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Manhattan plot for STAT4 locus. All imputed (solid red circles) and genome-wide association study (GWAS)-genotyped (open blue circles) SNPs are plotted together with a linkage disequilibrium structure below
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Background
Behçet’s disease (BD) susceptibility had been associated with single-nucleotide polymorphisms (SNPs) in IL23R–IL12RB2, IL10, STAT4, or ERAP1 locus in Japanese, Turkish, Chinese, and other populations, but not in a Korean genome-wide association study (GWAS). We aimed to fine-map BD risk association of these four loci using extensive impu...
Context in source publication
Context 1
... the STAT4 locus ranging from − 4.7 kb to + 9.4 kb, 25 SNPs had been genotyped [11] and 239 SNPs were imputed, but no SNPs were associated with BD risk in this Korean population (Fig. 3). In the ERAP1-ERAP2 locus ranging from − 14.0 kb of ERAP1 to + 112.0 kb of ERAP2, 43 SNPs had been genotyped [11] and 847 SNPs were imputed but no SNPs were associated (Fig. ...
Citations
... T-cell subsets (Th1 and Th17) were found to be higher in the peripheral blood of patients with BD than in healthy controls, suggesting an important role in the etiopathogenesis of BD (10,11). The role of the JAK/STAT pathway in BD predisposition is still unknown, as there are few and partially contradictory data in the literature (11)(12)(13)(14). ...
Behçet's disease (BD) is a chronic, multisystemic inflammatory disorder with an unknown etiology. T cells are crucial in the pathogenesis of BD. Janus kinase-2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) are intracellular signal transduction molecules that increase the risk of developing some autoimmune diseases. By modifying Th1 and Th17 responses, the JAK2 and STAT3 signaling pathways are believed to be effective in BD. This study aimed to determine whether BD in the Turkish population is related to JAK2 and STAT3 polymorphisms. Methods: A case-control study included a total of 197 patients with BD who were referred to the Ankara University Faculty of Medicine and 100 healthy individuals without a history of autoimmune disease or BD in their family or themselves. The genotypes of one single-nucleotide polymorphism (SNPs) (rs10974944) in JAK2 and one SNPs (rs2293152) in the STAT3 gene were analyzed using polymerase chain reaction restriction fragment length polymorphism. Results: The result of this investigation identified that in this disease, there was a significantly increased frequency of the CG genotype of the rs10974944 JAK2 in patients with BD compared with a control group (p=0.031, odds ratio [95% confidence interval: 0.392 (0.163-0.942)]. None of the tested SNPs (rs2293152) of STAT3 were associated with BD. Conclusion. This is the first investigation into JAK2 and STAT3 polymorphisms in Turkish patients with BD. These results suggest that a JAK2 genetic polymorphism may be associated with BD susceptibility.
... Accordingly, the interaction analyses according to haplotypes instead of SNPs were executed, and results implicated Hap10, which covers rs10050860, rs27044, rs17482078, rs30187 and rs2287987, as susceptible genes for the inclination of BD, which underlined the importance of haplotypes in BD risk (19). By comparison, nothing of any substantial contribution was derived in the Korean undertaking dealing with 43 ERAP1 SNPs comprised of rs10050860 and rs17482078 (20). However, the situation soon appeared a turning point again. ...
Objectives:
Substantial evidence has highlighted the mediation of endoplasmic reticulum aminopeptidase 1 (ERAP1) in the onset of Behçet's disease (BD), which can be differentially converted by ERAP1 variants. To comprehensively elaborate this issue, we undertook the meta-analysis to estimate the liaison of ERAP1 polymorphisms with BD risk.
Methods:
Literatures were retrieved in a standardised fashion and data underwent multi-perspective analyses utilizing STATA Statistical Software. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) of manifold comparisons between BD sufferers and healthy masses were exploited to evaluate the extent of relevance.
Results:
Overall analyses suggested that the meanings of ERAP1 polymorphisms in BD susceptibility varied among plentiful variations, where rs10050860, rs17482078, rs2287987, rs1065407 and rs72773968 presented pathogenic influence and rs26618 acted out beneficial function, while rs27044, rs26653, rs27895 and rs3734016 had no pronounced biological significance. Additionally, the effect of rs30187 is not yet determined. Moreover, race appeared a crucial ingredient as Mongolian were more susceptible to suffering from BD than Caucasian, while the diagnostic criteria of BD exerted a relative inconspicuous role, where the International Study Group criteria slightly attenuated the pathogenicity of ERAP1 polymorphisms compared with the International Criteria for Behçet's Disease. Finally, an exceeding importance was attached to the proceeding analysis based on disparities in BD symptoms, ERAP1 haplotypes and HLA-B*51 in computing the hazard zonation of ERAP1 polymorphisms on BD tendency.
Conclusions:
The present meta-analysis prompted the heterogeneous influences of ERAP1 polymorphisms on BD development, which were malleable under the discrepancies in genetic grounds and disease diagnoses.
... A meta-analysis of the association data (including a total of 2430 BD cases and 2660 controls) provided strong evidence for associations of the IL23R/IL12RB2 loci with BD [55]. The IL-23R/IL-12RB2 genes were associated with BD, in multiple reports with different populations including Japanese, Chinese, and Korean [56][57][58]. ...
Behçet’s disease (BD; MIM 109650) is an autoinflammatory disease characterized by with recurrent oral aphthae, genital ulcers and vasculitis involving the skin, joints, eyes, veins, arteries, nervous and gastrointestinal systems. Although the pathogenesis remains uncertain, genome-wide and validation studies have demonstrated that genetic predisposition is a major factor in disease susceptibility. Several gene polymorphisms that are involved in the response to pathogens and modulate inflammation have been associated with the pathophysiology of BD. Understanding the genetic association with BD may ensure insight into the pathogenesis and for development of targeted therapies for this autoinflammatory disease. This chapter will deal the role of genetic and epigenetic factors as contributing factors in the pathogenesis of BD.
... reproduced the association of BD and IL-23R-IL-12RB2 in the Korean population but not between BD and IL-10 or ERAP1 [39,40]. Notably, the GIMAP cluster, which is involved in T-cell survival, was identified as a novel susceptibility loci for Korean BD, thus suggesting that aberration of the T-cell response may contribute to the development of Korean BD. ...
... Given this finding, the role of HLA-A in the immunopathogenesis of Korean BD should be further studied and elucidated. Studies on genetic predisposition of BD in Korean population is summarized in Table 2 [39,40,42,43,[45][46][47][48][49]. ...
Behçet's disease (BD) is a multisystem disease in which environmental factors provoke an adverse immune response in patients with genetic susceptibility towards BD, subsequently leading to a cascade of dysregulated inflammation throughout the body. It is particularly prevalent in regions spanning the ancient Silk Road, including Korea, where the first known case of BD was reported in 1961. We summarize the history, epidemiology, and clinical presentation of BD in Korea, highlighting the clinical tendencies that are particularly seen in the Korean BD population as compared to European populations. Analysis of epidemiologic trends over the past three decades in Korea shows a decreasing prevalence of complete BD and a higher prevalence of intestinal BD. We also discuss the ever-evolving understanding of the pathogenesis of BD, noting the complex interplay among genetics, environment, and immunology. The HLA-B51 allele is the most significant known genetic risk factor in developing BD. We also discuss more recently studied associations between BD and immune factors such as IL-10, IL-23R-IL-12RB2, IL-1A-IL-1B, CCR1, ERAP1, and the GIMAP cluster, the last of which has been found to have an association with BD specifically in Korea. Environmental factors such as pollution and microbials are often the inciting event in developing BD, as they trigger an imbalanced immune response in genetically susceptible individuals, one that has been often found to exhibit an aberrant Th1/Th17 response. There would be value to further studying the pathogenesis and clinical characteristics of Korean BD.
... In fact, several BS susceptibility loci were highlighted outside the HLA in genome wide association studies (GWASs). Non-HLA variations have also been investigated and their association with BS has been demonstrated for several genes, such as Endoplasmic reticulum aminopeptidase 1 (ERAP1), Interleukin 10 (IL10), IL-23 receptor-IL-12 receptor β2 (IL23R-IL12RB2), Signal transducer and activator of transcription 4 (STAT4), C-C Motif Chemokine Receptor 1 (CCR1), Killer Cell Lectin Like Receptor C4 (KLRC4), Ubiquitin-associated domaincontaining protein 2 (UBAC2), Toll-like receptor 4 (TLR4), Mediterranean fever (MEFV), and Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) genes (Kirino et al. 2013;Conde-Jaldon et al. 2014;Gul 2014Gul , 2015Ombrello et al. 2015;Sousa et al. 2015;Takeuchi et al. 2015Takeuchi et al. , 2016Burillo-Sanz et al. 2017;Jung et al. 2017;Kang et al. 2017;Wang et al. 2017;Deng et al. 2018;Padula et al. 2018Padula et al. , 2019aPadula et al. , 2019b. ...
Behçet syndrome (BS) is a vasculitis characterized by several clinical manifestations including the rare neurological involvement (neuro-BS, NBS). The aim of our pivotal study was to investigate the mutational status of several inflammation-related genes in a cohort of Italian patients with and without the neurological involvement (20 NBS vs 40 no-NBS patients). The preliminary in silico single nucleotide polymorphism (SNP) selection and primer design were performed by NCBI Primer-Blast tool. Genomic DNA was isolated and amplified using PCR. PCR amplicons were sequenced and bioinformatically analysed. Twelve tagSNPs were selected and genotyped: ERAP1 rs30187, rs17482078, and rs27044; IL10 rs1800872 and rs1518111, IL12A rs17810546, IL23R rs17375018, IL23R-IL12RB2 rs924080, STAT4 rs7572482, CCR1 rs7616215, KLRC4 rs2617170, and UBAC2 rs3825427. ERAP1 and IL23R SNPs showed statistically significant higher frequencies in NBS group than no-NBS. ERAP1 rs30187 AA was more common in no-NBS patients (20.0% NBS vs 47.5% no-NBS; p < 0.05), while rs17482078 GA frequency was higher in NBS patients (55.0% NBS vs 22.5% no-NBS; p < 0.05, OR: 4.21). IL23R rs17375018 GG was more frequent in NBS group (65.0% NBS vs 40.0% no-NBS; p < 0.05), according to a previous finding. No other statistically significant differences were found. In conclusion, ERAP1 and IL23R SNPs were found associated with neurological involvement of BS. Additional and larger analyses were required to verify our preliminary findings.
... Meta-analysis of both data sets further identified rs1495965 as associated with BD (33, 34). These associations have been supported in several other studies in different patient cohorts (35)(36)(37)(38)(39). These mutations have been linked to enhanced expression of IL-23R and potential upregulation of the IL-17 pathway. ...
Behçet’s disease (BD) is a multisystem autoinflammatory condition characterized by mucosal ulceration, breakdown of immune privilege sites and vasculitis. A genetic basis for BD has been described in genome-wide and validation studies. Similarly, dysbiosis of oral and gut microbiomes have been associated with BD. This review will describe links between genetic polymorphisms in genes encoding molecules involved in gut biology and changes seen in microbiome studies. A potential decrease in bacterial species producing short chain fatty acids linked to mutations in genes involved in their production suggests a potential therapy for BD.
... These two SNPs have been shown to be in moderate LD and may predict the same functional variant in both Turkish and Japanese populations. In a study by Kang et al. it was shown that three intergenic SNPs rs1495965, rs4655535, and rs1495966 located in IL23R-IL12RB2 locus was significantly associated with BD risk in the pooled meta-analysis of the discovery and replication phases in the Korean population [83]. ...
Behçet's disease (BD) is a systemic and inflammatory disease, characterized mainly by recurrent oral and genital ulcers, eye involvement, and skin lesions. Although the exact etiopathogenesis of BD remains unrevealed, a bulk of studies have implicated the genetic contributing factors as critical players in disease predisposition. In countries along the Silk Road, human leukocyte antigen (HLA)-B51 has been reported as the strongest genetically associated factor for BD. Genome-wide association studies, local genetic polymorphism studies, and meta-analysis of combined data from Turkish, Iranian, and Japanese populations have also identified new genetic associations with BD. Among these, other HLA alleles such as HLA-B*15, HLA-B*27, HLA-B*57, and HLA-A*26 have been found as independent risk factors for BD, whereas HLA-B*49 and HLA-A*03 are independent protective alleles for BD. Moreover, other genes have also reached the genome-wide significance level of association with BD susceptibility, including IL10, IL23R-IL12RB2, IL12A, CCR1-CCR3, STAT4, TNFAIP3, ERAP1, KLRC4, and FUT2. Also, several rare nonsynonymous variants in TLR4, IL23R, NOD2, and MEFV genes have been reported to be involved in BD pathogenesis. According to genetic determinants in the loci outside the MHC region that are contributed to the host defense, immunity, and inflammation pathways, it is suggested that immune responses to the pathogen as an important environmental factor and mucosal immunity contribute to BD susceptibility.
... Bugüne kadar BH genetik yatkınlığı ile ilgili birçok genom boyu ilişkilendirme (GWAS) çalışmaları yapılmıştır. Bu çalışmalarda Japon, Türk, Çin ve diğer topluluklarda, BH ile IL23R-IL12RB2, IL10 ve STAT4 gibi lokuslarda yer alan SNP'ler ilişkilendirilmiştir (5,6,7,8). ...
... A significant association (reaching a GWAS p value) of the IL-23R gene with BD was found at the SNP rs11209026 (Gly149Arg) in Japanese, and at the SNP rs76418789 (Arg381Gln) in Turkish cohort [61]. The association between BD and the IL-23R/IL-12RB2 genes appeared to be consistent in multiple reports with different populations including Turkey [52], Japanese [53], Han Chinese [62, 63], Iranian [64], Western Algeria [65], and Korean [66]. ...
... The associations of the TLR4 gene with BD are conflict in different reports. It was found in Japanese [91], Korea [92] and Turkish cohorts [66], but not in Italian [93], Tunisian [94], and Chinese cohorts [95]. Of note, two BD protective TLR4 variants identified in the Turkish cohort, p.Asp299Gly (rs4986790) and p.Thr399Ile (rs4986791) were associated with hyporesponsiveness to endotoxin [96]. ...
... Recently, several different genetic studies have also identified non-HLA variants with biological meaning (e.g., IL10, IL23RIL12RB2) [10,11]. A GWAS has recently shown that the Endoplasmic Reticulum Aminopeptidase Protein 1 (ERAP1) gene is associated with BS, and that ERAP1 is epistatic with HLA-B*51 allele [11]. ...
... Recently, several different genetic studies have also identified non-HLA variants with biological meaning (e.g., IL10, IL23RIL12RB2) [10,11]. A GWAS has recently shown that the Endoplasmic Reticulum Aminopeptidase Protein 1 (ERAP1) gene is associated with BS, and that ERAP1 is epistatic with HLA-B*51 allele [11]. Interestingly, ERAP1 encodes for a molecule in the endoplasmic reticulum that cuts the N-terminal amino acids from epitope precursors for HLA class I presentation [10,12,13]. ...
