Coustet Baptiste, Dieudé Philippe, Guedj Mickael, Bouaziz Mathieu, Avouac Jerome, Ruiz Barbara, Hachulla Eric, Diot Elisabeth, Cracowski Jean-Luc, Tiev Kiet, Sibilia Jean, Mouthon Luc, Frances Camille, Amoura Zahir, Carpentier Patrick, Cosnes Anne, Meyer Olivier, Kahan Andre, Boileau Catherine, Chiocchia Gilles, Allanore Yannick
INSERM U1016, Université Paris Descartes, Paris, France.
Arthritis Rheum. 2011 Jul;63(7):2091-6. doi: 10.1002/art.30379.
Accumulating evidence suggests that B cells are involved in systemic sclerosis (SSc). BANK1 has been reproducibly reported to be associated with diffuse cutaneous SSc (dcSSc). BLK encodes another B cell signal transducer, and a functional variant at the C8orf13-BLK locus has been found to be associated with SSc in Caucasians. However, no independent replication has been reported, and there are discrepancies in the genotype-phenotype correlation between these studies in Caucasians and another study performed in the Japanese population. Therefore, in a large cohort of French Caucasians and using a meta-analysis of the available data, this study was undertaken to determine whether the C8orf13-BLK locus is associated with SSc, and to assess the possibility of interaction between BLK and BANK1 in SSc.
The C8orf13-BLK rs13277113 genotype was determined in 1,031 patients with SSc and 1,014 control subjects for whom BANK1 genotypes were available. Meta-analysis of the 3 available data sets (6,078 individuals) was also performed.
Minor allele frequencies for rs13277113 revealed an association restricted to the dcSSc subtype (P = 0.012, odds ratio [OR] 1.29) in the French sample. Meta-analysis of the combined Caucasian populations showed an association of this genotype with both SSc (P = 0.0013, OR 1.16, 95% confidence interval [95% CI] 1.06-1.26) and dcSSc (P = 0.0012, OR 1.23, 95% CI 1.08-1.39). Inclusion of the Japanese population confirmed the overall association with the disease, with the strongest association observed with dcSSc (P = 3.27 × 10⁻⁵, OR 1.27). Secondary analysis in the French sample revealed additive effects between C8orf13-BLK and BANK1, mainly in the dcSSc subset.
These results confirm C8orf13-BLK as an SSc risk locus. The strongest effects, and particularly additive effects, were observed in the interaction between C8orf13-BLK and BANK1 in the dcSSc subset.
越来越多的证据表明B细胞参与系统性硬化症（SSc）。已有重复性报道称BANK1与弥漫性皮肤型SSc（dcSSc）相关。BLK编码另一种B细胞信号转导分子，并且已发现C8orf13 - BLK基因座上的一个功能性变体与白种人中的SSc相关。然而，尚未有独立重复验证的报道，而且这些白种人研究与另一项在日本人群中进行的研究在基因型 - 表型相关性方面存在差异。因此，在一大群法国白种人中，并通过对现有数据进行荟萃分析，开展本研究以确定C8orf13 - BLK基因座是否与SSc相关，并评估BLK和BANK1在SSc中相互作用的可能性。
在1031例SSc患者和1014例可获取BANK1基因型的对照受试者中确定C8orf13 - BLK rs13277113基因型。还对3个可用数据集（共6078例个体）进行了荟萃分析。
在法国样本中，rs13277113的次要等位基因频率显示仅与dcSSc亚型相关（P = 0.012，比值比[OR] 1.29）。对白种人合并人群的荟萃分析表明该基因型与SSc（P = 0.0013，OR 1.16，95%置信区间[95%CI] 1.06 - 1.26）和dcSSc（P = 0.0012，OR 1.23，95%CI 1.08 - 1.39）均相关。纳入日本人群后证实了该基因型与疾病的总体相关性，其中与dcSSc的相关性最强（P = 3.27×10⁻⁵，OR 1.27）。在法国样本中的二次分析揭示了C8orf13 - BLK和BANK1之间的加性效应，主要在dcSSc亚组中。
这些结果证实C8orf13 - BLK是一个SSc风险基因座。在dcSSc亚组中，C8orf13 - BLK和BANK1之间的相互作用观察到最强效应，尤其是加性效应。
