ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1942

Genome-wide Association Study in a Japanese Population Revealed Novel Candidate Genes for Antineutrophil Cytoplasmic Antibody-associated Vasculitis

Masayoshi Harigai1, Aya Kawasaki 2, Naoyuki Tsuchiya 2, Ken-Ei Sada 3, Fumio Hirano 4, Takahiko Sugihara 5, Koichi Amano 6, Kunihiro Yamagata 7, Hiroaki Dobashi 8, Kenji Nagasaka 9, Tatsuya Atsumi 10, Seik-Soon Khor 11, Katsushi Tokunaga 12, Shoichi Ozaki 13, Seiichi Matsuo 14, Yoshihiro Arimura 15 and Hirofumi Makino 16, 1Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Shinjuku-ku, Tokyo, Japan, 2Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, 3Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, 4Department of Rheumatology, Tokyo Medical and Dental University, Tokyo, Japan, 5Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan, 6Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Kawagoe, Japan, 7Department of Nephrology, University of Tsukuba, Tsukuba, Ibaraki, Japan, 8Kagawa University, Kagawa, Japan, 9Department of Rheumatology, Ome Municipal General Hospital, Ome, Japan, 10Hokkaido University, Sapporo, Japan, 11Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan, 12National Center for Global Health and Medicine, Tokyo, Japan, 13St. Marianna University School of Medicine, Kawasaki, Japan, 1413. Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan, 15Nephrology and Rheumatology, Kyorin University School of Medicine, Tokyo, Japan, 16Okayama University, Okayama, Japan

Meeting: 2019 ACR/ARP Annual Meeting

Keywords:

Session Information

Date: Tuesday, November 12, 2019

Session Title: Genetics, Genomics & Proteomics Poster

Session Type: Poster Session (Tuesday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Clinical and serological features of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are different across geographical regions and ethnicities, which strongly indicates significant roles of genetic factors in development of AAV. In AAV patients with Asian ethnicity, MHC and non-MHC genes associated with susceptibility or clinical characteristics of AAV were reported using the candidate-gene approach, but genome-wide association study (GWAS) has not been reported. We implemented GWAS to identify single nucleotide variants (SNV) associated with AAV in the Japanese population.

Methods: GWAS was implemented using samples from 374 Japanese patients with AAV comprised of 214 with microscopic polyangiitis (MPA), 75 with granulomatosis with polyangiitis (GPA), and 45 with eosinophilic granulomatosis with polyangiitis (EGPA). Myeloperoxidase (MPO)-ANCA was positive in 300 patients and proteinase 3 (PR3)-ANCA was positive in 47 patients. Data were compared with those of 2,994 healthy Japanese owned by Japan PGx Data Science Consortium. The genotype data were obtained using HumanOmni 2.5-8 BeadChip Kits (Illumina, San Diego, CA, USA). From the genotypes of several SNVs around HLA regions, two alleles of each subject were predicted by HIBAG algorithm using the parameters tuned by Japanese population. The four-digit HLA alleles on six loci (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, HLA-DPB1) for ANCA subjects were predicted. For JPDSC data, alleles of HLA-DQB1 were also predicted and other HLA loci were genotyped using the Luminex assay as four digits HLA allele.

Results: GWAS revealed substantially different associations from those reported from populations of European ancestry. SNVs rs2858331 in a region between HLA-DQB1 and HLA-DQA2 was associated with MPO-ANCA (OR=1.649, P=9.504E-09) at the genome-wide significance level, and tended to be associated with the phenotype MPA as well (OR=1.631, P=1.373E-06). HLA association test showed significant association of HLA-B*51:01-C*14:02 haplotype in addition to the previously reported HLA-DRB1*09:01-DQB1*03:03 haplotype with MPA and MPO-ANCA. SNV rs749873 in a region near CXCR4 gene showed a trend toward association with GPA (OR=8.058, P=6.755E-08).

Conclusion: GWAS demonstrated multiple association signals in MHC class I and class II regions, as well as potential associations in the non-MHC regions, not previously reported from European populations.
The authors are the members of Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) and Research Committee of Progressive Renal Disease, Ministry of Health, Labour, and Welfare of Japan. This study was performed in collaboration with Japan PGx Data Science Consortium.

Disclosure: M. Harigai, AbbVie Japan GK, 2, 8, Ayumi Pharmaceutical Co. Ltd., 2, Bristol Meyers Squib, 2, 5, 8, Bristol-Myers Squibb Co. Ltd, 2, 5, 8, Chugai Pharmaceutical Co. Ltd., 2, 5, 8, Chugai Pharmaceutical Co., Ltd., 2, 5, 8, Eisai Co. Ltd., 2, Eisai Co., Ltd., 2, Eli Lilly, 5, 8, Mitsubishi Tanabe Pharma Co., 2, Mitsubishi Tanabe Pharma Corp., 2, Nippon Kayaku Co. Ltd., 2, Taisho Toyama Pharmaceutical Co. Ltd., 2, Takeda Pharmaceutical Co., 2, Takeda Pharmaceutical Co., Ltd., 2, Teijin Pharma Ltd., 2, 8, Teijin Pharma, Ltd., 2, 8; A. Kawasaki, None; N. Tsuchiya, Ayumi Pharmaceutical Corporation, 8, Bristol-Myers Squibb, 2, Bristol-Myers Squibb Co. Ltd, 2, Japan College of Rheumatology, 2, Japan Rheumatism Foundation, 2; K. Sada, None; F. Hirano, Chugai Pharmaceutical Co, Ltd., 2, 8, Ono Pharmaceuticals, 2, 8, CSL Behring, 2, Towa Pharmaceutical Co, Ltd., 2, Abbvie Japan Co, Ltd., 2, Japan Blood Products Organization, 2, Ayumi Pharmaceutical Co, 2, Nippon Kayaku Co, Ltd., 2, Astellas Pharma Inc., 8, Sumitomo Dainippon Pharma, 8, UCB Japan, 2; T. Sugihara, Chugai Pharmaceutical Co, Ltd., 2, 8, Takeda Pharmaceutical Co. Ltd., 2, 8, Mitsubishi Tanabe Pharma Co., 2, 8, Astellas Pharma Inc., 2, 8, Bristol Meyers Squib, 2, 8, Ayumi Pharmaceutical Co, 2, 8, Pfizer Japan Inc., 2, 8, Eli Lilly Japan K.K., 2, 8, UCB Japan, 2, 8, Abbvie Japan Co., Ltd., 2, 8, Teijin Pharma Ltd., 2, 8, CSL Behring K.K., 2, Japan Blood Products Organization, 2, Nippon Kayaku Co., Ltd., 2, AsahiKASEI Co., Ltd., 2; K. Amano, Asahi Kasei Pharma, 2, Chugai Pharmaceutical Co. Ltd., 2, 8, Astellas, 8, Eli Lilly, 8, Pfizer Japan, 8, Mitsubishi Tanabe Pharma, 8; K. Yamagata, None; H. Dobashi, None; K. Nagasaka, Teijin Pharma Ltd., 8, Bristol Meyers Squib, 8, Chugai Pharmaceutical Co. Ltd., 8; T. Atsumi, AbbVie, 5, 8, Abbvie, 5, 8, Asahi Kasei Pharma Corporation, 8, Astellas Pharma, 8, 9, Astellas Pharma Inc, 8, AstraZeneca, 5, AstraZeneca plc, 5, 8, Bayer Yakuhin, 8, Bayer Yakuhin, Ltd., 8, Bristol-Myers Squibb, 8, 9, Chugai Pharmaceutical Co Ltd, 8, Chugai Pharmaceutical Co., 8, 9, Daiichi Sankyo, 8, 9, Daiichi Sankyo Co Ltd, 8, Eisai Co., Ltd, 8, Eli Lilly and Company, 8, 9, Eli Lilly Japan KK, 8, Elsai Co Ltd, 8, Gilead Sciences, 8, Gilead Sciences, Inc., 8, MEDICAL & BIOLOGICAL LABORATORIES CO., 5, Medical and Biological Laboratories Co Ltd, 5, Mitsubishi Tanabe Pharma, 8, 9, Nippon Shinyaku Co., 8, Novartis, 5, Novartis Pharma KK, 5, Ono Pharmaceutical, 5, ONO Pharmaceutical Co Ltd, 5, Otsuka Pharmaceutical, 8, Pfizer, 5, 9, Pfizer Inc, 5, 8, Sanofi, 9, Takeda Pharmaceutical Company, 8, Takeda Pharmaceuticals, 8; S. Khor, None; K. Tokunaga, None; S. Ozaki, None; S. Matsuo, None; Y. Arimura, None; H. Makino, AbbVie, 5, Boehringer-Ingelheim, 5, Teijin Pharma Ltd., 5.

To cite this abstract in AMA style:

Harigai M, Kawasaki A, Tsuchiya N, Sada K, Hirano F, Sugihara T, Amano K, Yamagata K, Dobashi H, Nagasaka K, Atsumi T, Khor S, Tokunaga K, Ozaki S, Matsuo S, Arimura Y, Makino H. Genome-wide Association Study in a Japanese Population Revealed Novel Candidate Genes for Antineutrophil Cytoplasmic Antibody-associated Vasculitis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/genome-wide-association-study-in-a-japanese-population-revealed-novel-candidate-genes-for-antineutrophil-cytoplasmic-antibody-associated-vasculitis/. Accessed April 13, 2021.

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