Behçet's disease is an inflammatory disease characterized by recurrent oral and genital ulcers and significant organ involvement. Localizing the genetic association between HLA-B*51 and Behçet's disease and exploring additional susceptibility loci in the human leukocyte antigen (HLA) region are complicated by the strong linkage disequilibrium in this region. We genotyped 8,572 variants in the extended HLA locus and carried out imputation and meta-analysis of 24,834 variants in 2 independent Behçet's disease cohorts from 2 ancestry groups. Genotyped SNPs were used to infer classical HLA alleles in the HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1 and HLA-DRB1 loci. Our data suggest that the robust HLA-B*51 association in Behçet's disease is explained by a variant located between the HLA-B and MICA genes (rs116799036: odds ratio (OR) = 3.88, P = 9.42 × 10(-50)). Three additional independent genetic associations within PSORS1C1 (rs12525170: OR = 3.01, P = 3.01 × 10(-26)), upstream of HLA-F-AS1 (rs114854070: OR = 1.95, P = 7.84 × 10(-14)) and with HLA-Cw*1602 (OR = 5.38, P = 6.07 × 10(-18)) were also identified and replicated.
Objectives
Using a genome-wide association scan and DNA pooling, we previously identified 5 novel genetic susceptibility loci for Behçet’s disease. Herein, we establish the genetic effect within the UBAC2 gene, replicate this genetic association, and identify a functional variant within this locus.
Methods
A total of 676 Behçet’s disease patients and 1,096 controls were studied. The discovery set included 156 patients and 167 controls from Turkey, and the replication sets included 376 patients and 369 controls, and 144 patients and 560 controls, from Turkey and Italy, respectively. Genotyping of 14 SNPs within and around UBAC2 was performed using TaqMan SNP genotyping assays.
Results
The genetic association between Behçet’s disease and UBAC2 was established, replicated and confirmed (Meta-analysis OR= 1.84, meta-analysis P= 1.69X10−7). Haplotype analysis identified both a disease risk and a protective haplotype (P= 0.00014 and 0.0075, respectively). Using conditional haplotype analysis we identified the SNP rs7999348 (A/G) within UBAC2 as the most likely SNP with a genetic effect independent of the haplotypic effect formed by the remaining associated SNPs in this locus. Indeed, we demonstrate that rs7999348 tags a functional variant associated with increased mRNA expression of a UBAC2 transcript variant in PBMCs of individuals homozygous for the Behçet’s disease-associated “G” allele. Further, our data suggest the possibility of multiple genetic effects that increase susceptibility to Behçet’s disease in the UBAC2 locus.
Conclusion
We established and confirmed the genetic association between UBAC2 and Behçet’s disease in three independent sets of patients and controls. We identified the minor allele in rs7999348 as a disease-risk allele that tags altered UBAC2 expression.
Objective
Behçet’s disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet’s disease in a diverse multiethnic population.
Methods
A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray‐24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed.
Results
We identified 2 novel genetic susceptibility loci for Behçet’s disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10−9) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10−8). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide‐stimulated monocytes. In addition, our results replicated the association (P < 5 × 10−8) of 6 previously identified susceptibility loci in Behçet’s disease: IL10, IL23R, IL12A‐AS1, CCR3, ADO, and LACC1, reinforcing the notion that these loci are strong genetic factors in Behçet’s disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (P < 5 × 10−5), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet’s disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated.
Conclusion
We performed the largest genetic association study in Behçet’s disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries.
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