Association of GTF2I Region Polymorphism with Systemic Lupus Erythematosus and Systemic Sclerosis, but Not with ANCA-Associated Vasculitis and Polymyositis/Dermatomyositis, in a Japanese Population

Nozomi Yokoyama^1,2, Aya Kawasaki^1,2, Takashi Matsushita³, Hiroshi Furukawa^1,2,4, Yuya Kondo⁵, Fumio Hirano^6,7, Ken-ei Sada⁸, Isao Matsumoto⁵, Makio Kusaoi⁹, Hirofumi Amano⁹, Shohei Nagaoka¹⁰, Keigo Setoguchi¹¹, Tatsuo Nagai¹², Kota Shimada^4,13, Shouji Sugii¹⁴, Atsushi Hashimoto¹⁵, Toshihiro Matsui¹⁶, Akira Okamoto¹⁷, Noriyuki Chiba¹⁸, Eiichi Suematsu¹⁹, Shigeru Ohno²⁰, Masao Katayama²¹, Kiyoshi Migita²², Hajime Kono²³, Minoru Hasegawa²⁴, Shigeto Kobayashi²⁵, Hidehiro Yamada²⁶, Kenji Nagasaka²⁷, Takahiko Sugihara²⁸, Kunihiro Yamagata²⁹, Shoichi Ozaki²⁶, Manabu Fujimoto³⁰, Naoto Tamura⁹, Yoshinari Takasaki⁹, Hiroshi Hashimoto³¹, Hirofumi Makino³², Yoshihiro Arimura³³, Masayoshi Harigai³⁴, Shinichi Sato³⁵, Takayuki Sumida⁵, Shigeto Tohma^36,37, Kazuhiko Takehara³ and Naoyuki Tsuchiya^1,2, ¹University of Tsukuba, Graduate School of Comprehensive Human Sciences, Masters' Program in Medical Sciences, Tsukuba, Japan, ²University of Tsukuba, Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, Tsukuba, Japan, ³Kanazawa University, Department of Dermatology, Kanazawa, Japan, ⁴National Hospital Organization Sagamihara l Hospital, Clinical Research Center for Allergy and Rheumatology, Sagamihara, Japan, ⁵Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, ⁶Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Department of Rheumatology, Tokyo, Japan, ⁷Tokyo Medical and Dental UniversityGraduate School of Medical and Dental Sciences, Department of Lifetime Clinical Immunology, Tokyo, Japan, ⁸Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama, Japan, ⁹Juntendo University, School of Medicine, Department of Internal Medicine and Rheumatology, Tokyo, Japan, ¹⁰Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Japan, ¹¹Allergy and Immunological Diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan, ¹²Kitasato University, Department of Rheumatology and Infectious Diseases, Sagamihara, Japan, ¹³Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan, ¹⁴Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan, ¹⁵Rheumatology, National Hospital Organization Sagamihara Hospital, Sagamihara, Japan, ¹⁶National Hospital Organization Sagamihara l Hospital, Clinical Research Center for Allergy and Rheumatology, Kanagawa, Japan, ¹⁷Department of Rheumatology, Himeji Medical Center, National Hospital Organization, Himeji, Japan, ¹⁸Department of Rheumatology, Morioka Hospital, National Hospital Organization, Morioka, Japan, ¹⁹Clinical Research Institute, Department of Internal Medicine and Rheumatology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan, ²⁰Center for Rheumatic Disease, Yokohama City University Medical Center, Yokohama, Japan, ²¹Department of Internal Medicine, Nagoya Medical Center, National Hospital Organization, Nagoya, Japan, ²²Fukushima Medical University, School of Medicine, Fukushima, Japan, ²³Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan, ²⁴University of Fukui, Department of Dermatology, Fukui, Japan, ²⁵Department of Internal Medicine, Juntendo University Koshigaya Hospital, Koshigaya, Japan, ²⁶St. Marianna University, School of Medicine, Department of Internal Medicine, Kawasaki, Japan, ²⁷Department of Rheumatology, Ome Municipal General Hospital, Ome, Japan, ²⁸Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan, ²⁹University of Tsukuba, Faculty of Medicine, Department of Nephrology, Tsukuba, Japan, ³⁰University of Tsukuba, Faculty of Medicine, Department of Dermatology, Tsukuba, Japan, ³¹Juntendo University School of Medicine, Tokyo, Japan, ³²Okayama University Hospital, Okayama, Japan, ³³Kyorin University School of Medicine, First Department of Internal Medicine, Tokyo, Japan, ³⁴Tokyo Women's Medical University, Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, Institute of Rheumatology, Tokyo, Japan, ³⁵The University of Tokyo, Department of Dermatology, Tokyo, Japan, ³⁶National Hospital Organization Tokyo National Hospital, Kiyose, Japan, ³⁷National Hospital Organization Tokyo Hospital, Sagamihara, Japan

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: genetics, polymorphism, systemic lupus erythematosus (SLE) and systemic sclerosis

Session Information

Date: Tuesday, October 23, 2018

Title: Genetics, Genomics and Proteomics Poster

Session Type: ACR Poster Session C

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

Background/Purpose: Genome-wide association studies of systemic lupus erythematosus (SLE) in Chinese and Korean populations identified striking association with a single nucleotide polymorphism (SNP) rs73366469, located upstream of GTF2I gene encoding a transcription factor functional in the immune system. The association of NCF1 in linkage disequilibrium with rs73366469 has also been reported, and causative association signal of this region requires further study. The GTF2I-NCF1 region is also associated with Sjögren syndrome (SS) and rheumatoid arthritis (RA) in the Asian populations. However, to our knowledge, association studies with systemic sclerosis (SSc), ANCA-associated vasculitis (AAV), and polymyositis/dermatomyositis (PM/DM) have not been reported. In this study, in addition to confirming association of this SNP with SLE in a Japanese population, we tested its association with clinical phenotypes of SLE. Furthermore, we examined whether the SNP is also associated with SSc, AAV and PM/DM.

Methods: Genotyping of rs73366469 was performed on 842 Japanese SLE patients, 467 SSc patients, 477 AAV patients, 153 PM/DM patients and 934 healthy controls using TaqMan SNP Genotyping Assay. Case-control and case-only association studies were performed by chi-square test. Correction for multiple testing was performed by calculating FDR q values using Benjamini-Hochberg method, and q<0.05 was considered significant. Statistical power was calculated by Power and Sample Size Calculation.

Results: When compared with healthy controls, striking association of rs73366469 C was detected in SLE patients (p=9.5×10^-16, q=3.7×10^-14, odds ratio [OR]=2.27)(Table). When the case-only analysis was performed between SLE patients with and without specific clinical phenotypes (central nervous system disorders, renal disorders, presence of anti-dsDNA, anti-Sm or anti-U1-RNP antibodies), significant difference was not observed. When the association was tested in SSc patients, the same C allele was significantly increased in SSc (p=0.0028, q=0.012, OR=1.47)(Table). Similarly, the association was observed regardless of the clinical phenotypes (lcSSc or dcSSc, presence or absence of anti-centromere, anti-topoisomerase I or anti-U1-RNP antibodies, interstitial lung disease or pulmonary hypertension), significant difference was not observed. In contrast, increase in C allele frequency was not detected in AAV and PM/DM(Table).

Conclusion: Association of GTF2I rs73366469 C with SLE was replicated in a Japanese population. In addition, the same allele was found to be associated with SSc. This allele was associated with susceptibility to overall SLE and SSc, but not with specific clinical phenotypes. In contrast, association was not detected in AAV and PM/DM. Taken together with previous reports on RA and SS, GTF2I region appears to be associated with susceptibility to multiple, but not all, systemic rheumatic diseases.

Table. Association study of rs73366469 and SLE, SSc, AAV and PM/DM in a Japanese population
	n	Genotype frequency n (%)			C allele frequency (%)	Allelic association (C vs T)			Power calculation (%)
	n	C/C	C/T	T/T	C allele frequency (%)	p	q	OR (95%CI)	Power calculation (%)
SLE	842	25 (3.0)	250 (29.7)	567 (67.3)	17.8	9.5×10^-16	3.7×10^-14	2.27 (1.86-2.77)	100
SSc	467	15 (3.2)	85 (18.2)	367 (78.6)	12.3	0.0028	0.012	1.47 (1.14-1.89)	52.3
AAV	477	1 (0.2)	79 (16.6)	397 (83.2)	8.5	0.83	0.97	0.97 (0.73-1.28)	5.3
PM/DM	153	2 (1.3)	22 (14.4)	129 (84.3)	8.5	0.90	0.97	0.97 (0.63-1.50)	5.2
Healthy controls	934	7 (0.7)	149 (16.0)	778 (83.3)	8.7

Disclosure: N. Yokoyama, None; A. Kawasaki, None; T. Matsushita, None; H. Furukawa, None; Y. Kondo, None; F. Hirano, Chugai Pharmaceutical Co., Ltd.; Ono Pharmaceuticals; Mitsubishi Tanabe Pharma Co.; UCB Japan; CSL Behring; Towa Pharmaceutical Co., Ltd.; Abbvie Japan Co., Ltd.; Japan Blood Products Organization; Ayumi Pharmaceutical Co.; and Nippon Kayaku Co., Ltd.., 5,Sumitomo Dainippon Pharma Chugai Pharmaceutical Co., Ltd., 8; K. E. Sada, None; I. Matsumoto, None; M. Kusaoi, None; H. Amano, None; S. Nagaoka, None; K. Setoguchi, None; T. Nagai, None; K. Shimada, None; S. Sugii, Bristol-Meyers Squibb, Tanabe Mitsubishi Pharma, Chugai Pharmaceutical Co., Takeda Pharmaceutical Co., Pfizer, AYUMI Pharmaceutical Co, 8; A. Hashimoto, None; T. Matsui, None; A. Okamoto, None; N. Chiba, None; E. Suematsu, None; S. Ohno, None; M. Katayama, None; K. Migita, None; H. Kono, Celgene Corporation, 2; M. Hasegawa, None; S. Kobayashi, None; H. Yamada, None; K. Nagasaka, None; T. Sugihara, Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Mitsubishi-Tanabe Pharma Co., Astellas Pharma Inc., Bristol Myers Squibb K.K. and Abbvie Japan Co., Ltd., 5; K. Yamagata, None; S. Ozaki, None; M. Fujimoto, None; N. Tamura, None; Y. Takasaki, None; H. Hashimoto, None; H. Makino, None; Y. Arimura, None; M. Harigai, None; S. Sato, None; T. Sumida, None; S. Tohma, None; K. Takehara, None; N. Tsuchiya, Japan Rheumatism Foundation, 2.

To cite this abstract in AMA style:

Yokoyama N, Kawasaki A, Matsushita T, Furukawa H, Kondo Y, Hirano F, Sada KE, Matsumoto I, Kusaoi M, Amano H, Nagaoka S, Setoguchi K, Nagai T, Shimada K, Sugii S, Hashimoto A, Matsui T, Okamoto A, Chiba N, Suematsu E, Ohno S, Katayama M, Migita K, Kono H, Hasegawa M, Kobayashi S, Yamada H, Nagasaka K, Sugihara T, Yamagata K, Ozaki S, Fujimoto M, Tamura N, Takasaki Y, Hashimoto H, Makino H, Arimura Y, Harigai M, Sato S, Sumida T, Tohma S, Takehara K, Tsuchiya N. Association of GTF2I Region Polymorphism with Systemic Lupus Erythematosus and Systemic Sclerosis, but Not with ANCA-Associated Vasculitis and Polymyositis/Dermatomyositis, in a Japanese Population [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/association-of-gtf2i-region-polymorphism-with-systemic-lupus-erythematosus-and-systemic-sclerosis-but-not-with-anca-associated-vasculitis-and-polymyositis-dermatomyositis-in-a-japanese-population/. Accessed .

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