Meta-analysis of 65,734 Individuals Identifies TSPAN15 and SLC44A2 as Two Susceptibility Loci for Venous Thromboembolism
Meta-analysis of 65,734 Individuals Identifies TSPAN15 and SLC44A2 as Two Susceptibility Loci for Venous Thromboembolism
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DOI：
10.1016/j.ajhg.2015.01.019
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发表时间：
2015-04-02
影响因子：
9.8
通讯作者：
Morange, Pierre-Emmanuel
中科院分区：
文献类型：
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作者：
Germain, Marine;Chasman, Daniel I.;Morange, Pierre-Emmanuel
静脉血栓栓塞症（VTE）是一种复杂的血栓性疾病，具有环境和遗传因素，是心血管死亡的第三大原因。尽管已经发现了几种与VTE相关的遗传变异，但它们解释了病例中一小部分VTE风险。我们对全基因组关联研究（GWAS）进行了荟萃分析，以确定其他VTE易感基因。12个GWAS，共计7，507名VTE病例受试者和52，632名对照受试者，形成了我们的发现阶段，其中测试了6，751，884个SNP与VTE的关联。9个基因座达到全基因组显著性水平5 × 10 ~（-8），包括6个已知与VTE相关的基因座（ABO、F2、F5、F11、FGG和PROCR）和3个未被怀疑的基因座。在三项独立的病例对照研究中，选择了与后者映射的SNP进行复制，共计3，009名受VTE影响的个体和2，586名对照受试者。这一策略导致了两个VTE相关基因座TSPAN 15和SLC 44 A2的鉴定和复制，其主要风险等位基因与疾病的比值比分别为1.31（p = 1.67 x 10（-16））和1.21（p = 2.75 x 10（-15））。TSPAN 15位点的前导SNP是内含子rs78707713，前导SLC 44 A2 SNP是先前显示与输血相关急性肺损伤相关的非同义rs 2288904。我们进一步表明，这两种变体与已知的止血血浆标志物无关。TSPAN 15和SLC 44 A2不属于血栓形成的常规途径，并且与其他心血管疾病或相关的定量生物标志物无关。我们的发现揭示了静脉血栓栓塞病因的意外因素，并为静脉血栓栓塞病理生理学的新机制概念铺平了道路。
Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 x 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 x 10(-16)) and 1.21 (p = 2.75 x 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.