Association of a TNFSF4 Upstream Region Single Nucleotide Polymorphism with Susceptibility to Proteinase 3-ANCA Positive Vasculitis in a Japanese Population

Yuka Iwahashi¹, Aya Kawasaki¹, Fumio Hirano², Ken-ei Sada³, Daisuke Tsukui⁴, Yuya Kondo⁵, Shigeto Kobayashi⁶, Hidehiro Yamada⁷, Hiroshi Furukawa¹, Kenji Nagasaka⁸, Takahiko Sugihara⁹, Kunihiro Yamagata¹⁰, Takayuki Sumida⁵, Shigeto Tohma¹¹, Hajime Kono⁴, Shoichi Ozaki⁷, Seiichi Matsuo¹², Hiroshi Hashimoto¹³, Hirofumi Makino¹⁴, Yoshihiro Arimura¹⁵, Masayoshi Harigai¹⁶ and Naoyuki Tsuchiya¹, ¹Molecular and Genetic Epidemiology Laboratory, University of Tsukuba, Faculty of Medicine, Tsukuba, Japan, ²Departments of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan, ³Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, ⁴Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan, ⁵Department of Internal Medicine, University of Tsukuba, Faculty of Medicine, Tsukuba, Japan, ⁶Department of Internal Medicine, Juntendo University Koshigaya Hospital, Koshigaya, Japan, ⁷Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan, ⁸Department of Rheumatology, Ome Municipal General Hospital, Ome, Japan, ⁹Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan, ¹⁰Department of Nephrology, University of Tsukuba, Faculty of Medicine, Tsukuba, Japan, ¹¹Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan, ¹²Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan, ¹³Juntendo University School of Medicine, Tokyo, Japan, ¹⁴Okayama University Hospital, Okayama, Japan, ¹⁵First Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan, ¹⁶Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: ANCA, genetics, Polymorphism and vasculitis

Session Information

Date: Monday, November 6, 2017

Title: Vasculitis Poster II: ANCA-Associated Vasculitis

Session Type: ACR Poster Session B

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

Background/Purpose:

In the epidemiology of ANCA-associated vasculitis (AAV), an obvious difference between European and Asian populations has been reported. According to the clinical classification, granulomatosis with polyangiitis (GPA) is predominant in UK, while microscopic polyangiitis (MPA) is predominant in Japan. Based on the ANCA specificity, most of Japanese AAV are myeloperoxidase (MPO)-ANCA positive, whereas more than half of UK AAV patients are proteinase 3 (PR3)-ANCA positive. Differences in the genetic background between populations may play a role in such epidemiological differences. Thus far, HLA-DPB1*04:01, SERPINA1 and PRTN3 are associated with GPA in the Caucasian populations, while HLA-DRB1*09:01 haplotype with Japanese MPO-ANCA positive AAV.

TNFSF4 encodes OX40 ligand (OX40L), which is expressed on endothelial cells and antigen presenting cells and plays a role in T cell activation through OX40. A single nucleotide polymorphism (SNP) rs2205960 G>T, located upstream of TNFSF4, has been associated with upregulation of OX40L, and with susceptibility to systemic lupus erythematosus (SLE) in the British, Chinese, and Korean populations.

Based on substantial sharing of susceptibility genes among multiple autoimmune diseases, and potential role of OX40L-OX40 interaction between T cells and endothelial cells, we considered TNFSF4 as an attractive candidate for a susceptibility gene to AAV. No association study has been reported between AAV and TNFSF4. In this study, we conducted an association study of rs2205960 in Japanese AAV.

Methods:

Case-control association analysis was performed on 467 Japanese AAV patients and 1100 healthy controls under the allele model, using chi-square test. The P values were corrected for multiple testing using Bonferroni correction. The patients were classified into 285 MPA, 92 GPA, 56 eosinophilic granulomatosis with polyangiitis, and 34 were unclassifiable, according to the European Medicines Agency (EMEA) algorithm. With respect to ANCA specificity, PR3-ANCA were positive in 62 patients, and MPO-ANCA in 376 patients.

Results:

The results are shown in Table 1. Significant association was detected in PR3-ANCA positive (P=0.00583, P_Bonferroni=0.032, odds ratio [OR]=1.75), but not in MPO-ANCA positive, patients. In addition, tendency towards association was detected in GPA (P=0.0507, OR=1.41). When the GPA patients were classified according to the ANCA specificity, association was preferentially detected in PR3-ANCA positive GPA (P=0.0213, OR=1.81) than in MPO-ANCA positive GPA (P=0.326, OR=1.32). The risk allele was T, which was the same as in SLE.

Conclusion:

Association of a TNFSF4 upstream region SNP rs2205960T with PR3-AAV in a Japanese population was detected for the first time. This allele seemed to be more strongly associated with PR3-ANCA positivity than with the clinical classification of GPA.

Table 1. Allelic association of TNFSF4 rs2205960 with AAV subsets in a Japanese population
rs2205960 G>T	n	MAF (%)	P	P_Bonferroni	OR	95“CI
MPO-ANCA positive AAV	376	20.6	0.527		1.07	0.87-1.31
PR3-ANCA positive AAV	62	29.8	0.00538	0.032	1.75	1.17-2.61

MPA	285	20.5	0.600		1.06	0.85-1.34
GPA	92	25.5	0.0507		1.41	1.00-2.00

MPO positive GPA	35	24.3	0.326		1.32	0.76-2.30
PR3 positive GPA	36	30.6	0.0213	0.128	1.81	1.08-3.02

healthy controls	1100	19.5	ref		ref
MAF: minor allele frequency, OR: odds ratio, CI: confidence interval

Disclosure: Y. Iwahashi, None; A. Kawasaki, 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, 3,Astellas Pharma Inc, 5; K. E. Sada, None; D. Tsukui, None; Y. Kondo, None; S. Kobayashi, None; H. Yamada, None; H. Furukawa, Bristol-Myers Squibb Co., 2,Ayumi Pharmaceutical Corporation, 5; K. Nagasaka, Chugai Pharmaceutical Co., Ltd., Bristol Myers Squibb K.K., Teijin Pharma Ltd., Actelion Pharmaceuticals Ltd., Ayumi Pharmaceutical Co., Ltd.., 5; T. Sugihara, Takeda Pharmaceutical Co. Ltd., Mitsubishi-Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Ayumi Pharmaceutical Co., Ltd., UCB Japan Co. Ltd, Astellas Pharma Inc., Janssen Pharmaceutical K.K., Pfizer Japan Inc., and Bristol Myers Squibb K.K, 5; K. Yamagata, None; T. Sumida, None; S. Tohma, None; H. Kono, None; S. Ozaki, None; S. Matsuo, None; H. Hashimoto, None; H. Makino, None; Y. Arimura, None; M. Harigai, Eisai Ltd, Takeda Ltd, Teijin, 2,Eli Lilly and Company, BMS, Chugai, Janssen, 5; N. Tsuchiya, Novartis Pharmaceutical Corporation, 2,Ayumi Pharmaceutical Co, 5.

To cite this abstract in AMA style:

Iwahashi Y, Kawasaki A, Hirano F, Sada KE, Tsukui D, Kondo Y, Kobayashi S, Yamada H, Furukawa H, Nagasaka K, Sugihara T, Yamagata K, Sumida T, Tohma S, Kono H, Ozaki S, Matsuo S, Hashimoto H, Makino H, Arimura Y, Harigai M, Tsuchiya N. Association of a TNFSF4 Upstream Region Single Nucleotide Polymorphism with Susceptibility to Proteinase 3-ANCA Positive Vasculitis in a Japanese Population [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/association-of-a-tnfsf4-upstream-region-single-nucleotide-polymorphism-with-susceptibility-to-proteinase-3-anca-positive-vasculitis-in-a-japanese-population/. Accessed .

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