Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis

被引：81

作者：

Terao, Chikashi ^{[1
,2
,3
,4
,5
]}

Kawaguchi, Takahisa ^{[1
]}

Dieude, Philippe ^{[6
]}

Varga, John ^{[7
]}

Kuwana, Masataka ^{[8
]}

Hudson, Marie ^{[9
,10
]}

Kawaguchi, Yasushi ^{[11
]}

Matucci-Cerinic, Marco ^{[12
]}

Ohmura, Koichiro ^{[13
]}

Riemekasten, Gabriela ^{[14
,15
]}

Kawasaki, Aya ^{[16
]}

Airo, Paolo ^{[17
]}

Horita, Tetsuya ^{[18
]}

Oka, Akira ^{[19
]}

Hachulla, Eric ^{[20
]}

Yoshifuji, Hajime ^{[13
]}

Caramaschi, Paola ^{[21
]}

Hunzelmann, Nicolas ^{[22
]}

Baron, Murray ^{[9
,10
]}

Atsumi, Tatsuya ^{[18
]}

Hassoun, Paul ^{[23
]}

Torii, Takeshi ^{[24
]}

Takahashi, Meiko ^{[1
]}

Tabara, Yasuharu ^{[1
]}

Shimizu, Masakazu ^{[1
]}

Tochimoto, Akiko ^{[11
]}

Ayuzawa, Naho ^{[25
]}

Yanagida, Hidetoshi ^{[25
]}

Furukawa, Hiroshi ^{[16
,26
]}

Tohma, Shigeto ^{[26
]}

Hasegawa, Minoru ^{[27
]}

Fujimoto, Manabu ^{[28
]}

Ishikawa, Osamu ^{[29
]}

Yamamoto, Toshiyuki ^{[30
]}

Goto, Daisuke ^{[31
]}

Asano, Yoshihide ^{[32
]}

Jinnin, Masatoshi ^{[33
]}

Endo, Hirahito ^{[34
]}

Takahashi, Hiroki ^{[35
]}

Takehara, Kazuhiko ^{[36
]}

Sato, Shinichi ^{[32
]}

Ihn, Hironobu

Raychaudhuri, Soumya ^{[3
,4
,5
,37
]}

Liao, Katherine ^{[3
]}

Gregersen, Peter ^{[38
]}

Tsuchiya, Naoyuki ^{[16
]}

Riccieri, Valeria ^{[39
]}

Melchers, Inga ^{[40
]}

Valentini, Gabriele ^{[41
]}

Cauvet, Anne ^{[42
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Ctr Genom Med, Kyoto, Japan

[2] Kyoto Univ, Ctr Promot Interdisciplinary Educ & Res, Grad Sch Med, Kyoto, Japan

[3] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA

[4] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA USA

[5] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[6] Paris 7 Univ, Rheumatol Bichat Hosp, Paris, France

[7] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA

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

[9] Jewish Gen Hosp, Montreal, PQ, Canada

[10] Lady Davis Res Inst, Montreal, PQ, Canada

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

[12] Univ Florence, Dept Expt & Clin Med, Dept Med & Geriatr Med, Div Rheumatol AOUC, Florence, Italy

[13] Kyoto Univ, Grad Sch Med, Dept Rheumatol & Clin Immunol, Kyoto, Japan

[14] Univ Lubeck, Clin Rheumatol, Lubeck, Germany

[15] German Lung Ctr Borstel, Leibniz Inst, Hannover, Germany

[16] Univ Tsukuba, Fac Med, Mol & Genet Epidemiol Lab, Tsukuba, Ibaraki, Japan

[17] Spedali Civil Brescia, Rheumatol Unit, Brescia, Italy

[18] Hokkaido Univ, Grad Sch Med, Div Rheumatol Endocrinol & Nephrol, Sapporo, Hokkaido, Japan

[19] Tokai Univ, Inst Med Sci, Isehara, Kanagawa, Japan

[20] Lille Univ, Internal Med Dept, FHU Immune Mediated Inflammatory Dis & Targeted T, Lille, France

[21] Univ Verona, Azienda Osped Univ Integrata, Rheumatol Dept, Verona, Italy

[22] Univ Cologne, Dermatol Dept, Cologne, Germany

[23] Johns Hopkins Univ, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD USA

[24] Torii Clin, Kyoto, Japan

[25] Natl Hosp Org, Natl Utano Hosp, Dept Rheumatol, Kyoto, Japan

[26] Natl Hosp Org, Sagamihara Hosp, Clin Res Ctr Allergy & Rheumatol, Sagamihara, Kanagawa, Japan

[27] Univ Fukui, Fac Med Sci, Dept Dermatol, Div Med, Fukui, Japan

[28] Univ Tsukuba, Fac Med, Dept Dermatol, Tsukuba, Ibaraki, Japan

[29] Gunma Univ, Grad Sch Med, Dept Dermatol, Gunma, Japan

[30] Fukushima Med Univ, Dept Dermatol, Fukushima, Japan

[31] Univ Tsukuba, Fac Med, Dept Internal Med, Tsukuba, Ibaraki, Japan

[32] Univ Tokyo, Grad Sch Med, Dept Dermatol, Tokyo, Japan

[33] Kumamoto Univ, Fac Life Sci, Dept Dermatol & Plast Surg, Kumamoto, Japan

[34] Toho Univ, Sch Med, Dept Internal Med, Div Rheumatol, Tokyo, Japan

[35] Sapporo Med Univ, Sch Med, Dept Rheumatol & Clin Immunol, Sapporo, Hokkaido, Japan

[36] Kanazawa Univ, Fac Med, Inst Med Pharmaceut & Hlth Sci, Dept Dermatol, Kanazawa, Ishikawa, Japan

[37] Univ Manchester, Fac Biol Med & Hlth, Manchester Acad Hlth Sci Ctr, Arthrit Res UK Ctr Genet & Genom,Ctr Musculoskele, Manchester, Lancs, England

[38] Robert S Boas Ctr Genom & Human Genet, Feinstein Inst Med Res, Manhasset, NY USA

[39] Sapienza Univ Rome, Rome, Italy

[40] Univ Med Ctr, Freiburg, Germany

[41] Univ Naples 2, Dept Clin & Expt Med, Rheumatol Sect, Naples, Italy

[42] Paris Descartes Univ, Cochin Inst, INSERM, U1016 UMR 8104, Paris, France

[43] Batiment B Purpan Hosp Toulouse, INSERM, U1220, IRSD, Paris, France

来源：

ANNALS OF THE RHEUMATIC DISEASES | 2017年 / 76卷 / 06期

关键词：

GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; LUPUS-ERYTHEMATOSUS; RISK-FACTOR; LOCI; VARIANTS; VISUALIZATION; REPLICATION; SCAN;

D O I：

10.1136/annrheumdis-2016-210645

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objectives Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. Methods We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. Results We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4x10(-10) and 6.6x10(-10), respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naive primary T cell. Conclusions GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

引用

页码：1150 / 1158

页数：9

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