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

Bossini Castillo, Lara; Martín, José-Ezequiel; Callejas Rubio, José Luis; Martin, Javier

doi:10.1093/hmg/ddr522

Artículo principal (190.2Kb)

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URI: https://hdl.handle.net/10481/88469

DOI: 10.1093/hmg/ddr522

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Fecha

2012

Referencia bibliográfica

Bossini-Castillo L, Martin JE, Broen J, Gorlova O, Simeón CP, Beretta L, Vonk MC, Callejas JL, Castellví I, Carreira P, García-Hernández FJ, Fernández Castro M; Spanish Scleroderma Group; Coenen MJ, Riemekasten G, Witte T, Hunzelmann N, Kreuter A, Distler JH, Koeleman BP, Voskuyl AE, Schuerwegh AJ, Palm Ø, Hesselstrand R, Nordin A, Airó P, Lunardi C, Scorza R, Shiels P, van Laar JM, Herrick A, Worthington J, Denton C, Tan FK, Arnett FC, Agarwal SK, Assassi S, Fonseca C, Mayes MD, Radstake TR, Martin J. A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. Hum Mol Genet. 2012 Feb 15;21(4):926-33. doi: 10.1093/hmg/ddr522. Epub 2011 Nov 10. PMID: 22076442; PMCID: PMC3298110.

Patrocinador

This work was supported by the following grants: J.M. was funded by GEN-FER from the Spanish Society of Rheumatol- ogy, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucı́a, Spain, in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain and by Fondo Europeo de Desarrollo Regional (FEDER). T.R.D.J.R. was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). J.M. and T.R.D.J.R. were sponsored by the Orphan Disease Program grant from the Euro- pean League Against Rheumatism (EULAR). B.P.C.K. is sup- ported by the Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). T.W. was granted by DFG WI 1031/6.1 and DFG KFO 250 TP03. N.O. was funded by PI-0590-2010, Con- sejerı́a de Salud, Junta de Andalucı́a, Spain. The USA studies were supported by NIH/NIAMS Scleroderma Registry and DNA Repository (N01-AR-0-2251), NIH/NIAMS-RO1- AR055258 and NIH/NIAMS Center of Research Translation in Scleroderma (1P50AR054144) and the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-07-01-0111).

Resumen

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 × 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 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(χ2) = 2.82 × 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 × 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.

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