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

Nozomu Yokoyama ,Akira Okamoto,Yoshihiro Arimura,Nobutaka Chiba ,Shinya Nagaoka ,Ken‐Ei Sada ,Minoru Hasegawa,Hiroshi Hashimoto,Keigo Setoguchi,Kenji Nagasaka,Naoto Tamura,T Matsushita ,Fumio Hirano,Shigeru Ohno,Hírofumi Makino ,Kazuhiko Takehara,Hisakata Yamada ,Toshihiro Matsui,Masao Kameyama ,Aya Kawasaki,Shoichi Ozaki,Shinichi Sato,Atsushi Hashimoto,Masayoshi Harigai,Takahiko Sugihara,Kunihiro Yamagata,Shoji Suzuki ,Tatsuo Nagai,Eiichi Suematsu,Takayuki Sumida,Kota Shimada,Makio Kusaoi,Kiyoshi Migita,Yoshinari Takasaki,Yuya Kondo,Hirofumi Amano,Hajime Kono,Hiroshi Furukawa,Shigeto Kobayashi,Shigeto Tohma,Isao Matsumoto,Naoyuki Tsuchiya

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.

Highlights

Genome wide association study (GWAS) of autoimmune rheumatic diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV) unanimously demonstrated that the strongest association signal is present within the major histocompatibility complex (MHC)[1] until 2013, when GWAS of Sjögren’s syndrome (SS) in the Chinese population surprisingly demonstrated striking associations of single nucleotide polymorphisms (SNPs), rs73366469 (T > C), rs117026326 (C > T) and rs80346167 (G > A), in a region encoding general transcription factors GTF2I and GTF2IRD1, which were even stronger than that of the MHC region[2]
When compared with healthy controls, the same alleles as in SLE were significantly associated with SSc (Table 1)
Among the SNPs, NCF1 SNP rs201802880 showed the strongest associations with susceptibility to SLE and SSc (SLE: uncorrected P value [Puncorr] = 3.77 × 10−44, false discovery rate (FDR) P value [Q] = 8.29 × 10−43, Odds Ratio [OR] = 3.57, 95%CI 2.99-4.28; SSc: Puncorr = 2.40 × 10−4, Q = 0.0011, OR = 1.50, 95%CI 1.21–1.87, both under the additive model)

Summary

Introduction

This region has been associated with susceptibility to Sjögren syndrome and rheumatoid arthritis; association studies with systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV) have not been reported. GWAS of autoimmune rheumatic diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV) unanimously demonstrated that the strongest association signal is present within the major histocompatibility complex (MHC)[1] until 2013, when GWAS of Sjögren’s syndrome (SS) in the Chinese population surprisingly demonstrated striking associations of single nucleotide polymorphisms (SNPs), rs73366469 (T > C), rs117026326 (C > T) and rs80346167 (G > A), in a region encoding general transcription factors GTF2I and GTF2IRD1, which were even stronger than that of the MHC region[2].

Methods

Results

Conclusion