Association of NCF1 polymorphism with systemic lupus erythematosus and systemic sclerosis but not with ANCA-associated vasculitis in a Japanese population

Nozomi Yokoyama^{1

2}, Aya Kawasaki^{3

4}, Takashi Matsushita⁵, Hiroshi Furukawa^{1

2

6

7}, Yuya Kondo⁸, Fumio Hirano^{9

10}, Ken-Ei Sada¹¹, Isao Matsumoto⁸, Makio Kusaoi¹², Hirofumi Amano¹², Shouhei Nagaoka¹³, Keigo Setoguchi¹⁴, Tatsuo Nagai¹⁵, Kota Shimada^{6

16}, Shoji Sugii¹⁶, Atsushi Hashimoto⁶, Toshihiro Matsui⁶, Akira Okamoto¹⁷, Noriyuki Chiba¹⁸, Eiichi Suematsu¹⁹, Shigeru Ohno²⁰, Masao Katayama²¹, Kiyoshi Migita²², Hajime Kono²³, Minoru Hasegawa²⁴, Shigeto Kobayashi²⁵, Hidehiro Yamada^{26

27}, Kenji Nagasaka²⁸, Takahiko Sugihara^{9

10

29}, Kunihiro Yamagata³⁰, Shoichi Ozaki²⁶, Naoto Tamura¹², Yoshinari Takasaki^{12

25}, Hiroshi Hashimoto³¹, Hirofumi Makino³², Yoshihiro Arimura³³, Masayoshi Harigai³⁴, Shinichi Sato³⁵, Takayuki Sumida⁸, Shigeto Tohma^{6

7}, Kazuhiko Takehara⁵, Naoyuki Tsuchiya^{36

37}

Affiliations

¹ University of Tsukuba, Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, Tsukuba, Japan.
² University of Tsukuba, Graduate School of Comprehensive Human Sciences, Master's Program in Medical Sciences, Tsukuba, Japan.
³ University of Tsukuba, Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, Tsukuba, Japan. a-kawasaki@umin.net.
⁴ University of Tsukuba, Graduate School of Comprehensive Human Sciences, Master's Program in Medical Sciences, Tsukuba, Japan. a-kawasaki@umin.net.
⁵ Kanazawa University, Graduate School of Medical Sciences, Department of Dermatology, Kanazawa, Japan.
⁶ National Hospital Organization Sagamihara National Hospital, Clinical Research Center for Allergy and Rheumatology, Sagamihara, Japan.
⁷ National Hospital Organization Tokyo National Hospital, Kiyose, Japan.
⁸ University of Tsukuba, Faculty of Medicine, Department of Internal Medicine, Tsukuba, Japan.
⁹ Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Department of Rheumatology, Tokyo, Japan.
¹⁰ Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Department of Lifetime Clinical Immunology, Tokyo, Japan.
¹¹ Okayama University, Graduate School of Medicine, Density and Pharmaceutical Sciences, Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama, Japan.
¹² Juntendo University, School of Medicine, Department of Internal Medicine and Rheumatology, Tokyo, Japan.
¹³ Yokohama Minami Kyosai Hospital, Yokohama, Japan.
¹⁴ Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
¹⁵ Kitasato University, Department of Rheumatology and Infectious Diseases, Sagamihara, Japan.
¹⁶ Tokyo Metropolitan Tama Medical Center, Fuchu, Japan.
¹⁷ Himeji Medical Center, National Hospital Organization, Himeji, Japan.
¹⁸ Morioka Medical Center, National Hospital Organization, Morioka, Japan.
¹⁹ Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan.
²⁰ Yokohama City University Medical Center, Yokohama, Japan.
²¹ Nagoya Medical Center, National Hospital Organization, Nagoya, Japan.
²² Fukushima Medical University, School of Medicine, Fukushima, Japan.
²³ Teikyo University School of Medicine, Department of Internal Medicine, Tokyo, Japan.
²⁴ University of Fukui, Department of Dermatology, Fukui, Japan.
²⁵ Juntendo University Koshigaya Hospital, Koshigaya, Japan.
²⁶ St. Marianna University, School of Medicine, Department of Internal Medicine, Kawasaki, Japan.
²⁷ Center for Rheumatic Diseases, Seirei Yokohama Hospital, Yokohama, Japan.
²⁸ Ome Municipal General Hospital, Ome, Japan.
²⁹ Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
³⁰ University of Tsukuba, Faculty of Medicine, Department of Nephrology, Tsukuba, Japan.
³¹ Juntendo University School of Medicine, Tokyo, Japan.
³² Okayama University Hospital, Okayama, Japan.
³³ Kyorin University School of Medicine, First Department of Internal Medicine, Mitaka, Japan.
³⁴ Department of Rheumatology, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
³⁵ The University of Tokyo, Department of Dermatology, Tokyo, Japan.
³⁶ University of Tsukuba, Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, Tsukuba, Japan. tsuchiya-tky@umin.net.
³⁷ University of Tsukuba, Graduate School of Comprehensive Human Sciences, Master's Program in Medical Sciences, Tsukuba, Japan. tsuchiya-tky@umin.net.

PMID: 31705128
PMCID: PMC6842004
DOI: 10.1038/s41598-019-52920-0

Association of NCF1 polymorphism with systemic lupus erythematosus and systemic sclerosis but not with ANCA-associated vasculitis in a Japanese population

Nozomi Yokoyama et al. Sci Rep. 2019.

. 2019 Nov 8;9(1):16366.

doi: 10.1038/s41598-019-52920-0.

Authors

Affiliations

¹ University of Tsukuba, Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, Tsukuba, Japan.
² University of Tsukuba, Graduate School of Comprehensive Human Sciences, Master's Program in Medical Sciences, Tsukuba, Japan.
³ University of Tsukuba, Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, Tsukuba, Japan. a-kawasaki@umin.net.
⁴ University of Tsukuba, Graduate School of Comprehensive Human Sciences, Master's Program in Medical Sciences, Tsukuba, Japan. a-kawasaki@umin.net.
⁵ Kanazawa University, Graduate School of Medical Sciences, Department of Dermatology, Kanazawa, Japan.
⁶ National Hospital Organization Sagamihara National Hospital, Clinical Research Center for Allergy and Rheumatology, Sagamihara, Japan.
⁷ National Hospital Organization Tokyo National Hospital, Kiyose, Japan.
⁸ University of Tsukuba, Faculty of Medicine, Department of Internal Medicine, Tsukuba, Japan.
⁹ Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Department of Rheumatology, Tokyo, Japan.
¹⁰ Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Department of Lifetime Clinical Immunology, Tokyo, Japan.
¹¹ Okayama University, Graduate School of Medicine, Density and Pharmaceutical Sciences, Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama, Japan.
¹² Juntendo University, School of Medicine, Department of Internal Medicine and Rheumatology, Tokyo, Japan.
¹³ Yokohama Minami Kyosai Hospital, Yokohama, Japan.
¹⁴ Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
¹⁵ Kitasato University, Department of Rheumatology and Infectious Diseases, Sagamihara, Japan.
¹⁶ Tokyo Metropolitan Tama Medical Center, Fuchu, Japan.
¹⁷ Himeji Medical Center, National Hospital Organization, Himeji, Japan.
¹⁸ Morioka Medical Center, National Hospital Organization, Morioka, Japan.
¹⁹ Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan.
²⁰ Yokohama City University Medical Center, Yokohama, Japan.
²¹ Nagoya Medical Center, National Hospital Organization, Nagoya, Japan.
²² Fukushima Medical University, School of Medicine, Fukushima, Japan.
²³ Teikyo University School of Medicine, Department of Internal Medicine, Tokyo, Japan.
²⁴ University of Fukui, Department of Dermatology, Fukui, Japan.
²⁵ Juntendo University Koshigaya Hospital, Koshigaya, Japan.
²⁶ St. Marianna University, School of Medicine, Department of Internal Medicine, Kawasaki, Japan.
²⁷ Center for Rheumatic Diseases, Seirei Yokohama Hospital, Yokohama, Japan.
²⁸ Ome Municipal General Hospital, Ome, Japan.
²⁹ Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
³⁰ University of Tsukuba, Faculty of Medicine, Department of Nephrology, Tsukuba, Japan.
³¹ Juntendo University School of Medicine, Tokyo, Japan.
³² Okayama University Hospital, Okayama, Japan.
³³ Kyorin University School of Medicine, First Department of Internal Medicine, Mitaka, Japan.
³⁴ Department of Rheumatology, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
³⁵ The University of Tokyo, Department of Dermatology, Tokyo, Japan.
³⁶ University of Tsukuba, Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, Tsukuba, Japan. tsuchiya-tky@umin.net.
³⁷ University of Tsukuba, Graduate School of Comprehensive Human Sciences, Master's Program in Medical Sciences, Tsukuba, Japan. tsuchiya-tky@umin.net.

PMID: 31705128
PMCID: PMC6842004
DOI: 10.1038/s41598-019-52920-0

Abstract

Genome-wide association studies of systemic lupus erythematosus (SLE) in Chinese and Korean populations demonstrated strong association of single nucleotide polymorphisms (SNPs) located in the GTF2I-NCF1 region, rs73366469 (GTF2I), rs117026326 (GTF2I), rs80346167(GTF2IRD1) and rs201802880 (NCF1). This region has also been associated with susceptibility to Sjögren syndrome and rheumatoid arthritis; however, association studies with systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV) have not been reported. Here we made an attempt to confirm their associations with SLE in the Japanese population, to find the primarily associated SNP, and to investigate whether these SNPs are also associated with susceptibility to SSc and AAV. By genotyping these four SNPs on 842 SLE, 467 SSc, 477 AAV patients and 934 healthy controls, striking association was confirmed in Japanese SLE. In addition, these SNPs were significantly associated with susceptibility to SSc, but not with AAV. Conditional logistic regression analysis revealed that the association of NCF1 rs201802880, a missense SNP encoding p.Arg90His, can account for the association of other SNPs by linkage disequilibrium. These results suggested that GTF2I-NCF1 region is associated with susceptibility to multiple autoimmune rheumatic diseases but not with AAV, and the primarily associated variant may be the missense SNP in NCF1.

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Conflict of interest statement

Dr. Hirano is employed by The Department of Lifetime Clinical Immunology of Tokyo Medical and Dental University (TMDU), which has received unrestricted research grants from 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., with which TMDU currently pays the salary of Dr. Hirano. Dr. Hirano has also received speaking fees from Ono Pharmaceuticals, Astellas Pharma Inc., Sumitomo Dainippon Pharma and Chugai Pharmaceutical Co., Ltd. Dr. Shimada has received lecture fee from Chugai. Dr. Furukawa has the following conflicts, and the following funders are supported wholly or in part by the indicated pharmaceutical companies. The Japan Research Foundation for Clinical Pharmacology is run by Daiichi Sankyo, the Takeda Science Foundation is supported by an endowment from Takeda Pharmaceutical Company and the Nakatomi Foundation was established by Hisamitsu Pharmaceutical Co., Inc. The Daiwa Securities Health Foundation was established by Daiwa Securities Group Inc. and Mitsui Sumitomo Insurance Welfare Foundation was established by Mitsui Sumitomo Insurance Co., Ltd. Dr. Furukawa was also supported by research grants from Bristol-Myers Squibb Co., and received honoraria from Ajinomoto Co., Inc., Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Company, Luminex Japan Corporation Ltd., and Ayumi Pharmaceutical Corporation. Dr. Tohma was supported by research grants from Abbott Japan Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Merck Sharp and Dohme Inc., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited and Teijin Pharma Limited. Dr. Sugihara has received honoraria from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Mitsubishi-Tanabe Pharma Co., Astellas Pharma Inc., Bristol Myers Squibb K.K., Pfizer Japan Inc., UCB Japan Co. Ltd., and Abbvie Japan Co., Ltd., and has received research grant support from Takeda Pharmaceutical Co., Ltd, Astellas Pharma Inc., and Teijin Pharma Ltd. Dr. A. Hashimoto has received research funding from Chugai Pharmaceutical Co., Ltd. Dr. Matsui has received research funding from Chugai Pharmaceutical Co., Ltd. and Janssen Pharmaceutical K K. Dr. Tamura has received research grant from Ayumi Pharmaceutical Co., Asahi Kasei. Pharma Co., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Mitsubishi-Tanabe Pharma Co., Astellas Pharma Inc., Bristol Myers Squibb K.K., Abbvie Japan Co., Ltd., and Eisai Co., Ltd., and speaker’s fee from Abbvie Japan Co., Ltd., Bristol Myers Squibb K.K., Janssen. Pharmaceutical K.K., and Chugai Pharmaceutical Co. Dr. Makino is a consultant for AbbVie and Teijin, receives speaker honoraria from Boehringer-Ingelheim. Dr. Harigai has received research grants and/or honoraria from Abbott Japan Co., Ltd.; Astellas Pharma Inc.; Bristol-Myers Squibb K.K.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Janssen Pharmaceutical K.K.; Mitsubishi Tanabe Pharma Co.; Santen Pharmaceutical Co.; Ltd.; Takeda Pharmaceutical Co., Ltd.; Teijin Pharma, Ltd.; and Pfizer Japan Inc. Dr. Tsuchiya has received a research grant from Bristol-Myers Squibb, 2015 Japan College of Rheumatology Award from Japan College of Rheumatology and 2017 Novartis Rheumatology Award from Japan Rheumatism Association with research funding, and speaker’s honoraria from Ayumi Pharmaceutical Corporation.

Figures

**Figure 1**
Genomic configuration and linkage disequilibrium (LD) of the SNPs in *GTF2I-NCF1* region. Upper panel shows the genomic configuration of rs73366469 (*GTF2I-GTF2IRD1*), rs117026326 (*GTF2I*), rs80346167 (*GTF2IRD1*) and rs201802880 (*NCF1*). Lower panel; shows the LD plots of the SNPs in 876 Japanese healthy controls of our study (Left: D’, Right: r²).

See this image and copyright information in PMC

References

1. Parkes M, Cortes A, van Heel DA, Brown MA. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet. 2013;14:661–673. doi: 10.1038/nrg3502. - DOI - PubMed
1. Li Y, et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren’s syndrome at 7q11.23. Nat Genet. 2013;45:1361–1365. doi: 10.1038/ng.2779. - DOI - PubMed
1. Sun C, et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat Genet. 2016;48:323–330. doi: 10.1038/ng.3496. - DOI - PMC - PubMed
1. Kim K, et al. Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis. Sci Rep. 2016;6:27563. doi: 10.1038/srep27563. - DOI - PMC - PubMed
1. Langefeld CD, et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun. 2017;8:16021. doi: 10.1038/ncomms16021. - DOI - PMC - PubMed

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Association of NCF1 polymorphism with systemic lupus erythematosus and systemic sclerosis but not with ANCA-associated vasculitis in a Japanese population

Affiliations

Association of NCF1 polymorphism with systemic lupus erythematosus and systemic sclerosis but not with ANCA-associated vasculitis in a Japanese population

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Medical

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