Identification of IL12RB1 as a Novel Systemic Sclerosis Susceptibility Locus

This is the authors' abstract. We don't add key points for this paper.

Objective: A recent large-scale fine mapping study -Immunochip- in systemic sclerosis (SSc) identified suggestive association signals in the IL12RB1 locus. The aim of this study was to evaluate the contribution of IL12RB1 genetic region in the SSc genetic background through a follow-up strategy of the Immunochip data. Methods: Forty-six single-nucleotide polymorphisms (SNPs) within the IL12RB1 region were screened in a discovery cohort comprising 1,871 SSc cases and 3,636 controls from a previously published Immunochip dense fine-mapping study. Four IL12RB1 SNPs were selected for genotyping in an independent Caucasian replication cohort. A meta-analysis of the data from the original Immunochip discovery cohort and the replication cohort was performed for a combined total of 5,052 SSc patients and 8,712 healthy controls. Results: In the first phase of our study we observed nominal association signals for 11 SNPs (P-values between 5x10-3 and 5x10-5). After conditional logistic regression analyses, we selected four SNPs (rs8109496, rs2305743, rs436857 and rs11668601) as the genetic variants which better explained the observed signals in the IL12RB1 region. One SNP, rs2305743, reached the genome-wide significance level in the independent replication cohort (PMH = 3.936 x 10-8, OR= 0.79, CI 95% 0.73 to 0.86). Interestingly, the combined analysis (discovery plus replication cohorts) showed that the four selected SNPs were associated with SSc at the genome-wide significance level. Conclusion: This study provides robust evidences for the association of IL12RB1 locus with SSc adding a novel IL-12 pathway related gene into the list of SSc susceptibility loci.