Background/Purpose: Systemic sclerosis (SSc) is a fibrotic autoimmune disease that represents a clear example of a sex biased immune disorder. The X-chromosome gene IRAK1 has been associated with SSc and systemic lupus erythematosus (SLE), being an interesting candidate to explain this sexual dimorphism. However, IRAK1 is in the same haplotypic block as MECP2 on Xq28, and recent studies suggest that functional genetic variants of the latter locus may explain the association signals with SLE observed in IRAK1. We aimed to evaluate whether the SSc-associated IRAK1 polymorphism rs1059702 (Phe196Ser) is the causal variant of the Xq28 association or whether it reflects another association signal from the nearby MECP2.

Methods: Only women were included in the study. We analysed a total of 3065 SSc patients and 2630 healthy controls from five independent Caucasian cohorts (Spain, USA, Germany, The Netherlands, and UK). A tagging strategy was used to select four taggers that cover all the common genetic variation within MECP2 (r2≥0.8) in the CEU population of the HapMap database (rs3027935, rs17435, rs5987201 and rs5945175). We also included the SSc-associated IRAK1 genetic variant rs1059702. The genotyping was performed with predesigned TaqMan assays. Plink was used for the statistical analyses. P-values were corrected for multiple testing using FDR.

Results: IRAK1 rs1059702 was associated with diffuse cutaneous SSc (dcSSc; P_FDR=4.12×10-3, OR=1.27), and trends of association were evident in the global SSc/control (P_FDR=0.070, OR=1.13) and anti-topoisomerase positive (ATA+)/control (P_FDR=0.087, OR=1.23) comparisons, consistent with previously published data. Similarly, the MECP2 rs17435 variant reached statistical significance after comparing the global disease group and dcSSc subgroup with the control population (P_FDR=2.68 x10-3, OR=1.19, and P_FDR=5.26×10-4, OR=1.30, respectively). Conditional logistic regression analyses showed that the association of IRAK1 rs1059702 with dcSSc was explained by that of MECP2 rs17435, because only the latter remained significant after conditioned to each other (rs1059702 conditioned P=0.786; rs17435 conditioned P=0.049). However, the analysis of pulmonary fibrosis (PF) data suggested that IRAK1 rs1059702 was consistently associated with this feature, since statistical significance was observed when comparing PF+ vs controls (P_FDR=0.039, OR=1.30) and PF+ vs PF- (P=0.025, OR=1.26), but not PF- vs controls (P=0.574, OR=1.04).

Conclusion:

Our data suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 associated with PF, and another in MECP2 associated with dcSSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-association-of-irak1-and-mecp2-with-specific-systemic-sclerosis-phenotypes/