Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population
Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population
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DOI：
10.1136/ard.2009.127928
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发表时间：
2010-11-01
影响因子：
27.4
通讯作者：
Allanore, Y.
中科院分区：
文献类型：
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作者：
Dieude, P.;Guedj, M.;Allanore, Y.
背景：TNFAIP3编码泛素修饰酶，它是炎症信号通路的关键调节因子。目的探讨TNFAIP3基因多态与系统性硬化症(SSC)的关系。方法对1018例SSC患者和1012例法国高加索人对照的3个单核苷酸多态(SNPs)进行基因分型。选择了两个基因间SNPs rs10499194和rs6920220，以及一个位于TNFAIP3内含子2的SNP，rs5029939。在第一组中被发现与SSc相关的TNFAIP3 rs5029939在第二组中进行了基因分型，第二组包括来自德国的465名SSC患者和182名对照，以及来自意大利的184名SSC患者和124名对照。结果rs5029939 G等位基因与SSC易感性显著相关(合并OR=2.08(95%CI 1.59~2.72)；p=1.16×10(-7))，而rs10499194和rs6920220变异与SSC易感性无关。在法国样本中，只有一种预测的单倍型与SSc显著相关(p=8.91x10(-8))，并且该单倍型只有在存在rs5029939风险等位基因时才具有区别性，这表明该SNP标记了关联信号。Rs5029939与弥漫性皮肤SSC(合并OR=2.71(1.94~3.79)，p=5.2x10(-9))、纤维性肺泡炎(合并OR=2.26(1.61~3.17)，p=2.5x10(-6))和肺动脉高压(合并OR=3.11(1.86~5.17)，p=1.3x10(-5))的关联最强。结论TNFAIP3是SSC的遗传易感因素。
Background TNFAIP3 encodes the ubiquitin-modifying enzyme, a key regulator of inflammatory signalling pathways. Convincing associations between TNFAIP3 variants and autoimmune diseases have been reported.Objective To investigate the association of TNFAIP3 polymorphisms with systemic sclerosis (SSc).Methods Three single nucleotide polymorphisms (SNPs) in a set of 1018 patients with SSc and 1012 controls of French Caucasian origin were genotyped. Two intergenic SNPs, rs10499194 and rs6920220, and one located in TNFAIP3 intron 2, rs5029939, were selected. The TNFAIP3 rs5029939 found to be associated with SSc in this first set was then genotyped in a second set of 465 patients with SSc and 182 controls from Germany and 184 patients with SSc and 124 controls from Italy. Pooled odd ratios were calculated by Mantel-Haenszel meta-analysis.Results The rs5029939 G allele was found to be significantly associated with SSc susceptibility (pooled OR=2.08 (95% CI 1.59 to 2.72); p=1.16x10(-7)), whereas the rs10499194 and rs6920220 variants displayed no association. Only one of the predicted haplotypes investigated in the French sample was significantly associated with SSc (p=8.91x10(-8)), and this haplotype was discriminating only in the presence of the rs5029939 risk allele, suggesting that this SNP tags the association signal. The strongest associations of rs5029939 with subphenotypes, having large magnitudes for complex genetic disorders, were observed for diffuse cutaneous SSc (pooled OR=2.71 (1.94 to 3.79), p=5.2x10(-9)), fibrosing alveolitis (pooled OR=2.26 (1.61 to 3.17), p=2.5x10(-6)) and pulmonary arterial hypertension (pooled OR=3.11 (1.86 to 5.17), p=1.3x10(-5)).Conclusion These results suggest that TNFAIP3 is a genetic susceptibility factor for SSc.