A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations

被引：66

作者：

Bossini-Castillo, Lara ^{[1
]}

Martin, Jose-Ezequiel ^{[1
]}

Broen, Jasper ^{[2
]}

Gorlova, Olga ^{[3
]}

Simeon, Carmen P. ^{[4
]}

Beretta, Lorenzo ^{[5
,6
]}

Vonk, Madelon C. ^{[2
]}

Luis Callejas, Jose ^{[7
]}

Castellvi, Ivan ^{[8
]}

Carreira, Patricia ^{[9
]}

Jose Garcia-Hernandez, Francisco ^{[10
]}

Fernandez Castro, Monica ^{[11
]}

Coenen, Marieke J. H. ^{[12
]}

Riemekasten, Gabriela ^{[13
]}

Witte, Torsten ^{[14
]}

Hunzelmann, Nicolas ^{[15
]}

Kreuter, Alexander ^{[16
]}

Distler, Joerg H. W. ^{[17
]}

Koeleman, Bobby P. ^{[18
]}

Voskuyl, Alexandre E. ^{[19
]}

Schuerwegh, Annemie J. ^{[20
]}

Palm, Oyvind ^{[21
]}

Hesselstrand, Roger ^{[22
]}

Nordin, Annika ^{[23
]}

Airo, Paolo ^{[24
]}

Lunardi, Claudio ^{[25
]}

Scorza, Raffaella ^{[5
,6
]}

Shiels, Paul ^{[26
]}

van Laar, Jacob M. ^{[27
]}

Herrick, Ariane ^{[28
]}

Worthington, Jane ^{[28
]}

Denton, Christopher ^{[29
]}

Tan, Filemon K. ^{[30
]}

Arnett, Frank C. ^{[30
]}

Agarwal, Sandeep K. ^{[30
]}

Assassi, Shervin ^{[30
]}

Fonseca, Carmen ^{[29
]}

Mayes, Maureen D. ^{[30
]}

Radstake, Timothy R. D. J. ^{[2
]}

Martin, Javier ^{[1
]}

机构：

[1] IPBLN CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18100, Spain

[2] Radboud Univ Nijmegen, Med Ctr, Dept Rheumatol, NL-6525 Nijmegen, Netherlands

[3] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[4] Hosp Valle de Hebron, Serv Med Interna, Barcelona 08035, Spain

[5] IRCCS Fdn Policlin Mangiagalli Regina Elena, I-20122 Milan, Italy

[6] Univ Milan, I-20122 Milan, Italy

[7] Hosp Clin Univ San Cecilio, Serv Med Interna, Unidad Enfermedades Sistem Autoinmunes, Granada 18012, Spain

[8] Hosp Santa Creu & Sant Pau, Serv Reumatol, Barcelona 08025, Spain

[9] Hosp 12 Octubre, Serv Reumatol, E-28041 Madrid, Spain

[10] Hosp Virgen del Rocio, Serv Med Interna, Seville 41013, Spain

[11] Hosp Univ Puerta del Hierro Majadahonda, Serv Reumatol, Madrid 28222, Spain

[12] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 Nijmegen, Netherlands

[13] Charite, Dept Rheumatol & Clin Immunol, D-12203 Berlin, Germany

[14] Hannover Med Sch, D-30625 Hannover, Germany

[15] Univ Cologne, Dept Dermatol, D-50923 Cologne, Germany

[16] Ruhr Univ Bochum, D-44801 Bochum, Germany

[17] Univ Erlangen Nurnberg, Inst Clin Immunol, Dept Internal Med 3, D-91054 Erlangen, Germany

[18] Univ Med Ctr Utrecht, Dept Med Genet, Sect Complex Genet, NL-3508 AB Utrecht, Netherlands

[19] Vrije Univ Amsterdam, Med Ctr, Dept Rheumatol, NL-1081 Amsterdam, Netherlands

[20] Leiden Univ, Med Ctr, Dept Rheumatol, NL-2333 Leiden, Netherlands

[21] Oslo Univ Hosp, Rikshosp, Dept Rheumatol, N-0027 Oslo, Norway

[22] Lund Univ, Dept Rheumatol, S-22241 Lund, Sweden

[23] Karolinska Inst, S-17177 Stockholm, Sweden

[24] Serv Reumatol & Immunol Clin Spedali Civili, I-25018 Brescia, Italy

[25] Univ Verona, Dept Med, I-37129 Verona, Italy

[26] Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland

[27] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[28] Univ Manchester, Manchester Acad Hlth Sci Ctr, Arthrit Res UK Epidemiol Unit, Manchester M13 9PT, Lancs, England

[29] Royal Free & Univ Coll Med Sch, Ctr Rheumatol, London NW3 2QG, England

[30] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA

来源：

HUMAN MOLECULAR GENETICS | 2012年 / 21卷 / 04期

关键词：

GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; BEHCETS-DISEASE; TYROSINE PHOSPHORYLATION; CONFERS SUSCEPTIBILITY; RECEPTOR GENE; TH1; CELLS; IL-12; IL23R; INTERLEUKIN-12;

D O I：

10.1093/hmg/ddr522

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P-MH = 1.92 x 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P-MH = 4.84 x 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P-chi 2 = 2.82 x 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P-MH = 2.82 x 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.

引用

页码：926 / 933

页数：8

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