Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose
A recent large-scale fine mapping study -Immunochip- in systemic sclerosis (SSc) identified 3 novel genome-wide significant hits as well as a wide number of loci putatively associated with SSc (P-values between 5×10-3 and 5×10-8), which might result in real association signals that could be masked owing to a limited power. In this line, one of the locus that showed suggestive association signals was IL12RB1, which encodes the beta 1 subunit of the interleukin-12 (IL-12) receptor. Interestingly, several IL-12 pathway-related genes are confirmed genetic risk factors for SSc, such as IL12RB2, STAT4 and IL12A. Therefore, our aim was to evaluate the genetic contribution of the IL12RB1region in SSc through a follow-up strategy.
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 the previously published Immunochip dense fine-mapping study. Four IL12RB1 SNPs were selected for genotyping in a large 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. We also performed in sillico functional analyses for SNPs characterization.
Results
In the first phase of our study, 11 out of the 46 SNPs showed nominal association signals (P-values between 5×10-3 and 5×10-5). 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). Interestingly, the combined analysis (discovery plus replication cohorts) showed that the four selected SNPs were associated with SSc at the genome-wide significance level. Finally, our in silico functional analyses showed that the minor allele of rs436857 promoter SNP was in an IL12RB1 cis-expression Quantitative Trait Loci (eQTL) that decreased IL12RB1 expression (P-value = 2.4 x 10-81, Z-score = -19.10). Additionally, rs436857 showed evidence to affect the binding of several transcription factors. These results pinpoint rs436857 as the most likely causal variant for driving the reported association, narrowing down the signal to the promoter region of the gene.
Conclusion
The present study reports for the first time robust evidence for the implication of IL12RB1 in SSc genetic background and highlights the importance of the follow-up studies. The results reinforce the relevance of IL-12 pathway in SSc pathophysiology, shedding light on our understanding of the immune system processes implicated in SSc development, and suggest that blocking this pathway could be a possible new therapeutic target.
Disclosure:
E. Lopez-Isac,
None;
L. Bossini-Castillo,
None;
S. G. Guerra,
None;
S. Assassi,
None;
X. Zhou,
None;
C. P. Simeón,
None;
N. Ortego-Centeno,
None;
I. Castellvi,
None;
P. Carreira,
None;
O. Gorlova,
None;
L. Beretta,
None;
A. Santaniello,
None;
C. Lunardi,
None;
R. Hesselstrand,
None;
A. Nordin,
None;
G. Riemekasten,
None;
T. Witte,
None;
N. Hunzelmann,
None;
A. Kreuter,
None;
J. H. Distler,
None;
A. E. Voskuyl,
None;
J. K. De Vries-Bouwstra,
None;
B. P. C. Koeleman,
None;
A. Herrick,
None;
J. Worthington,
None;
C. Denton,
None;
C. Fonseca,
None;
T. R. D. J. Radstake,
None;
M. D. Mayes,
None;
J. Martin,
None.
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-il12rb1-as-a-novel-systemic-sclerosis-susceptibility-locus/