Presentation Information
[OE7-2]The Largest Asian GWAS for Systemic Sclerosis Identified a Novel Risk Causal SNP in the Fc gamma Receptor Gene Region
○Yuki Ishikawa1, Nao Tanaka1, Yoshihide Asano2,3 Masanari Kodera4, Yuichiro Shirai5, Mitsuteru Akahoshi6,7, Minoru Hasegawa8, Takashi Matsushita9, Kazuyoshi Saito10, Sei-Ichiro Motegi 11, Hajime Yoshifuji12, Ayumi Yoshizaki3, Tomohiro Komoto13, Kae Takagi14, Akira Oka15, Miho Kanda4, Yoshihito Tanaka4, Yumi Ito4, Kazuhisa Nakano10, Hiroshi Kasamatsu18, Akira Utsunomiya18, Akiko Sekiguchi11, Hiroaki Niro 6, Masatoshi Jinnin19, Katsunari Makino20, Takamitsu Makino20, Hironobu Ihn20, Motohisa Yamamoto 21, Chisako Suzuki22, Hiroki Takahashi22, Emi Nishida23,24, Akimichi Morita23, Toshiyuki Yamamoto25, Toshiyuki Yamamoto26, Yuya Kondo27, Daisuke Goto 27, Takayuki Sumida27, Naho Ayuzawa28, Hidetoshi Yanagida28, Tetsuya Horita29, Tatsuya Atsumi29, Hirahito Endo30, Yoshihito Shima31, Atsushi Kumanogoh31, Jun Hirata32, Nao Otomo1, Hiroyuki Suetsugu1, Yoshinao Koike1, Kohei Tomizuka1, Soichiro Yoshino1, Xiaoxi Liu1, Shuji Ito1, Keiko Hikino1, Akari Suzuki33, Yukihide Momozawa34, Shiro Ikegawa35, Yoshiya Tanaka10, Osamu Ishikawa11, Kazuhiko Takehara9, Takeshi Torii36, Shinichi Sato3, Yukinori Okada32, Tsuneyo Mimori12,37, Fumihiko Matsuda38, Koichi Matsuda39,40, Tiffany Amariuta41,42,43,44,45, Issei Imoto 46, Keitaro Matsuo47, Masataka Kuwana5, Yasushi Kawaguchi48, Koichiro Ohmura12, Chikashi Terao1,16,17 (1.RIKEN, Center for Integrative Medical Sciences, Laboratory for Statistical and Translational Medicine, Yokohama, Japan, 2.Tohoku University, Graduate School of Medicine, Department of Dermatology, Sendai, Japan, 3.The University of Tokyo, Department of Dermatology, Tokyo, Japan, 4.Chukyo Hospital, Japan Community Health Care Organization, Department of Dermatology, Nagoya, Japan, 5.Nippon Medical School Graduate School of Medicine, Department of Allergy and Rheumatology, Tokyo, Japan, 6.Kyushu University, Faculty of Medicine, Department of Medicine and Biosystemic Science, Fukuoka, Japan, 7.Department of Rheumatology, Saga University Hospital, Saga, Japan, 8. Faculty of Medical Sciences, University of Fukui, Department of Dermatology, Fukui, Japan, 9.Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Department of Molecular Pathology of Skin, Faculty of Medicine, Kanazawa, Japan, 10. School of Medicine, University of Occupational and Environmental Health, The First Department of Internal Medicine, Kitakyushu, Japan, 11.Gunma University Graduate School of Medicine, Department of Dermatology, Maebashi, Japan, 12.Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 13. Aichi Cancer Center Research Institute, Division of Molecular Genetics, Nagoya, Japan, 14. Tokyo Women's Medical University, Adachi Medical Center, Tokyo, Japan , 15. Department of Molecular Life Sciences, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Japan, 16.Shizuoka General Hospital, The Clinical Research Center, Shizuoka, Japan, 17.School of Pharmaceutical Sciences, University of Shizuoka, The Department of Applied Genetics, Shizuoka, Japan, 18.Faculty of Medical Sciences, University of Fukui, Department of Dermatology, Fukui, Japan, 19.Wakayama Medical University Graduate School of Medicine, Department of Dermatology, Wakayama, Japan, 20.Faculty of Life Sciences, Kumamoto University, Department of Dermatology and Plastic Surgery, Kumamoto, Japan, 21.IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Department of Rheumatology and Allergy, Tokyo, Japan, 22. Sapporo Medical University School of Medicine, Department of Rheumatology and Clinical Immunology, Sapporo, Japan, 23.Nagoya City University Graduate School of Medical Sciences, Department of Geriatric and Environmental Dermatology, Nagoya, Japan, 24. Okazaki City Hospital, Department of Dermatology, Okazaki, Japan, 25.Fukushima Medical University, School of Medicine, Department of Dermatology, Fukushima, Japan, 26. Graduate School of Medicine, Osaka University, Department of Dermatology, Osaka, Japan, 27.Faculty of Medicine, University of Tsukuba, Department of Internal Medicine, Tsukuba, Japan, 28.National Hospital Organization, Utano National Hospital, Department of Clinical Immunology, Kyoto, Japan, 29.Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Department of Rheumatology, Endocrinology and Nephrology, Sapporo, Japan, 30.Omori Medical Center, Toho University, Rheumatic Disease Center, Tokyo, Japan, 31.Graduate School of Medicine, Osaka University, Department of Respiratory Medicine and Clinical Immunology, Osaka, Japan, 32.Immunology Frontier Center, Osaka University, Statistical Immunology, Osaka, Japan, 33.RIKEN Center for Integrative Medical Sciences, The Laboratory for Autoimmune Diseases, Yokohama, Japan, 34.RIKEN Center for Integrative Medical Sciences, The Laboratory for Genotyping Development, Yokohama, Japan, 35.RIKEN Center for Integrative Medical Sciences, The Laboratory for Bone and Joint Diseases, Yokohama, Japan, 36.Torii Clinic, Maizuru, Japan, 37.Ijinkai Takeada General Hospital, Kyoto, Japan, 38.Graduate School of Medicine, Kyoto University, Center for Genomic Medicine, Kyoto, Japan, 39.Institute of Medical Science, The University of Tokyo, Laboratory of Genome Technology, Human Genome Center, Tokyo, Japan, 40.Graduate School of Frontier Sciences, The University of Tokyo, Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Tokyo, Japan, 41.Center for Data Sciences, Harvard Medical School, Boston, MA, USA, 42.Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA, 43.Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA, 44.Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA, 45.Graduate School of Arts and Sciences, Harvard University, Cambridge, MA, USA, 46.Aichi Cancer Center Research Institute, Nagoya, Japan, 47.Aichi Cancer Center Research Institute, Division of Cancer Epidemiology and Prevention, Nagoya, Japan, 48.Tokyo Women's Medical University, Division of Rheumatology, Department of Internal Medicine, Tokyo, Japan)
【Objectives】To identify novel causal SNPs specific to Japanese with systemic sclerosis (SSc) as well as those shared with Europeans and clarify mechanistic effects of these SNPs.【Methods】A total of 1,499 cases and 112,609 controls were enrolled. We conducted a GWAS for Japanese SSc and meta-analyzed it with the latest European GWAS. Polygenicity, enrichment of functional annotations, and predictive performance of PRS were also examined.【Results】We identified three and four novel loci in the Japanese GWAS and the trans-ancestry meta-analysis, respectively. One of the Japanese novel risk SNPs located within FCGR gene clusters had a strong effect size (OR 2.05). The complete LD SNP, rs10917688, was positioned in a CRE, which had a binding motif for IRF8. IRF8 was a genome-wide significant locus in our trans-ancestry meta-analysis and the latest European GWAS and the association of rs10917688 was significant only in the presence of the risk allele of IRF8. rs10917688 was enriched with an enhancer-related histone mark, H3K4me1, in B cells. LDSC identified significant heritability enrichment of active histone marks in B cells both in European and Japanese. PRS moderately fit in the development of Japanese SSc (AUC 0.604) with further improvement by prioritizing IMPACT-annotated SNPs for IRF8-biding in the B-cell line (AUC 0.610).【Conclusion】We identified seven novel susceptibility loci in SSc. A novel disease mechanism, where an interactive role of FCGR gene(s) and IRF8 may accelerate disease development and B cells may play a key role on the pathogenesis, was implicated.