A Genome-Wide Association Study Identified AFF1 as a Susceptibility Locus for Systemic Lupus Eyrthematosus in Japanese

Yukinori Okada,Michito Hirakata,Koichiro Higasa,Naoya Hosono,Naoyuki Kamatani,Kazuyoshi Saito,Yasushi Kawaguchi,Kenshi Hayashi,Chikashi Terao,Hisashi Yamanaka,Kenichi Shimane,Yuya Kondo,Norihiro Nishimoto,Yuta Kochi,Yusuke Nakamura,Michiaki Kubo,Akiko Okamoto,Makoto Kamachi,Tatsuya Atsumi,Takayuki Sumida,Kazuki Takada,Tsuneyo Mimori,Koichi Matsuda,Tatsuhiko Tsunoda,Ryo Yamada,Tomonori Ishii,Takao Koike,Tetsuya Horita,Akari Suzuki,Hirofumi Amano,Keiko Myouzen,Atsushi Takahashi,Kazuhiko Yamamoto,Tomoko Tahira,Yoshiya Tanaka,Katsunori Ikari,Takahiko Horiuchi,Fumihiko Matsuda,Satoshi Ito,Keishi Fujio,Koichiro Ohmura,Yoshinari Takasaki,Wael Osman ,Akio Matsubara

doi:10.1371/journal.pgen.1002455

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10−9, odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4+ and CD19+ peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset.

Highlights

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production, complement activation, and multi-organ damage [1]
Considering that abnormalities in B cell activity play essential roles in SLE, prioritization based on an expression quantitative trait loci study for B cells would be a promising approach
We report a genome-wide association studies (GWAS) and multi-stage replication studies for SLE examining 2,278 SLE cases and 31,948 controls in Japanese subjects

Summary

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production, complement activation, and multi-organ damage [1]. Genetic studies using candidate geneapproaches, and recently, genome-wide association studies (GWAS), have uncovered more than 25 SLE susceptibility genes, including HLA-DRB1, IRF5, STAT4, ITGAM, BLK, TNFAIP3, and others [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18] Most of these studies were conducted in European populations [3,4,5,6,7,8,9,10,11,12,13,15,17], and few studies have been conducted in Asian populations [14,16,18]. It is of note that GWAS for SLE in Chinese populations identified novel loci that had not been detected in Europeans, such as ETS1, IKZF1, and WDFY4 [14,16]

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