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

被引：91

作者：

Okada, Yukinori ^{[1
,2
,3
]}

Shimane, Kenichi ^{[1
,2
]}

Kochi, Yuta ^{[1
,2
]}

Tahira, Tomoko ^{[4
]}

Suzuki, Akari ^{[1
]}

Higasa, Koichiro ^{[3
]}

Takahashi, Atsushi ^{[3
]}

Horita, Tetsuya ^{[5
]}

Atsumi, Tatsuya ^{[5
]}

Ishii, Tomonori ^{[6
]}

Okamoto, Akiko ^{[2
]}

Fujio, Keishi ^{[2
]}

Hirakata, Michito ^{[7
]}

Amano, Hirofumi ^{[8
]}

Kondo, Yuya ^{[9
]}

Ito, Satoshi ^{[9
]}

Takada, Kazuki ^{[10
,11
]}

Mimori, Akio ^{[12
]}

Saito, Kazuyoshi ^{[13
]}

Kamachi, Makoto ^{[14
]}

Kawaguchi, Yasushi ^{[15
]}

Ikari, Katsunori ^{[15
]}

Mohammed, Osman Wael ^{[16
]}

Matsuda, Koichi ^{[16
]}

Terao, Chikashi ^{[17
,18
]}

Ohmura, Koichiro ^{[17
]}

Myouzen, Keiko ^{[1
]}

Hosono, Naoya ^{[19
]}

Tsunoda, Tatsuhiko ^{[20
]}

Nishimoto, Norihiro ^{[21
]}

Mimori, Tsuneyo ^{[17
]}

Matsuda, Fumihiko ^{[18
]}

Tanaka, Yoshiya ^{[13
]}

Sumida, Takayuki ^{[9
]}

Yamanaka, Hisashi ^{[15
]}

Takasaki, Yoshinari ^{[8
]}

Koike, Takao ^{[5
]}

Horiuchi, Takahiko ^{[22
]}

Hayashi, Kenshi ^{[4
]}

Kubo, Michiaki ^{[19
]}

Kamatani, Naoyuki ^{[3
]}

Yamada, Ryo ^{[1
,18
]}

Nakamura, Yusuke ^{[16
]}

Yamamoto, Kazuhiko ^{[1
,2
]}

机构：

[1] RIKEN, CGM, Lab Autoimmune Dis, Yokohama, Kanagawa, Japan

[2] Univ Tokyo, Dept Allergy & Rheumatol, Grad Sch Med, Tokyo, Japan

[3] RIKEN, CGM, Lab Stat Anal, Yokohama, Kanagawa, Japan

[4] Kyushu Univ, Med Inst Bioregulat, Div Genome Anal, Res Ctr Genet Informat, Fukuoka 812, Japan

[5] Hokkaido Univ, Grad Sch Med, Dept Med 2, Sapporo, Hokkaido, Japan

[6] Tohoku Univ, Dept Hematol & Rheumatol, Grad Sch Med, Sendai, Miyagi 980, Japan

[7] Keio Univ, Sch Med, Dept Internal Med, Div Rheumatol, Tokyo, Japan

[8] Juntendo Univ, Sch Med, Dept Internal Med & Rheumatol, Tokyo 113, Japan

[9] Univ Tsukuba, Div Clin Immunol, Doctoral Program Clin Sci, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki, Japan

[10] Tokyo Med & Dent Univ, Grad Sch, Dept Med, Tokyo, Japan

[11] Tokyo Med & Dent Univ, Grad Sch, Dept Rheumatol, Tokyo, Japan

[12] Natl Ctr Global Hlth & Med, Div Rheumat Dis, Tokyo, Japan

[13] Univ Occupat & Environm Hlth, Dept Internal Med 1, Kitakyushu, Fukuoka 807, Japan

[14] Nagasaki Univ, Grad Sch Biomed Sci, Unit Translat Med, Dept Immunol & Rheumatol, Nagasaki 852, Japan

[15] Tokyo Womens Med Univ, Inst Rheumatol, Tokyo, Japan

[16] Univ Tokyo, Inst Med Sci, Mol Med Lab, Ctr Human Genome, Tokyo, Japan

[17] Kyoto Univ, Grad Sch Med, Dept Rheumatol & Clin immunol, Kyoto, Japan

[18] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan

[19] RIKEN, CGM, Lab Genotyping Dev, Yokohama, Kanagawa, Japan

[20] RIKEN, CGM, Lab Med Informat, Yokohama, Kanagawa, Japan

[21] Wakayama Med Univ, Lab Immune Regulat, Wakayama, Japan

[22] Kyushu Univ, Grad Sch Med Sci, Dept Med & Biosyst Sci, Fukuoka 812, Japan

来源：

PLOS GENETICS | 2012年 / 8卷 / 01期

关键词：

SINGLE-NUCLEOTIDE-POLYMORPHISM; RHEUMATOID-ARTHRITIS; GENE-EXPRESSION; FUNCTIONAL VARIANTS; RISK LOCI; ERYTHEMATOSUS; POPULATION; DISEASE; TNFAIP3; ITGAM;

D O I：

10.1371/journal.pgen.1002455

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 = 8.3x10(-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.

引用

页数：10

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