Brief Report: Association of CCR1, KLRC4, IL12A–AS1, STAT4, and ERAP1 With Behçet's Disease in Iranians

Abstract

Objective. To independently replicate the top findings from 4 published genome-wide association studies (GWAS) of susceptibility genes in Behçet's disease (BD).Methods. We tested 14 single-nucleotide polymorphisms (SNPs) in 13 genomic loci (excluding the major histocompatibility complex [MHC], IL10, and IL23R-IL12RB2, which have already been associated with BD in Iranians) for allelic and genotypic associations with BD in 973 patients and 828 controls from Iran and performed meta-analyses of the significantly associated markers.Results. Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [p.Asn104Ser] in KLRC4, rs17810546 in IL12A-AS1, rs7574070 in STAT4, and rs10050860 [p.Asp575Asn] and rs13154629 in ERAP1) were nominally associated with BD in both allelic association tests (5.05 3 10 29 £ P allele £ 7.55 3 10 23 ) and sex-adjusted genotypic association tests (6.01 3 10 29 £ adjusted P value £ 1.30 3 10 22 ). For all 6 SNPs tested by meta-analysis (P meta ), the association with BD was strengthened, because the direction and magnitude of association were similar across populations (e.g., for rs7574070, odds ratio [OR] Conclusion. This study reinforces the notion that CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 are bona fide susceptibility genes for BD, in addition to the MHC, IL10, and IL23R-IL12RB2 loci. Future genetic and functional studies are now warranted to uncover the roles of these genes in the pathogenesis of BD.Behçet's disease (BD) is a chronic multisystem vasculitis involving several organs, such as the skin, mucocutaneous membranes (oral and genital aphthae), eyes, joints, lungs, and the gastrointestinal and central nervous systems (1). Although the etiology and pathogenesis of BD remain unclear, the mechanism of BD is thought to be complex, with multiple genetic and environmental factors contributing to the clinical manifestations. Genome-wide association studies (GWAS) are currently the preferred method used to identify novel genetic risk variants, and the results of such studies have provided new insights into the biologic and genetic bases of many complex disorders. The use of association strategies at the whole-genome level led to the discovery of causal loci for numerous disorders.GWAS in patients with BD have been performed in Turkish, Japanese, Korean, Chinese, and Iranian populations (2-8). With the exception of the major histocompatibility complex (MHC), IL10, IL23R-IL12RB2, and STAT4 loci (3-6), these GWAS did not replicate the top findings of each other, which reinforces the need for well-powered independent replication studies in other populations to distinguish true universal association signals from population-specific associations. Therefore, we conducted a replication study of previous top GWAS Supported by the Portuguese Fundação para a Ciência e a Tecnologia (grants PTDC/SAU-GMG/098937

Behçet’s syndrome: focus on pathogenetic background, clinical phenotypes and specific treatments

“…In addition, the risk hypothetically attributable to the genetic component of the disease was estimated, showing that AA genotype has a large effect on the disease risk. In comparison to other populations [8,10,[16][17][18], in the Italian cohort, the association between rs17482078 and BS susceptibility was weaker. No genotypic correlations, neither 1 3 functional effects were found for the rs27044 G polymorphism in the Italian population.…”

A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet's disease in HLA-B*51 carriers

“…Individual variants encoding these haplotype tagging SNPs, Met349Val (rs2287987), Asp575Asn (rs10050860) and Arg725Gln (rs17482078), were previously reported recessively associated with Behçet's disease in Turkish3 and Iranian13 studies. Their genotype frequencies were also consistent with recessive association in the Spanish and Chinese populations, but did not reach statistical significance 5 14…”

Genetics of Behçet’s Disease

“…Killer cell lectin-like receptor subfamily C, member 4 (KLRC4) is a member of NKG2 receptor family that regulates NK cell function. The association of the KLRC4 gene and BD was first suggested in the GWAS of Turkish and Japanese cohorts [36], and then replicated in the independent study of an Iranian cohort [103].…”

“…The Several SNPs at CCR1-CCR3 locus were associated with BD including rs7616215 in Turkish [40] and rs13084057, rs13092160 and rs13075270 in Chinese Cohorts [102]. In addition, the CCR1 gene was individually associated with BD in multiple cohorts including Turkish, Japanese, and Iranian cohorts [36,103]. Functional studies indicated that CCR1 gene expression in primary human monocytes carrying the BD-risk allele was reduced along with a weaker activity of monocyte chemotaxis [36].…”