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=6.8×10−5, 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=3.6×10−4, OR 1.32, 95%CI 1.1–1.6) and was significant in the combined analyses of the two series (P=2.0×10−3; OR 1.20, 95%CI 1.1–1.3). Both variants demonstrated an association with the anti-centromere antibody (P=2.2×10−6 and P=5.5×10−4, respectively) and limited SSc (P=3.3×10−5 and P=2.9×10−3, respectively) in the combined analysis. Peripheral blood gene expression profiles suggest that B-cell receptor and NFκB 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.

Genetic risk factors for sclerotic graft-versus-host disease

“…The MAF for each SNP was consistent with the values reported in studies of systemic sclerosis. [11][12][13][14][15][16][17][18][19] Two SNPs (rs11642873 and rs1234314) did not pass quality control because of low call rates on one of the genotyping platforms (see supplemental Table 1, available on the Blood Web site). Supplemental Table 2 shows the genotype distributions and MAFs for each SNP, according to the presence or absence of sclerosis.…”

“…MAFs were similar between donors and recipients, and are consistent with results from studies of patients with systemic sclerosis. [11][12][13][14][15][16][17][18][19] ‡All ORs were derived from allelic genetic models.…”

Unraveling the genetic component of systemic sclerosis

“…In the Wrst report of BLK inXuence in SSc genetic predisposition, the combined analysis of Caucasian US and European cohorts revealed the association of the minor allele of two genetic variants (rs13277113 and rs2736340) with increased susceptibility to SSc, and speciWcally with the lcSSc and ACA+ subsets (Gourh et al 2010a). Moreover, the risk haplotype comprising both minor alleles was associated with disrupted gene expression of peripheralblood circulating B cells, especially NFkB signaling pathway (Gourh et al 2010a). Analysis of rs13277113 polymorphism in a Japanese cohort showed association of this marker with the whole disease independently of the subtype or autoantibody subgroup (Ito et al 2010).…”

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

“…49,[56][57][58][59][60][61][62][63][64][65][66][67] Americans of non-European descent showed a very low T allele frequency, as low as 1.1% in Mexico. 68 North Africa had a similar T allele frequency to Turkey and the Middle East, which ranged from 2 to 3.5%; [69][70][71][72][73][74][75] however, PTPN22 is not polymorphic in the black African population.…”