Novel Susceptible Genes for Behçet's Disease Identified By Dense Genotyping of Immune-Related Loci Implicate Host Responses to Microbial Exposure

Masaki Takeuchi^1,2, Nobuhisa Mizuki³, Akira Meguro⁴, Michael J. Ombrello⁵, Yohei Kirino⁶, Colleen Satorius⁷, Julie Le¹, Mary Blake⁸, Burak Erer⁹, Tatsukata Kawagoe², Duran Ustek¹⁰, Ilknur Tugal-tutkun¹¹, Emire Seyahi¹², Yilmaz Ozyazgan¹³, Inês Sousa¹⁴, Fereydoun Davatchi¹⁵, Vânia Francisco¹⁴, Farhad Shahram¹⁶, Bahar Abdollahi¹⁷, Abdolhadi Nadji¹⁷, Niloofar Shafiee¹⁷, Fahmida Ghaderibarmi¹⁸, Shigeaki Ohno¹⁹, Atsuhisa Ueda⁶, Yoshiaki Ishigatsubo²⁰, Massimo G. Gadina²¹, Sofia Oliveira¹⁴, Ahmet Gul⁹, Daniel L. Kastner¹ and Elaine F. Remmers²², ¹National Human Genome Research Institute, Bethesda, MD, ²Yokohama City University Graduate School of Medicine, Yokohama, Japan, ³Yokohama City University, Yokohama, Japan, ⁴Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan, ⁵Translational Genetics and Genomics Unit, NIAMS, NIH, Bethesda, MD, ⁶Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan, ⁷NIAMS, N.I.H, Bethesda, MD, ⁸National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ⁹Department of Internal Medicine, Division of Rheumatology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey, ¹⁰Istanbul University, Istanbul, Turkey, ¹¹Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey, ¹²Istanbul University, Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Rheumatology, Istanbul, Turkey, ¹³Ophthalmology, Istanbul University, Cerrahpasa Medical Faculty, Department of Ophthalmology, Istanbul, Turkey, ¹⁴Universidade de Lisboa, Lisboa, Portugal, ¹⁵Internal Medicine, Rheumatology Research Ctr-Tehran Univ, Tehran, Iran, ¹⁶Tehran University of Medical Sciences, Tehran, Iran (Islamic Republic of), ¹⁷Tehran University of Medical Sciences, Teheran, Iran (Islamic Republic of), ¹⁸Tehran University of Medical Sciences, Teheran, Portugal, ¹⁹Hokkaido University Graduate School of Medicine, Hokkaido, Japan, ²⁰Int. Med. & Clin. Immunology, Yokohama City Grad Sch of Med, Yokohama, Japan, ²¹Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ²²National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Behcet's syndrome, IL-1 and major histocompatibility complex (MHC)

Session Information

Date: Monday, November 14, 2016

Title: Genetics, Genomics and Proteomics I

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Recent genetic studies have identified multiple susceptibility loci for Behçet’s disease. However, these genetic factors do not fully explain the apparent disease heritability.The purpose of this study was to densely genotype loci associated with immune-related diseases to identify novel susceptibility loci for Behçet’s disease.

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.

Disclosure: M. Takeuchi, None; N. Mizuki, None; A. Meguro, None; M. J. Ombrello, None; Y. Kirino, None; C. Satorius, None; J. Le, None; M. Blake, None; B. Erer, None; T. Kawagoe, None; D. Ustek, None; I. Tugal-tutkun, None; E. Seyahi, None; Y. Ozyazgan, None; I. Sousa, None; F. Davatchi, None; V. Francisco, None; F. Shahram, None; B. Abdollahi, None; A. Nadji, None; N. Shafiee, None; F. Ghaderibarmi, None; S. Ohno, None; A. Ueda, None; Y. Ishigatsubo, None; M. G. Gadina, None; S. Oliveira, None; A. Gul, None; D. L. Kastner, None; E. F. Remmers, None.

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 .

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