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Masaki Takeuchi, Nobuhisa Mizuki, Akira Meguro, Michael Ombrello, Ilknur Tugal-tutkun, Yilmaz Ozyazgan, Shigeaki Ohno, Ahmet Gul, Daniel L Kastner, Elaine F Remmers; Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet’s disease susceptibility. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6573.
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© ARVO (1962-2015); The Authors (2016-present)
Behçet’s disease is a systemic vasculitis that manifests with oral ulcers, uveitis, skin inflammation, genital ulcers, and inflammation in other organs. Although HLA-B*51, IL10, IL23R-IL12RB2, CCR1, STAT4, KLRC4, ERAP1, MEFV, IL12A, and FUT2 have been reported to be susceptibility genes in previous studies, the pathogenesis of BD remains unclear. The purpose of this study was to densely genotype loci associated with immune-related diseases to identify novel susceptibility loci for Behçet’s disease.
In this study, 1,900 Turkish Behçet’s disease patients and 1,779 controls were genotyped using the Immunochip. After strict quality control, we performed association tests. For novel loci with association test P<5×10-5, additional SNPs in the region were imputed using 1000 Genomes Project data as a reference. We also replicated the disease association with genotyping and GWAS data from 608 Japanese cases and 737 controls.
We identified 4 novel loci, IL1A-IL1B, EGR2, IRF8, and CEBPB-PTPN1, which exceeded genome-wide significance in Turks. In addition, we confirmed 4 loci, IL10, CCR1, IL12A, and FUT2. Meta-analysis of Turks and Japanese revealed two additional novel loci, RIPK2 and LACC1. The lead SNP, rs4402765, for IL1A-IL1B is also the most significantly IL1A expression-associated variant in a lymphoblastoid cell eQTL database. Homozygosity of FUT2 non-secretor alleles of the ancestry specific SNPs, rs601338 (Turkish) and rs1047781 (Japanese), showed strong disease association (P=1.95×10-11).
This study identified 6 new susceptibility loci, IL1A-IL1B, RIPK2, EGR2, IRF8, LACC1 and CEBPB-PTPN1 for Behçet’s disease increasing the total number to 16. In addition, our findings help to establish a link between genetic factors and environmental factors, such as microbial exposures. Our findings that the disease-associated allele of IL1A is associated with decreased gene expression and that disease-associated FUT2 structural variants are hypofunctional suggest that an impaired host response to microbes may contribute to Behçet’s disease susceptibility.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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