Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations

Abstract

Objective: Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc.

Methods: Two variants in the C8orf13-BLK region (rs13277113 & rs2736340) were tested for association with 1050 SSc cases and 694 controls of North Americans of European descent and replicated in a second series 589 SSc cases and 722 controls from Spain.

Results: The "T" allele at rs2736340 variant was associated with SSc in both the U.S. and Spanish case-control series (P = 6.8 x 10(-5), OR 1.27, 95% CI 1.1-1.4). The "A" allele at rs13277113 variant was associated with SSc in the U.S. series only (P = 3.6 x 10(-4), OR 1.32, 95% CI 1.1-1.6) and was significant in the combined analyses of the two series (P = 2.0 x 10(-3); OR 1.20, 95% CI 1.1-1.3). Both variants demonstrated an association with the anti-centromere antibody (P = 2.2 x 10(-6) and P = 5.5 x 10(-4), respectively) and limited SSc (P = 3.3 x 10(-5) and P = 2.9 x 10(-3), respectively) in the combined analysis. Peripheral blood gene expression profiles suggest that B-cell receptor and NFkappaB signaling are dysregulated based on the risk haplotype of these variants.

Conclusion: We identify and replicate the association of the C8orf13-BLK region as a novel susceptibility factor for SSc, placing it in the category of common autoimmune disease susceptibility genes.

Figure 1

Estimated risk of rs2736340 (A,B,C) and rs13277113 (D,E,F) variants in SSc patients versus controls, by logistic regression analysis. A,D- North American samples controlling for the confounding effects of gender. B,E- Spanish samples controlling for the confounding effects of gender. C,F- Combined samples controlling for the confounding effects of gender and two case-control series. SSc = systemic sclerosis; OR = odds ratio; 95% CI = 95% confidence interval. ACA = anticentromere antibody; ATA = anti-topoisomerase I antibody; ARA = anti-RNA polymerase III antibody. Control subjects are used as reference for all comparisons. Both variants showed an additive mode of inheritance

Figure 2

Top Pathways which discriminate SSc peripheral blood cells stratified by C8orf13-BLK variants modeling on the IPA canonical pathway knowledge base (A) and the IPA molecular toxicology knowledge base (B). Comparisons between the rs2736340-rs13277113 heterozygote versus homozygote in SSc were performed. Green represents downregulated, gray represents no change, red represents upregulated, and open represents no overlap with the data set.

Figure 3

Comparison of gene expression in peripheral blood cells stratified by the C8orf13-BLK variants rs2736340-rs13277113 heterozygote versus homozygote in SSc demonstrates alterations in B Cell Receptor Signaling Pathway (A) and NFκB Signaling Pathway (B). Red represents upregulated genes. Green represents downregulated genes.