Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Methods: 1900 Turkish Behçet’s disease patients and 1779 controls were genotyped using the Immunochip. For novel loci with association test P<5×10-5, additional SNPs in the region were genotyped or imputed using 1000 Genomes Project data as a reference. For replication, the lead genotyped SNP in each novel locus with P<5×10-5 in the Turkish population was genotyped in 982 cases and 826 controls from Iran. We also replicated disease associations with imputed previous GWAS data from 608 Japanese cases and 737 controls. P<5×10-8was considered the threshold for genome-wide significance.
Results: HLA-B*51 was the strongest associated marker and rs1050502 the strongest associated SNP. rs1050502 is located in exon 2 of HLA-B and the risk allele T is a tag SNP for HLA-B*51. Outside of the MHC region, we identified 4 novel loci, IL1A-IL1B, ADO-EGR2, IRF8, and CEBPB-PTPN1, which exceeded genome-wide significance in Turks. Genotyping Iranian samples and meta-analysis with Turkish data replicated associations of three loci, ADO-EGR2, IRF8 and CEBPB-PTPN1. Comprehensive meta-analysis of the regional imputed genotype data of Turks and Japanese replicated two loci, ADO-EGR2 and IRF8, and revealed two additional novel loci, RIPK2 and LACC1. The disease associated allele of rs4402765, the lead marker of the IL1A-IL1B locus, was associated with both decreased interleukin-1α and increased interleukin-1β protein production. Ancestry specific FUT2non-secretor genotypes, homozygous rs601338 (p.Trp143Ter) in Turks and Iranians and rs1047781 (p.Ile129Phe) in Japanese, showed strong disease association. The non-secretor genotype has been associated with Crohn’s disease and gut microbiome composition.
Conclusion: Here, we conducted an Immunochip study in the largest Behçet’s disease discovery cohort ever with multiple populations for replication. This study identified 6 novel loci (IL1A-IL1B, RIPK2, ADO-EGR2, LACC1, IRF8, and CEBPB-PTPN1) with genome-wide significance for Behçet’s disease. Our findings that the disease-associated allele of IL1A is associated with dysregulated IL-1 biology, with less IL-1alpha and more IL-1beta production, and that functionally defective structural FUT2 variants are associated with disease risk suggest that an impaired host response to microbes, including those of the microbiome, may contribute to Behçet’s disease susceptibility.
To cite this abstract in AMA style:Takeuchi M, Mizuki N, Meguro A, Ombrello MJ, Kirino Y, Satorius C, Le J, Blake M, Erer B, Kawagoe T, Ustek D, Tugal-tutkun I, Seyahi E, Ozyazgan Y, Sousa I, Davatchi F, Francisco V, Shahram F, Abdollahi B, Nadji A, Shafiee N, Ghaderibarmi F, Ohno S, Ueda A, Ishigatsubo Y, Gadina MG, Oliveira S, Gul A, Kastner DL, Remmers EF. Novel Susceptible Genes for Behçet’s Disease Identified By Dense Genotyping of Immune-Related Loci Implicate Host Responses to Microbial Exposure [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/novel-susceptible-genes-for-behcets-disease-identified-by-dense-genotyping-of-immune-related-loci-implicate-host-responses-to-microbial-exposure/. Accessed December 3, 2021.
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