proximal promoter. After sequencing, some corrections within the initial cDNA sequence have been made. Human ABP/DAO corresponds to a 751-residue polypeptide. The promoter activity of 1800 base pairs upstream of the transcription start sites of the long form has been analyzed. Two bulks of cis-activating sequences have been identified. One of them constitutes the proximal promoter. It contains a palindromic sequence previously described as E-PAL. This motif is essential for the full activity of the promoter and behaves like a composite element. This first molecular cloning of a human gene coding for a diamine oxidase will allow us to further understand its regulation during cell growth and/or embryonic development.
The authors assessed whether genetic variation at the DAOA/G30 locus contributes to panic disorder (PD) and analyzed five SNPs at this locus in 152 patients and 208 controls. In the single-locus analyses, three SNPs were significantly associated with PD. Further support was obtained at the haplotypic level. Given that the authors have previously observed the same alleles and haplotypes to be associated with bipolar affective disorder and schizophrenia, the results suggest that DAOA/G30 contributes to psychiatric disease beyond diagnostic boundaries.
Structural polymorphism of DNA is a widely accepted property. A simple addition to this perception has been our recent finding, where a single nucleotide polymorphism (SNP) site present in a quasipalindromic sequence of beta-globin LCR exhibited a hairpin-duplex equilibrium. Our current studies explore that secondary structures adopted by individual complementary strands compete with formation of a perfect duplex. Using gel-electrophoresis, ultraviolet (UV)-thermal denaturation, circular dichroism (CD) techniques, we have demonstrated the structural transitions within a perfect duplex containing 11 bp quasipalindromic stretch (TGGGG(G/C)CCCCA), to hairpins and bulge duplex forms. The extended version of the 11 bp duplex, flanked by 5 bp on both sides also demonstrated conformational equilibrium between duplex and hairpin species. Gel-electrophoresis confirms that the duplex coexists with hairpin and bulge duplex/cruciform species. Further, in CD spectra of duplexes, presence of two overlapping positive peaks at 265 and 285 nm suggest the features of A- as well as B-type DNA conformation and show oligomer concentration dependence, manifested in A --> B transition. This indicates the possibility of an architectural switching at quasipalindromic region between linear duplex to a cruciform structure. Such DNA structural variations are likely to be found in the mechanics of molecular recognition and manipulation by proteins.
Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. Histamine is a biogenic amine that occurs to various degrees in many foods. In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity. Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. The ingestion of histamine-rich food or of alcohol or drugs that release histamine or block DAO may provoke diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with histamine intolerance. Symptoms can be reduced by a histamine-free diet or be eliminated by antihistamines. However, because of the multifaceted nature of the symptoms, the existence of histamine intolerance has been underestimated, and further studies based on double-blind, placebo-controlled provocations are needed. In patients in whom the abovementioned symptoms are triggered by the corresponding substances and who have a negative diagnosis of allergy or internal disorders, histamine intolerance should be considered as an underlying pathomechanism.
Two different methods of presenting quantitative gene expression exist: absolute and relative quantification. Absolute quantification calculates the copy number of the gene usually by relating the PCR signal to a standard curve. Relative gene expression presents the data of the gene of interest relative to some calibrator or internal control gene. A widely used method to present relative gene expression is the comparative C(T) method also referred to as the 2 (-DeltaDeltaC(T)) method. This protocol provides an overview of the comparative C(T) method for quantitative gene expression studies. Also presented here are various examples to present quantitative gene expression data using this method.
... Thomas D Schmittgen 1 & Kenneth J Livak 2 . ABSTRACT. ... N. Engl. J . Med. ... 32, e178 (2004). | Article | PubMed | ChemPort |; Livak , KJ & Schmittgen , TD Analysis of relative gene expression data using real - time quantitative PCR and the 2 (- Delta Delta C(T)) Method . ...
... Thomas D Schmittgen 1 & Kenneth J Livak 2 . ABSTRACT. ... N. Engl. J . Med. ... 32, e178 (2004). | Article | PubMed | ChemPort |; Livak , KJ & Schmittgen , TD Analysis of relative gene expression data using real - time quantitative PCR and the 2 (- Delta Delta C(T)) Method . ...
Two different methods of presenting quantitative gene expression exist: absolute and relative quantification. Absolute quantification calculates the copy number of the gene usually by relating the PCR signal to a standard curve. Relative gene expression presents the data of the gene of interest relative to some calibrator or internal control gene. A widely used method to present relative gene expression is the comparative CT method also referred to as the 2−ΔΔCT method. This protocol provides an overview of the comparative CT method for quantitative gene expression studies. Also presented here are various examples to present quantitative gene expression data using this method.
Objective To analyze the occurrence and the functional effects of nonsynonymous single nucleotide polymorphisms in the human diamine oxidase (ABP1) gene. Methods Genomic DNA from 134 healthy Caucasian individuals was analyzed for three nonsynonymous single nucleotide polymorphisms in the ABP1 gene. Serum diamine oxidase activity was studied in 37 individuals with known ABP1 genotype. Results Variant ABP1 alleles leading to the amino-acid substitutions Thr16Met, Ser332Phe and His645Asp were identified with frequencies of 25.4, 6.3 and 30.6%, respectively. Over 70% of the population (95% confidence interval, 62.4-77.9%) carry at least one amino-acid substitution. Each amino-acid substitution was at Hardy-Weinberg's equilibrium, but linkage disequilibrium between variant alleles was observed. The percentage of individuals carrying simultaneously the three amino-acid substitutions in heterozygosity or homozygosity (9%, 95% confidence interval, 4.2-13.8%) was over three times that expected from a random association (P<0.05). Individuals carrying the 645Asp amino acid displayed lower serum diamine oxidase activity as compared with noncarriers (P<0.001) with a significant gene-dose effect (P<0.05). This was due to an increase in the Michaelis-Menten constant. Individuals heterozygous for 645Asp show V-max/K-m values of 66% and homozygous 51% as compared with noncarriers. The effect of the 16Met variant allele was lower and that of the rarest allele 332Phe was negligible. Conclusion Nonsynonymous ABP1 gene polymorphisms are common in humans; they cause relevant functional effects and can be considered as major determinants of variability for human diamine oxidase activity. Pharmacogenetics and Genomics 17:687-693 (c) 2007 Lippincott Williams & Wilkins.
Parallel-stranded (ps) DNAs with mixed AT/GC content comprising G.C pairs in a varying sequence context have been investigated. Oligonucleotides were devised consisting of two 10-nt strands complementary either in a parallel or in an antiparallel orientation and joined via nonnucleotide linkers so as to form 10-bp ps or aps hairpins. A predominance of intramolecular hairpins over intermolecular duplexes was achieved by choice of experimental conditions and verified by fluorescence determinations yielding estimations of rotational relaxation times and fractional base pairing. A multistate mode of ps hairpin melting was revealed by temperature gradient gel electrophoresis (TGGE). The thermal stability of the ps hairpins with mixed AT/GC content depends strongly on the specific sequence in a manner peculiar to the ps double helix. The thermodynamic effects of incorporating trans G.C base pairs into an AT sequence are context-dependent: an isolated G.C base pair destabilizes the duplex whereas a block of greater than or equal to 2 consecutive G.C base pairs exerts a stabilizing effect. A multistate heterogeneous zipper model for the thermal denaturation of the hairpins was derived and used in a global minimization procedure to compute the thermodynamic parameters of the ps hairpins from experimental melting data. In 0.1 M LiCl at 3 degrees C, the formation of a trans G.C pair in a GG/CC sequence context is similar to 3 kT mol(-1) more favorable than the formation of a trans A.T pair in an AT/TA sequence context. However, GC/AT contacts contribute a substantial unfavorable free energy difference of similar to 2 kT mol(-1). As a consequence, the base composition and fractional distribution of isolated and clustered G.C base pairs determine the overall stability of ps-DNA with mixed AT/GC sequences. Thus, the stability of ps-DNA comprising successive greater than or equal to 2 G.C base pairs is greater than that of ps-DNA with an alternating AT sequence, whereas increasing the number of AT/GC contacts by isolating G.C base pairs exerts a destabilizing effect on the ps duplex. Molecular modeling of the various helices by force field techniques provides insight into the structural basis for these distinctions.
Inverted repeats are important elements in the human genome. Because of their nature, inverted repeats can engage in intra- and intermolecular basepairing. The ability to adopt hairpin and cruciform secondary structures is associated with frameshift mutations. These sequences also can be utilized by the polymerase allowing both intra- and interstrand switching events. Such mechanisms can involve imperfect inverted repeats and lead to additional mutations. Several human genetic diseases illustrate inverted repeat mediated mutagenesis.
Genetic polymorphisms for histamine-metabolizing enzymes are responsible for interindividual variation in histamine metabolism and are associated with diverse diseases. Initial reports on polymorphisms of histamine-related genes including those coding for the enzymes histidine decarboxylase (HDC), diamine oxidase (ABP1) and histamine N-methyltransferase (HNMT), as well as histamine receptor genes, often have pointed to polymorphisms that occur with extremely low frequencies or that could not be verified by later studies. In contrast, common and functionally significant polymorphisms recently described have been omitted in many association studies. In this review we analyze allele frequencies, functional and clinical impact and interethnic variability on histamine-related polymorphisms. The most relevant nonsynonymous polymorphisms for the HDC gene are rs17740607 Met31Thr, rs16963486 Leu553Phe and rs2073440 Asp644Glu. For ABP1 the most relevant polymorphisms are rs10156191 Thr16Met, rs1049742 Ser332Phe, and particularly because of its functional effect, rs1049793 His645Asp. In addition the ABP1 polymorphisms rs45558339 Ile479Met and rs35070995 His659Asn are relevant to Asian and African subjects, respectively. For HNMT the only nonsynonymous polymorphism present with a relevant frequency is rs1801105 Thr105Ile. For HRH1 the polymorphism rs7651620 Glu270Gly is relevant to African subjects only. The HRH2 rs2067474 polymorphism, located in an enhancer element of the gene promoter, is common in all populations. No common nonsynonymous SNPs were observed in the HRH3 gene and two SNPs were observed with a significant frequency in the HRH4 gene: rs11665084 Ala138Val and rs11662595 His206Arg. This review summarizes relevant polymorphisms, discusses controversial findings on association of histamine-related polymorphisms and allergies and other diseases, and identifies topics requiring further investigation.
Currently, a lack of consensus exists on how best to perform and interpret quantitative real-time PCR (qPCR) experiments. The problem is exacerbated by a lack of sufficient experimental detail in many publications, which impedes a reader's ability to evaluate critically the quality of the results presented or to repeat the experiments.
The Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines target the reliability of results to help ensure the integrity of the scientific literature, promote consistency between laboratories, and increase experimental transparency. MIQE is a set of guidelines that describe the minimum information necessary for evaluating qPCR experiments. Included is a checklist to accompany the initial submission of a manuscript to the publisher. By providing all relevant experimental conditions and assay characteristics, reviewers can assess the validity of the protocols used. Full disclosure of all reagents, sequences, and analysis methods is necessary to enable other investigators to reproduce results. MIQE details should be published either in abbreviated form or as an online supplement.
Following these guidelines will encourage better experimental practice, allowing more reliable and unequivocal interpretation of qPCR results.
Complex genetic disease is caused by the interaction between genetic and environmental variables and is the predominant cause of mortality globally. Recognition that susceptibility arises through the combination of multiple genetic pathways that influence liability factors in a nonlinear manner suggests that a process of 'decanalization' contributes to the epidemic nature of common genetic diseases. The rapid evolution of the human genome combined with marked environmental and cultural perturbation in the past two generations might lead to the uncovering of cryptic genetic variation that is a major source of disease susceptibility.
Chronic urticaria, recurrent angioedema and non-allergic asthma have all been associated with pseudoallergic reactions to food ingredients. For atopic dermatitis and diseases of the gastrointestinal tract, this association is controversial. Pseudoallergic reactions can be elicited by additives as well as by natural food ingredients. An altered histamine metabolism may be associated with pseudoallergy.
Acute urticaria or a short episode of angioedema is not an indication for exhaustive evaluation. If basic diagnostic screening is negative in chronic urticaria, a low-pseudoallergen diet can be considered. Skin and serological tests are not objective diagnostic parameters for pseudoallergic reactions. The severity of symptoms should be documented while the patient is on a low-pseudoaller-gen diet.
Oral provocation with additives leads to reproducible symptoms only in a few cases. Therefore, if a low-pseudoallergen diet brings improvement, the patient is then exposed to a pseudoallergen-rich "super meal". After a positive reaction to the "super meal" the challenge with additives takes place in the form of collective group exposition. When the patient has asthma or a history of anaphylac-toid reactions, testing with individual substances in carefully increasing dosages is required.
The suspicion of adverse reactions against histamine can be confirmed by a challenge with histamine dihydrochloride. In the case of respiratory symptoms, provocation by inhalation should be considered. Objectifying symptoms especially in gastrointestinal diseases is mandatory and should include double-blind placebo-controlled food challenge, if possible.
The danger of luminal histamine administered orally or formed in the intestinal fluid by bacteria has long been neglected. However, the demonstration of blocking intestinal diamine oxidase (DAO) by a variety of common drugs has revived the discussion and has created a new disease concept: enteral-induced histaminosis. In an animal model the three central prognostic variables of this disease concept (large amounts of histamine in food to make the individual ill, blocking of DAO by commonly used drugs, and the relationship between increased plasma histamine levels and disease manifestation by exogenous histamine application) were tested with randomized trials in vivo and biochemical tests in vitro using semipurified enzymes from pig and man.
In the first trials authentic histamine in quantities similar to that in normal amounts of food or cheese bought from a supermarket produced lifethreatening reactions if the DAO was inhibited by pretreatment with aminoguanidine. In the second series of experiments in vitro a numerous commonly used drugs was shown to inhibit both the porcine and human enzyme. Some of the inhibitors were really strong, such as dihydralazine, chloroquine, pentamidine, cycloserine, clavulanic acid, dobutamine, pancuronium and others. The type of inhibition was sometimes competitive as in the case of dihydralazine and pancuronium, sometimes non competitive (e.g. pentamidine) which may be important for long-term treatment. In the third group of experiments a relationship between the dose of i.v. injected histamine and the elevation in plasma histamine levels and clinical symptoms in pigs was demonstrated. Hence, elevated plasma histamine in pigs acts as a pathogenetic factor for the disease manifestation. It is concluded that after modelling enteral-induced histaminosis in an animal the trias of variables shown in this study should be consequently investigated in man.
In a randomized controlled trial, 30 pigs were orally treated with histamine (60 mg). In addition, half of the animals underwent a specific blockade of the enzyme diamine oxidase (DAO), which is the main histamine catabolising enzyme in the intestinal tract. Only these DAO-blocked animals exhibited severe clinical symptoms (e.g. hypotension, flush, vomiting) and, in parallel, showed tremendous elevations of plasma histamine levels of up to 160 ng/ml. 3 out of 15 animals in this group died within the experimental period. In contrast, the control animals neither exhibited plasma histamine levels above 5 ng/ml nor had any clinical reactions. These results contradict the current opinion that oral histamine intake in food is not clinically relevant, especially since many commonly used drugs are DAO-inhibitors and approximately 20% of our population take these drugs. Apart from drugs, some other factors (alcohol, spoilt food etc.) can also function via a blockade of DAO as an additional risk. DAO-blockade is therefore a real epidemiological problem. Evidence is presented here for the new disease concept: Food-Induced Histaminosis.
The method with 14C-putrescine as the substrate for routine measurement of serum (plasma) diamine oxidase (histaminase) during pregnancy, and mola hydatidosa (chorionepitelioma) has been modified. The optimal experimental conditions for determination of diamine oxidase (DAO) activity in normal human blood serum are given. Normal range for serum DAO is 0 to 20 mU/1. The majority, however, grouped around 4 mU/1, i.e., about 1/500 of the serum DAO activity in the last trimester of normal pregnancy.
Complexes of different electrophoretic mobility containing the stem-loop binding protein, a 45 kDa protein, bound to the stem-loop
at the 3′ end of histone mRNA, are present in both nuclear and cytoplasmic extracts from mammalian cells. We have determined
the effect of changes in the loop, in the stem and in the flanking sequences on the affinity of the SLBP for the 3′ end of
histone mRNA. The sequence of the stem is particularly critical for SLBP binding. Specific sequences both 5′ and 3′ of the
stem-loop are also required for high-affinity binding. Expanding the four base loop by one or two uridines reduced but did
not abolish SLBP binding. RNA footprinting experiments show that the flanking sequences on both sides of the stem-loop are
critical for efficient binding, but that cleavages in the loop do not abolish binding. Thus all three regions of the RNA sequence
contribute to SLBP binding, suggesting that the 26 nt at the 3′ end of histone mRNA forms a defined tertiary structure recognized
by the SLBP.
Patients with atopic dermatitis display substantial immunologic abnormalities, among which elevated total IgE is considered as a hallmark; however, a subgroup of atopic dermatitis patients exhibits normal IgE levels, but mechanisms contributing to the so-called "intrinsic" or "nonallergic" form of atopic dermatitis are obscure. In order to unravel similarities and differences of both atopic dermatitis subtypes, the phenotype of monocytes, total serum IgE levels, and serum levels of cytokines regulating the IgE production from nonatopic individuals and patients with allergic rhinitis, and extrinsic and intrinsic atopic dermatitis were measured. Concomitantly, genomic DNA probes of all subjects were analyzed for single nucleotide polymorphisms of candidate genes of structures involved in the regulation of the IgE synthesis, such as interleukin-4 and the interleukin-4R/interleukin-13R. Our data show that the surface expression of the high- and low-affinity receptor for IgE (FcepsilonRI and FcepsilonRII/CD23) and the interleukin-4Ralpha chain were significantly elevated in monocytes from patients with extrinsic atopic dermatitis. Furthermore, serum levels of interleukin-13 were significantly increased in patients with intrinsic atopic dermatitis. In addition, the frequency of the interleukin-4Ralpha polymorphism C3223T and the interleukin-4 polymorphism C590T tended to be higher in extrinsic atopic dermatitis than in intrinsic atopic dermatitis. Altogether our findings indicate that intrinsic atopic dermatitis patients exhibit phenotypic and immunologic features, which differ from those of patients with extrinsic atopic dermatitis or other atopic disorders.
Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Availability:http://www.broad.mit.edu/mpg/haploview/
Contact:jcbarret@broad.mit.edu
Histamine plays an important role in the allergic inflammation. Histamin N-Methyltransferase (HNMT) catalyses the major pathway of histamine metabolism in the human lung. A common functional single nucleotide polymorphism (SNP) within the HNMT gene (C314T) was recently related to asthma. We tested this SNP for associations with asthma and asthma associated traits in two German pediatric populations (1. MAS-cohort, n=888, 85 children with asthma; 2. asthmatic children from Freiburg, n=176). Non-asthmatic (n=515) and non-atopic (n=211) children from the MAS-cohort were used as controls. For genotyping melting curve analyses (Light Cycler System) were applied. In contrast to a previous study, no association of the HNMT 314T allele with asthma, bronchial hyperresponsiveness (BHR) or other asthma related phenotypes could be observed in either study population. We conclude that this SNP might not play a major role in the pathogenesis of asthma or BHR in German children.
Interactions with microbial pathogens are crucial for the maturation of the immune system. The nucleotide-binding oligomerization domain protein 1 (NOD1) is a cytosolic receptor sensing a muropeptide found mostly in gram-negative bacterial peptidoglycans. NOD1 is located on chromosome 7p14-p15, a region that has been linked with atopy. Recently, polymorphisms of the closely related NOD2 have been associated with atopy-related traits.
Within a large population-based cohort of German adults (n = 1417), a case-control population for atopic eczema (n = 454), and a large cohort of parent-offspring trios for atopic eczema (189 trios), we evaluated 11 NOD1 polymorphisms for associations with atopic phenotypes. Methods Subjects were phenotyped by standardized questionnaires and interviews, skin examination, and serum IgE measurements. Genotyping was performed by using matrix-assisted laser desorption ionization-time of flight mass spectrometry.
Analyses revealed significant association of one NOD1 haplotype with atopic eczema in the population-based cohort ( P = .004) and the case-control population ( P = .003). Another NOD1 haplotype was associated with decreased total IgE ( P = .008). In addition, significant associations with total serum IgE levels were observed for polymorphisms rs2907748 ( P = .006), rs2907749 ( P = .012), and rs2075822 ( P = .018). These polymorphisms were significantly associated with atopic eczema and asthma in the family-based association analyses ( P = .001-.043). Seven polymorphisms showed significant transmission distortion for total IgE levels ( P values < .0001-.029).
These data indicate that genetic variants within NOD1 are important determinants of atopy susceptibility.
A diminished histamine degradation based on a reduced diaminoxidase activity is suspected as a reason for non-IgE-mediated food intolerance caused by histamine. Atopic eczema (AE) is often complicated by relapses triggered by IgE-mediated allergy to different kinds of food. However, in a subgroup of patients with AE, allergy testing proves negative, although these patients report a coherence of food intake and worsening of AE and describe symptoms that are very similar to histamine intolerance (HIT).
It was the aim of our study to evaluate symptoms of HIT in combination with diaminoxidase levels in a total of 360 individuals consisting of patients with AE (n = 162) in comparison with patients with HIT (n = 124) without AE and healthy control volunteers (n = 85).
Histamine plasma level was determined with an ELISA and diaminoxidase serum activity with the help of radio extraction assays using [3H]-labeled putrescine-dihydrochloride as a substrate. Detailed clinical evaluations of characteristic features of AE and HIT were performed.
Reduced diaminoxidase serum levels leading to occurrence of HIT symptoms like chronic headache, dysmenorrhea, flushing, gastrointestinal symptoms, and intolerance of histamine-rich food and alcohol were significantly more common in patients with AE than in controls. Reduction of both symptoms of HIT and Severity Scoring of Atopic Dermatitis could be achieved by a histamine-free diet in the subgroup of patients with AE and low diaminoxidase serum levels.
Higher histamine plasma levels combined with a reduced histamine degradation capacity might influence the clinical course of a subgroup of patients with AE.
As HIT emerges in a subgroup of patients with AE, a detailed anamnestic evaluation of food intolerance and HIT symptoms complemented by an allergological screening for food allergy, a diet diary, and, in confirmed suspicion of HIT, measurement of diaminoxidase activity and a histamine-free diet should be undertaken.
To analyze the occurrence and the functional effects of nonsynonymous single nucleotide polymorphisms in the human diamine oxidase (ABP1) gene.
Genomic DNA from 134 healthy Caucasian individuals was analyzed for three nonsynonymous single nucleotide polymorphisms in the ABP1 gene. Serum diamine oxidase activity was studied in 37 individuals with known ABP1 genotype.
Variant ABP1 alleles leading to the amino-acid substitutions Thr16Met, Ser332Phe and His645Asp were identified with frequencies of 25.4, 6.3 and 30.6%, respectively. Over 70% of the population (95% confidence interval, 62.4-77.9%) carry at least one amino-acid substitution. Each amino-acid substitution was at Hardy-Weinberg's equilibrium, but linkage disequilibrium between variant alleles was observed. The percentage of individuals carrying simultaneously the three amino-acid substitutions in heterozygosity or homozygosity (9%, 95% confidence interval, 4.2-13.8%) was over three times that expected from a random association (P<0.05). Individuals carrying the 645Asp amino acid displayed lower serum diamine oxidase activity as compared with noncarriers (P<0.001) with a significant gene-dose effect (P<0.05). This was due to an increase in the Michaelis-Menten constant. Individuals heterozygous for 645Asp show Vmax/Km values of 66% and homozygous 51% as compared with noncarriers. The effect of the 16Met variant allele was lower and that of the rarest allele 332Phe was negligible.
Nonsynonymous ABP1 gene polymorphisms are common in humans; they cause relevant functional effects and can be considered as major determinants of variability for human diamine oxidase activity.
Histamine has been implicated in the pathogenesis of migraine. In the CNS, histamine is almost exclusively metabolized by the polymorphic enzyme histamine N-methyltransferase (HNMT). The HNMT gene (chromosome 2q22.1), shows diverse single nucleotide polymorphisms. One of these, located in exon 4 C314T, causes the amino acid substitution Thr105Ile, related to decreased enzyme activity. The aim of this study was to investigate the possible association between HNMT polymorphism and the risk for migraine.
We studied the frequency of the HNMT genotypes and allelic variantes in 197 patients with migraine and 245 healthy controls using a PCR-RLFP method.
The frequencies of the HNMT genotypes and allelic variants did not differ significantly between migraine patients and controls, and were unrelated with the age of onset of migraine attacks, gender, personal history of allergic diseases, family history of migraine, or presence of aura.
The results of the present study suggest that HNMT polymorphism in not related with the risk for migraine.
Food-induced histaminosis as cloning, sequencing, and characterization of the promoter
- J Sattler
- D Hafner
- Klotter Hj
- W Lorenz
- Wagner
Sattler J, Hafner D, Klotter HJ, Lorenz W, Wagner PK. Food-induced histaminosis as cloning, sequencing, and characterization of the promoter. J Biol Chem 1994;20:14484– 14489.
A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing
- R Development
- Core Team
R Development Core Team. A language and
environment for statistical computing. Vienna,
Austria: R Foundation for Statistical Computing, 2007.
Histamine N-methyltransferase (HNMT) enzyme and gene
- H G Schwelberger
Schwelberger HG. Histamine N-methyltransferase (HNMT) enzyme and gene. In: Falus
A, editor. Histamine: biology and medical
aspects. Budapest, Basel: SpringMed
Publishing, S. Karger AG, 2004:53-59.
- Jarisch