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

Lara Bossini-Castillo*, Jose Ezequiel Martin, Jasper Broen, Olga Gorlova, Carmen P. Simeón, Lorenzo Beretta, Madelon C. Vonk, Jose Luis Callejas, Ivan Castellví, Patricia Carreira, Francisco José García-Hernández, Mónica Fernández Castro, Marieke J.H. Coenen, Gabriela Riemekasten, Torsten Witte, Nicolas Hunzelmann, Alexander Kreuter, Jörg H.W. Distler, Bobby P. Koeleman, Alexandre E. VoskuylAnnemie J. Schuerwegh, Øyvind Palm, Roger Hesselstrand, Annika Nordin, Paolo Airó, Claudio Lunardi, Raffaella Scorza, Paul Shiels, Jacob M. van Laar, Ariane Herrick, Jane Worthington, Christopher Denton, Filemon K. Tan, Frank C. Arnett, Sandeep K. Agarwal, Shervin Assassi, Carmen Fonseca, Maureen D. Mayes, Timothy R.D.J. Radstake, Javier Martin

*Corresponding author for this work
63 Citations (Scopus)


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 [PMH5 1.92 3 10 -5 odds ratio (OR) 5 1.19] as the genetic variant with the firmest independent association observed in the analyzedGWASpeak of association. After the first follow-up phase, only the association of rs3790567 was consistent (PMH5 4.84 3 10 -3OR 5 1.12). The second follow-up phase confirmed this finding (Px2 5 2.82 3 10 -4 OR 5 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 (PMH5 2.82 3 10 -9 OR 5 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.

Original languageEnglish
Article numberddr522
JournalHuman Molecular Genetics
Issue number4
Pages (from-to)926-933
Number of pages8
Publication statusPublished - 02.2012

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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