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Gene-environment interaction in allergic disease: More questions, more answers?
... Allergic diseases of respiratory system, such as bronchial asthma and allergic rhinitis, are increasingly becoming global health problems. [1][2][3] Airborne fungi are significant environmental components involved in the aetiology of allergic respiratory diseases. 4,5 Aspergillus, Cladosporium, Alternaria, Curvularia and Fusarium species have been reported as the most prevalent components of indoor and outdoor aeromycota around the world. ...
Aspergillus species (A flavus and A niger) are important sources of inhalant allergens. Current diagnostic modalities employ crude Aspergillus extracts which only indicate the source to which the patient has been sensitized, without identifying the number and type of allergens in crude extracts. We report a study on the identification of major and minor allergens of the two common airborne Aspergillus species and heterogeneity of patients' IgE response to them. Skin prick tests were performed on 300 patients of bronchial asthma and/or allergic rhinitis and 20 healthy volunteers. Allergen specific IgE in patients' sera was estimated by enzyme allergosorbent test (EAST). Immunoblots were performed to identify major/minor allergens of Aspergillus extracts and to study heterogeneity of patients' IgE response to them. Positive cutaneous responses were observed in 17% and 14.7% of patients with A flavus and A niger extracts, respectively. Corresponding EAST positivity was 69.2% and 68.7%. In immunoblots, 5 allergenic proteins were identified in A niger extract, major allergens being 49, 55.4 and 81.5 kDa. Twelve proteins bound patients' IgE in A flavus extract, three being major allergens (13.3, 34 and 37 kDa). The position and slopes of EAST binding and inhibition curves obtained with individual sera varied from patient to patient. The number and molecular weight of IgE-binding proteins in both the Aspergillus extracts varied among patients. These results gave evidence of heterogeneity of patients' IgE response to major/minor Aspergillus allergens. This approach will be helpful to identify disease eliciting molecules in the individual patients (component resolved diagnosis) and may improve allergen-specific immunotherapy. Copyright© Summer 2015, Iran J Allergy Asthma Immunol. All rights reserved.
... In these candidate gene studies the main exposures examined included ETS exposure, air pollution, farming, and occupational exposures, and extensive reviews of these studies have been published. 17,[28][29][30][31][32][33][34][35][36][37] All these studies illustrate the difficulties of demonstrating robust GxE interactions, which might in part be due to the relatively small number of genetic polymorphisms investigated and the small sample sizes. This emphasizes the formidable challenge of dissecting the complex mechanisms underlying multifactorial diseases. ...
The concept of gene-environment (GxE) interactions has dramatically evolved in the last century and has now become a central theme in studies that assess the causes of human disease. Despite the numerous efforts to discover genes associated in asthma and allergy through various approaches, including the recent genome-wide association studies, investigation of GxE interactions has been mainly limited to candidate genes, candidate environmental exposures, or both. This review discusses the various strategies from hypothesis-driven strategies to the full agnostic search of GxE interactions with an illustration from recently published articles. Challenges raised by each piece of the puzzle (ie, phenotype, environment, gene, and analysis of GxE interaction) are put forward, and tentative solutions are proposed. New perspectives to integrate various types of data generated by new sequencing technologies and to progress toward a systems biology approach of disease are outlined. The future of a molecular network-based approach of disease to which GxE interactions are related requires space for innovative and multidisciplinary research. Assembling the various parts of a puzzle in a complex system could well occur in a way that might not necessarily follow the rules of logic.
... Environmental factors play an important contributory role in the expression of immunoglobulin E (IgE)-mediated allergic diseases such as bronchial asthma and allergic rhinitis, the most important etiologic factor being allergen exposure (1)(2)(3). The common inhalant allergens include pollen, fungal spores and associated fragments, house dust mite and house dust, animal danders, insect emanations and detritus, etc. ...
Airborne Aspergillus species are significant environmental components involved in the pathogenesis and persistence of allergic respiratory diseases. The detection and quantification of airborne allergens is important to elucidate the clinical implications of environmental exposure of patients suffering with allergic asthma and/or allergic rhinitis.
The authors report a simple volumetric approach to measure atmospheric concentration of four common airborne species of Aspergillus-A. flavus, A. fumigatus, A. niger, and A. tamarii.
As particulate aeroallergens may also exist in amorphous form in addition to morphologically identifiable fungal spores/hyphae, a volumetric technique using membrane filters was developed for simultaneous quantification of (a) viable Aspergillus counts, i.e., colony-forming units (cfu)/m(3), and (b) actual Aspergillus allergen content (ng/m(3)) in the air. Further, immunochemically quantified airborne Aspergillus allergens were compared with their corresponding colony counts.
The average monthly aerial counts of the four Aspergillus species recorded during the sampling year were A. flavus: 0.25-15.2 cfu/m(3); A. fumigatus: 1.25-15.6 cfu/m(3); A. niger: 0.75-16.0 cfu/m(3); and A. tamarii: 0.5-11.8 cfu/m(3) of air. Aerial Aspergillus allergen(s) concentration varied from species to species: A. flavus: 26.8-680.8 ng; A. fumigatus: 18.0-380.4 ng; A. niger: 28.2-1879.0 ng; and A. tamarii: 9.2-238.3 ng/m(3) of air. Seasonal distribution of airborne colony counts of the four species didn't correlate with their respective allergen content.
Aspergillus allergens were present in the air of Delhi area throughout the year with seasonal variations. The authors feel that by using the immunochemical technique it will be possible to measure actual exposure of patients to various airborne Aspergillus allergens.
... Allergic diseases of respiratory system, such as bronchial asthma and allergic rhinitis, are increasingly becoming global health problems (Masoli et al. 2004;Bousquet et al. 2008). The phenomenal increase in prevalence of allergies in the past decades is a result of changes in environment (Koppelman 2007). Fungi, ubiquitous in occurrence, have a great capacity to colonize many kinds of substrata and may develop in extreme environmental conditions, from where they become airborne. ...
Aspergillus-derived inhalant allergens play an important role in the etiology of allergic respiratory diseases. In the present study, we investigated the allergenic potential of Aspergillus tamarii, quantified its airborne content, identified its major/minor allergens, evaluated heterogeneity of patients' IgE response to its allergens and cross-reactivity of its allergens with other Aspergillus allergens. Skin prick tests with A tamarii extract were performed on 300 patients of bronchial asthma/allergic rhinitis and 20 healthy volunteers. Sixty-six patients (22%) elicited positive cutaneous reactions to A tamarii extract. Only one of the 20 non-allergic healthy volunteer showed a mild positive cutaneous reaction. Allergen-specific IgE levels increased with increase in patients' cutaneous response (0% in negative to 100% in 3+/4+). The skin positivity and allergen-specific IgE levels were significantly higher in patients compared to healthy volunteers (P>0.05). However, no differences were found for these two parameters among patients of bronchial asthma, allergic rhinitis and bronchial asthma with allergic rhinitis. The airborne A tamarii allergen content was highest in February and October. A tamarii extract revealed at least 22 proteins (13.3-120 kDa). Seventeen of these proteins bound patients' IgE with six being major allergens (13.3, 23, 25, 34, 39.5, 43 kDa). Three major allergens (13.3, 34, 43 kDa) were found to cross-react with A flavus and one (34 kDa) with A niger. Our results revealed that A tamarii allergen(s) are present in the air, which might serve as important inhalant allergens in IgE-mediated allergic respiratory diseases.
... More studies are needed to characterise the interaction of multiple genes and multiple environmental factors. These investigations are complicated by the fact that large sample sizes are needed [17]. ...
Asthma is a genetically complex disease caused by multiple genetic and environmental factors. An increasing number of asthma susceptibility genes are currently being identified. The present study addresses the question as to whether this genetic information can be used to predict asthma, particularly in pre-school children. The predictive value of a single gene test in a complex disease is very limited for diagnostic or preventive purposes and thus cannot be recommended. Based on data of simulation studies and other complex diseases, the use of genetic profiling that incorporates multiple genetic risk factors holds promise for clinical application. The results of genome-wide association studies will be crucial in establishing this genetic risk profile for asthma. In the future, asthma prediction may be possible, based on a prediction model that incorporates genes, personal factors and environmental risk factors. Studies in general and at-risk populations are needed to investigate and validate this approach.
This paper reviews the impact of infections on the onset and clinical course of bronchial asthma. A just emphasis is given to the role viral infections, particularly rhinovirus infections, play in exacerbations, and that played by respiratory syncytial virus, suspected of triggering the asthmatic syndrome. The mechanisms of the immune response to virus attacks are explained, highlighting the asthmatic and allergic patient's weakened response, particularly in the perinatal period. Further stressed is a potentiating effect of viral aggression on the allergic response. The hygiene hypothesis and its lack of scientific consistency is detailed, at least as far as the role it seeks to confer on an unproven antagonism of the Th1 and Th2 lymphocyte responses. The current importance of research not into bacteria, but into bacterial products, including endotoxins, on the modulation of asthma and allergy is noted. Studies which, along these lines, show an environmental impact on genetic secretion in the phenotype are underlined. Also discussed in passing are several mechanisms which go towards explaining neutrophilic asthma - for many a contradiction, given eosinophilia's stranglehold on asthmatic inflammation.
© 2008 Sociedade Portuguesa de Pneumologia.
Allergies are pathological manifestations originating from a trigger-sensitized immune system. Aspergillus species have been reported to be one of the important inhalant allergens in different geographical regions of the world. House dust mite (HDM) allergens play a major role in causing allergic diseases. The emerging literature indicates the allergenicity and contribution of Aspergillus species and HDMs. Allergies erupt when innocuous foreign components are confused as foes by the immune surveillance. The incidence of fungal sensitization in patients with allergic respiratory diseases has been reported from 2.3% to even 80% in various studies worldwide. Human skin scales provide food for both mites and fungi. Fungi may either constitute a food supplement for mites or may have an indirect effect by decomposing human dander, thus making it more accessible for HDMs. There is a mutual relationship between fungi and HDMs. In addition to avoid exposure to an allergen as a secondary or tertiary preventive strategy, which is often not sufficiently effective against domestic mites, the treatment of mite allergy is mainly based on allergen-specific immunotherapy (AIT). Treatment with azole antifungal drugs in patients with severe asthma is effective and improves patient quality of life.
It is generally believed that the immediate hypersensitivity is mediated by specific IgE antibody. But the roles of IgG antibody and its subunits in hypersensitivity have not been sufficiently clarified. Four subunits of IgG (IgG1, IgG2, IgG3 and IgG4) have been identified. The IgG subunits have different roles, for example, induction or inhibition of hypersensitivity, according to the different antigens, hypersensitive phases and atopic patients. With the more knowledge of IgG subunits, the roles of IgG subunits in hypersensitivity occurrence, diagnosis and therapy will be understood.
Vitamin D has been suggested to have an important impact on a much wider aspects on human health than calcium homeostasis and mineral metabolism, specifically in the field of human immunology. It has been reported that vitamin D influences the regulation of both innate and adaptive immune systems, which makes the association between vitamin D and allergic diseases a field of interest. Although many studies have sought to determine whether vitamin D has an influence on progression of allergic disease, the impact of vitamin D on atopic dermatitis development and severity remains unclear. In this review, we summarize recent studies relating vitamin D to atopic dermatitis and discuss its possible role in the pathogenesis of allergic skin diseases, emphasizing the need for well-designed, prospective trials on vitamin D supplementation in the context of prevention and treatment for allergic conditions.
In de preventie van allergie kan een onderscheid gemaakt worden in primaire, secundaire en tertiaire preventie. Van primaire
preventie wordt gesproken als er nog geen sprake is van sensibilisatie en ziekte. Van secundaire preventie is sprake als sensibilisatie
reeds heeft plaatsgevonden, maar de ziekte nog niet aanwezig is. Van tertiaire preventie wordt gesproken, indien zowel sensibilisatie
als ziekte aanwezig zijn. Dit is eigenlijk hetzelfde als behandeling, wat elders in dit boek besproken wordt. Preventieve
maatregelen kunnen worden onderverdeeld naar of vermijding van bepaalde factoren of juist blootstelling aan bepaalde factoren.
In het verleden is bij allergiepreventie vooral aan vermijding gedacht, terwijl de laatste jaren de gedachten meer uitgaan
naar blootstelling, mede onder invloed van de teleurstellende resultaten van de vermijdingsstudies. In dit hoofdstuk zullen
de termen ‘atopie’ en ‘allergie’ regelmatig gebruikt worden, reden om hier aan te geven wat er met die twee termen bedoeld
wordt. Atopie is hier gedefinieerd als de erfelijke aanleg om met de vorming van IgE-antistoffen te reageren op prikkels vanuit
de omgeving. Atopie kan bevestigd worden door of een verhoogde concentratie van IgE in het serum of een positieve huidtest
voor een specifiek allergeen. Allergie is hier gedefi nieerd als het aanwezig zijn van klinische verschijnselen van een allergische
aandoening als voedselallergie, constitutioneel ec zeem, astma, hooikoorts, urticaria of anafylaxie.
Identifying the genetic origins of human complex traits is a time-consuming and labor-intensive process that has as yet only yielded a relatively small number of confirmed susceptibility genes and an even smaller number of confirmed susceptibility alleles. One potential explanation for these difficulties might be the presence of unrecognized environmental factors that moderate the contribution of genetic loci to disease and vary between populations. These factors need not necessarily be limited to environmental parameters of intuitive importance (eg, cigarette smoke or allergen exposure) but also can include more cryptic sources of variation associated with the specific study environment (eg, study apparatus or ambient temperature). Analysis of these interactions in human subjects, although a gold standard, is time-consuming and constrained by ethical and technical issues. Investigations in mouse models, on the other hand, represent a simple and flexible system in which to explore gene-environment interaction effects. In this review we discuss the utility of mouse models in the detection of gene-environment interaction effects and consider the limitations on their application.
I t has been long recognised that asthma and related pheno-ty pes hav e an imp ortant hereditary na ture, in w hich inheritance does not follow the classical Mendelian patterns and the exact mode of inheritance is not known. Linkage, association studies and genome-wide screening suggest that many genes are involved in the pathogenesis of asthma. Twin studies have contributed significantly to our understanding on the genetics of asthma, especially the large-scale twin studies in different parts of the world which have showed comparable results. With the shortcomings of the twin method borne in mind, more twin studies are needed to investigate the heredity component of the intermediate phenotypes of asthma, that is, bronchial hyperresponsiveness, total immunoglobuli n E, skin test reactivity, specific IgE against different aeroallergens, and the variability of lung function. Twin studies are very suitable to unravel the intricate network of genes and environment which plays a role in asthma. Monozygotic twins and the co-twin control design are suitable for this purpose, while longitudinal twin studies are needed to solve the problem of the age related expression of genes which probably are involved in the pathogenesis of asthma. In the near future twin studies will play an important role in the detection of new, as yet undiscov-ered genes, but may be even more important in answering the most challenging of all questions: how do the environment interact with the genetics of asthma? Exchange of information and collaboration between the different research groups involved in the genetics of asthma will contribute to a better understanding of this condition.
It has been long recognised that asthma and related phenotypes have an important hereditary nature, in which inheritance does not follow the classical Mendelian patterns and the exact mode of inheritance is not known. Linkage, association studies and genome-wide screening suggest that many genes are involved in the pathogenesis of asthma. Twin studies have contributed significantly to our understanding on the genetics of asthma, especially the large-scale twin studies in different parts of the world which have showed comparable results. With the shortcomings of the twin method borne in mind, more twin studies are needed to investigate the heredity component of the intermediate phenotypes of asthma, that is, bronchial hyperresponsiveness, total immunoglobulin E, skin test reactivity, specific IgE against different aeroallergens, and the variability of lung function. Twin studies are very suitable to unravel the intricate network of genes and environment which plays a role in asthma. Monozygotic twins and the co-twin control design are suitable for this purpose, while longitudinal twin studies are needed to solve the problem of the age related expression of genes which probably are involved in the pathogenesis of asthma. In the near future twin studies will play an important role in the detection of new, as yet undiscovered genes, but may be even more important in answering the most challenging of all questions: how do the environment interact with the genetics of asthma? Exchange of information and collaboration between the different research groups involved in the genetics of asthma will contribute to a better understanding of this condition.
CD14 is a pattern recognition receptor that plays a central role in innate immunity through recognition of bacterial lipoglycans, primarily LPS. Recently, our group has identified a common single nucleotide polymorphism, -159C-->T, in the CD14 proximal promoter. Homozygous carriers of the T allele have a significant increase in soluble CD14, but a decreased total serum IgE. This epidemiologic evidence led us to investigate the molecular basis for the effects of CD14/-159C-->T on CD14 regulation in monocytes and hepatocytes, the two major cell types known to express this gene in vivo. EMSA analysis showed that the T allele results in decreased affinity of DNA/protein interactions at a GC box that contains a binding site for Sp1, Sp2, and Sp3 transcription factors. In reporter assays, the transcriptional activity of the T allele was increased in monocytic Mono Mac 6 cells, which express low levels of Sp3, a member of the Sp family with inhibitory potential relative to activating Sp1 and Sp2. By contrast, both alleles were transcribed equivalently in Sp3-rich hepatocytic HepG2 cells. Our data indicate that the interplay between CD14 promoter affinity and the [Sp3]:[Sp1 + Sp2] ratio plays a critical mechanistic role in regulating transcription of the two CD14 alleles. Variation in a key gene of innate immunity may be important for the pathogenesis of allergy and inflammatory disease through gene-by-gene and/or gene-by-environment interactions.
Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors
predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes–susceptibility genes identified a
common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive
association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous
for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not
inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.
Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10(-12). In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10(-22)) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.
Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex but also within other loci. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.
Although the literature concerning statistical testing for genotype-phenotype association in family-based and population-based studies is very extensive, until recently the sex chromosomes have received little attention. Here it is shown that the X chromosome in particular presents special problems with respect to efficient analysis of mixed-sex population studies, and as a result of X inactivation. This paper reviews recent developments in approaching these problems.
The term interaction has two specific meanings in epidemiology. The first definition is purely a statistical one. Interaction is defined as the coefficient of the product term of two or more risk factors. An alternative definition is a more biologically oriented one in which interaction between two risk factors is defined as their coparticipation in the same causal mechanism of disease development. There are at least five different types of biological gene by environment interaction. It is important to recognize that clinical or epidemiological studies alone are unable to distinguish between these five different types of biological interaction. Asthma is a prototypical complex trait in which gene by environment interaction is important in disease causation. Environmental factors important in asthma include cigarette smoking (active/passive), allergen exposure, viral and bacterial respiratory illness, occupation, and possibly diet. There are two primary study designs that have been utilized for the assessment of gene by environment interaction: a traditional case control study or a nested case control study or a case control study nested within the larger longitudinal cohort. There are three important methodological issues in the assessment of gene by environment interaction. The first is the issue of misspecification of either genotype or environmental exposure or, for that matter, disease status. The second is possible confounding, and the third is the confounding of interaction with dose response. The four most critical factors for determining sample size for gene by environment interaction studies are the odds ratio for the interaction, the prevalence for exposure in the population, the prevalence of the genotype in the population, and the case to control ratio. In general, sample sizes have been too small to detect meaningful gene by environment interactions.
Exploration of the human genome presents new challenges and opportunities for epidemiological research. Although the case-control design is quicker and cheaper for study of associations between genotype and risk of disease than the cohort design, cohort studies have been recommended because they can be used to study gene-environment interactions. Although the scientific relevance of statistical interaction is pertinent, the main disadvantage of the case-control design-susceptibility to bias when estimating effects of exposures that are measured retrospectively-does not necessarily apply when studying statistical interaction between genotype and environmental exposure. Because correctly designed genetic association studies are equivalent to randomised comparisons between genotypes, conclusions about cause can be drawn from genetic associations even when the risk ratio is modest. For adequate statistical power to detect such modest risk ratios, the case-control design is more feasible than the cohort design.
Consideration of gene-environment (GxE) interaction is becoming increasingly important in the design of new epidemiologic studies. We present a method for computing required sample size or power to detect GxE interaction in the context of three specific designs: the standard matched case-control; the case-sibling, and the case-parent designs. The method is based on computation of the expected value of the likelihood ratio test statistic, assuming that the data will be analysed using conditional logistic regression. Comparisons of required sample sizes indicate that the family-based designs (case-sibling and case-parent) generally require fewer matched sets than the case-control design to achieve the same power for detecting a GxE interaction. The case-sibling design is most efficient when studying a dominant gene, while the case-parent design is preferred for a recessive gene. Methods are also presented for computing sample size when matched sets are obtained from a stratified population, for example, when the population consists of multiple ethnic groups. A software program that implements the method is freely available, and may be downloaded from the website http://hydra.usc.edu/gxe.
Advances in human genetics could help us to assess prognosis on an individual basis and to optimise the management of complex diseases. However, different studies on the same genetic association sometimes have discrepant results. Our aim was to assess how often large studies arrive at different conclusions than smaller studies, and whether this situation arises more frequently when findings of first published studies disagree with those of subsequent research.
We examined the results of 55 meta-analyses (579 study comparisons) of genetic associations and tested whether the magnitude of the genetic effect differs in large versus smaller studies.
We noted significant between-study heterogeneity in 26 (47%) meta-analyses. The magnitude of the genetic effect differed significantly in large versus smaller studies in ten (18%), 20 (36%), and 21 (38%) meta-analyses with tests of rank correlation, regression on SE, and regression on inverse of variance, respectively. The largest studies generally yielded more conservative results than the complete meta-analyses, which included all studies (p=0.005). In 14 (26%) meta-analyses the proposed association was significantly stronger in the first studies than in subsequent research. Only in nine (16%) meta-analyses was the genetic association significant and replicated without hints of heterogeneity or bias. There was little concordance in first versus subsequent discrepancies, and large versus small discrepancies.
Genuine heterogeneity and bias could affect the results of genetic association studies. Genetic risk factors for complex diseases should be assessed cautiously and, if possible, using large scale evidence.
The search for biologically relevant gene-environment interactions has been facilitated by technological advances in genotyping. The design of studies to detect interactions on continuous traits such as blood pressure and insulin sensitivity is attracting increasing attention. We have previously described power calculations for such studies, and this paper describes the extension of those calculations to take account of measurement error.
The model considered in this paper is a simple linear regression relating a continuous outcome to a continuously distributed exposure variable in which the ratio of slopes for each genotype is considered as the interaction parameter. The classical measurement error model is used to describe the uncertainty in measurement in the outcome and the exposure. The sample size to detect differing magnitudes of interaction with varying frequencies of the minor allele are calculated for a given main effect observed with error both in the exposure and the outcome. The sample size to detect a given interaction for a given minor allele frequency is calculated for differing degrees of measurement error in the assessment of the exposure and the outcome.
The required sample size is dependent upon the magnitude of the interaction, the allele frequency and the strength of the association in those with the common allele. As an example, we take the situation in which the effect size in those with the common allele was a quarter of a standard deviation change in the outcome for a standard deviation change in the exposure. If a minor allele with a frequency of 20% leads to a doubling of that effect size, then the sample size is highly dependent upon the precision with which the exposure and outcome are measured. rho(Tx) and rho(Ty) are the correlation between the measured exposure and outcome, respectively and the true value. If poor measures of the exposure and outcome are used, (e.g. rho(Tx) = 0.3, rho(Ty) = 0.4), then a study size of 150 989 people would be required to detect the interaction with 95% power at a significance level of 10(-4). Such an interaction could be detected in study samples of under 10 000 people if more precise measurements of exposure and outcome were made (e.g. rho(Tx) = 0.7, rho(Ty) = 0.7), and possibly in samples of under 5000 if the precision of estimation were enhanced by taking repeated measurements.
The formulae for calculating the sample size required to study the interaction between a continuous exposure and a genetic factor on a continuous outcome variable in the face of measurement error will be of considerable utility in designing studies with appropriate power. These calculations suggest that smaller studies with repeated and more precise measurement of the exposure and outcome will be as powerful as studies even 20 times bigger, which necessarily employ less precise measures because of their size. Even though the cost of genotyping is falling, the magnitude of the effect of measurement error on the power to detect interaction on continuous traits suggests that investment in studies with better measurement may be a more appropriate strategy than attempting to deal with error by increasing sample sizes.
Exposure to furred pets might confer protection against the development of allergic sensitization through a mechanism that is incompletely understood.
The objective of this study was to determine the effects of pet exposure and genotype on immunologic development and the incidence of atopic markers and diseases in the first year of life.
Pet exposure in the home was compared with cytokine secretion patterns (mitogen-stimulated mononuclear cells at birth and age 1 year) and indicators of atopy (allergen-specific and total IgE, eosinophilia, food allergy, atopic dermatitis) in 285 infants. Interactions with genotype at the CD14 locus were also evaluated in the data analyses.
Exposure to dogs was associated with reduced allergen sensitization (19% vs 33%, P =.020) and atopic dermatitis (30% vs 51%, P <.001). The risk for atopic dermatitis was further influenced by genotype at the CD14 locus (P =.006), even after adjusting for exposure to dogs (P =.003). Furthermore, infants with the genotype -159TT were less likely to develop atopic dermatitis if they were exposed to a dog (5% vs 43%, P =.04). Last, dog exposure was associated with increased IL-10 (117 vs 79 pg/mL, P =.002) and IL-13 (280 vs 226 pg/mL, P =.013) responses at age 1 year.
Having a dog in infancy is associated with higher IL-10 and IL-13 cytokine secretion profiles and reduced allergic sensitization and atopic dermatitis. These findings suggest that postnatal exposure to dogs can influence immune development in a genotype-specific fashion and thereby attenuate the development of atopy in at-risk children.
Increasing evidence suggests that the interactions between genes and environment might play a critical role in the pathogenesis of complex diseases, such as asthma, that exhibit a heritable component but do not follow Mendel's laws. Gene-environment interactions are extremely complex and not linear, such that the same genetic variants might be associated with opposite phenotypes in different environments. This is particularly evident for innate immunity genes, which operate at the interface between the immune system and the pathogen world. This article examines gene-environment interactions by using CD14 as a model and argues that the conflicting results of epidemiologic studies on CD14*C-159T result from differences in environmental conditions essential to modulate CD14 gene expression. Furthermore, on the basis of how rapidly environmental changes have affected the incidence of immune diseases, I argue that a full understanding of gene-environment interactions requires that epigenetic as well as classical genetic mechanisms be taken into account. Recent data about the effect of diet on gene methylation and the release of hidden genetic variation by impairment of heat shock protein 90-mediated buffering systems offer eloquent examples of how epigenetic mechanisms might affect gene-environment interactions.
A recent family-based genomewide screen revealed linkage between the 5q31 region and the diagnosis of asthma, but only in those exposed to environmental tobacco smoke (ETS). Among the candidate genes in this region is CD14.
To determine whether polymorphisms in the CD14 gene are related to this gene-by-environment interaction in Latinos, we used both family-based and cross-sectional cohort analysis to test for interactions between CD14 genotypes/haplotypes, exposure to ETS, and asthma-related phenotypes in 659 Mexican and Puerto Rican families.
We identified 21 single nucleotide polymorphisms (SNPs) in the CD14 gene by sequencing 72 Puerto Ricans, Mexicans, and African Americans with asthma. Three SNPs, -810, -159, and +1437, were further genotyped in families with asthma. Among all subjects with asthma exposed to ETS, without regard to ethnicity, CD14 +1437 genotypes were associated with asthma severity. SNP +1437 GG or GC genotypes were significantly associated with lower baseline FEV1 using both family-based (p = 0.0009) and cross-sectional cohort (p = 0.03) analyses. Subjects with asthma with the GG or GC genotypes who were exposed to ETS had mean baseline FEV1 (% predicted) values 8.6% lower than subjects not exposed to ETS (p = 0.03). As previously observed in whites, we found an interaction between plasma IgE levels, SNP -159 genotypes, and ETS exposure (p = 0.0002). The lowest IgE levels were in those subjects with the TT genotype and who were exposed to ETS regardless of ethnicity.
Our data suggest a gene-by-environment interaction between CD14 genotypes and ETS, which affects pulmonary function and IgE levels among Latinos with asthma.
Most complex diseases are the result of interactions between polymorphisms in the genome and environmental exposures.
We sought to investigate the previously reported association between a polymorphism in the promoter region of CD 14 (CD 14/-260 C-->T) and serum IgE levels in relation to the environment to which children are exposed.
In 624 children living in 2 rural communities in Europe, we compared total and specific serum IgE levels between the genotypes of CD 14/-260 in relation to exposure to animals and in relation to house dust endotoxin.
We found that the C allele of CD 14/-260 was associated with higher levels of both total and specific serum IgE to aeroallergens in children with regular contact with pets, whereas an association in the opposite direction was found in children with regular contact with stable animals. This modifying effect of animal exposure was not explained by levels of house dust endotoxin. However, in children with high levels of house dust endotoxin, the C allele was associated with less specific IgE, independently from animal exposure.
Because CD 14 is a pattern recognition receptor for microbial molecules, the results suggest that the type and concentrations of such molecules present in the environment strongly determine the direction of the association between CD 14/-260 and serum markers of atopy.
We review the rationale behind and discuss methods of design and analysis of genetic association studies. There are similarities between genetic association studies and classic epidemiological studies of environmental risk factors but there are also issues that are specific to studies of genetic risk factors such as the use of particular family-based designs, the need to account for different underlying genetic mechanisms, and the effect of population history. Association differs from linkage (covered elsewhere in this series) in that the alleles of interest will be the same across the whole population. As with other types of genetic epidemiological study, issues of design, statistical analysis, and interpretation are very important.
Asthma is a chronic inflammatory disease of the airways that is highly prevalent in the Western world. It is a genetically complex disease caused by multiple genetic and environmental factors, which may interact. Genetic research has recently incorporated environmental factors to investigate gene by environment interaction, and the first examples of gene by environment interaction in asthma have been reported. Linkage analyses indicate that one or more genes on chromosome 5q interact with environmental tobacco smoke in infancy in asthma development. Several candidate genes have been consistently shown to interact with the environment. These include the innate immunity genes CD14 and Toll-like receptor 4, and microbial exposures, as well as the detoxifying gene family glutathione-S-transferase and environmental tobacco smoke exposure and air pollutants. Gene by environment interaction is important in asthma pathogenesis, and future studies should take the interaction of both factors into account.
A large number of studies have consistently shown that growing up on a farm in various rural areas in Europe confers protection from the development of hay fever, atopic sensitization, and less consistently of asthma from childhood into young adulthood. Exposures to livestock as well as consumption of unpasteurized milk are likely to be distinct and relevant sources of protective exposures. In turn, the underlying microbial exposures have not been identified with certainty. Although environmental exposures to bacterial and fungal components have been found to be inversely related to asthma and atopy, they do not explain the "farming effect." The mechanisms conveying the protection are still poorly understood. An important role for innate immune responses is suggested by findings relating to increased expression of genes of Toll-like receptors in exposed children. How this activation of innate immunity is translated into reduced IgE-specific adaptive immune responses remains to be elucidated, but may invoke a number of distinct allergen-specific steps.
Consumption of farm milk in early life is associated with less asthma and allergies.
We hypothesized that genetic variation in the innate immunity receptor CD14 might modify the association between farm milk consumption and asthma and atopy.
Questionnaire data, serum IgE levels, and genotypes for 4 single nucleotide polymorphisms in CD14 were assessed in farmers' and nonfarmers' children from 2 European populations (Allergy and Endotoxin study, n = 576; Prevention of Allergy Risk factors for Sensitization in children related to Farming and Anthroposophic Lifestyle study, n = 1539). In a subsample (n = 222) CD14 gene expression was measured in peripheral blood leukocytes. The effects of farm milk and CD14 genotypes on asthma, allergies, and CD14 expression and their interactions were investigated.
We found a significant interaction between genetic variation in CD14/-1721 and farm milk consumption. Adjusted odds ratios for the association between farm milk and asthma varied between the genotypes: AA, 0.18 (95% CI, 0.07-0.47); AG, 0.47 (95% CI, 0.26-0.86); and GG, 0.98 (95% CI, 0.46-2.08). Similar patterns were observed for symptoms of allergic rhinoconjunctivitis and pollen sensitization. CD14/-1721 also modified the association between farm milk and CD14 gene expression (adjusted geometric means ratios: AA, 1.61 (95% CI, 0.98-2.66); AG, 1.11 (95% CI, 0.71-1.72); and GG, 0.76 (95% CI, 0.39-1.48).
The protective effect of farm milk consumption on allergic diseases is stronger in children carrying the A allele in CD14/-1721 than in children homozygous for the G allele. This might be mediated through farm milk-induced upregulated CD14 gene expression.
Our results support the hypothesis that the inverse association between farm milk consumption and allergic diseases is mediated by CD14-activated innate immune mechanisms.
Contopoulos-Ioannidis DG. Ge-netic associations in large versus small studies: an empirical assessment
- Trikalinos Ta Ntzani
- Ee
Ioannidis JP, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG. Ge-netic associations in large versus small studies: an empirical assessment. Lancet 2003;361:567-71.
A polymorphism in CD14 modified the effect of farm milk con-sumption on allergic disease and CD14 gene expression
- C Bieli
- W Eder
- M Frei
- Braun
- C Fahrlander
- W Klimecki
- M Waser
Bieli C, Eder W, Frei M, Braun-Fahrlander C, Klimecki W, Waser M, et al. A polymorphism in CD14 modified the effect of farm milk con-sumption on allergic disease and CD14 gene expression. J Allergy Clin Immunol 2007; Oct 8 [epub ahead of print].