Combined effects of thrombosis pathway gene variants predict cardiovascular events.
Combined effects of thrombosis pathway gene variants predict cardiovascular events.
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DOI：
10.1371/journal.pgen.0030120
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发表时间：
2007-07
期刊：
影响因子：
4.5
通讯作者：
Perola M
中科院分区：
文献类型：
--
作者：
Auro K;Alanne M;Kristiansson K;Silander K;Kuulasmaa K;Salomaa V;Peltonen L;Perola M
复杂疾病的遗传背景被认为是由几个低风险基因座组成的。解决这种复杂性可能需要大样本量和同时分析不同的易感变异。我们研究了四种血栓形成基因：凝血因子V（F5）、细胞间粘附分子1（ICAM 1）、蛋白C（PROC）和血栓调节蛋白（THBD）在心血管疾病中的作用。在来自芬兰的两个独立采样的人群队列中分析了单个等位基因变异及其成对组合。从14，140名FINRISK参与者（FINRISK-92，n = 5，999和FINRISK-97，n = 8，141）中，我们选择了2，222名样本进行基因分型，包括528例心血管疾病（CVD）病例和随机亚组，共计786例。为了覆盖所有已知的常见单倍型（>10%），对54个单核苷酸多态性（SNP）进行了基因分型。分类树分析确定了11个SNPs，在考克斯的比例风险模型中进一步分析为单一变异和成对组合。通过使用两个独立的队列和错误发现率来控制多重测试。在女性中，F5 rs7542281 × THBD rs 1042580与三个单一F5 SNP的组合与CVD事件相关。在男性中，PROC rs 1041296与ICAM 1 rs 5030341或F5 rs 2269648结合时与总死亡率相关。作为单一变异，PROC rs 1401296与F5 Leiden突变一起与缺血性卒中事件相关。我们的策略是将分类树分析与更传统的遗传模型联合收割机结合起来，成功地鉴定了SNP--无论是联合作用还是作为单一变异--诱发CVD，并在两个独立的队列中产生了一致的结果。这些结果表明，在人群水平上，这四个血栓形成基因的变异有助于动脉心血管事件。心血管疾病的遗传背景在很大程度上仍然是未知的。与其他复杂疾病一样，遗传风险被认为包括几种遗传变异及其可能的相互作用。任何复杂性状的遗传成分的阐明最有可能需要同时检查各种基因在大的和良好的表征研究样品。我们的研究探讨了四种血栓形成基因在心血管疾病中的作用：凝血因子V，细胞间粘附分子1，蛋白C和血栓调节蛋白。这些基因形成一个生理途径，是凝血级联反应的一部分。他们的缺陷，如因子V基因的莱顿突变，易患静脉血栓形成，使他们成为参与心血管事件的诱人候选人。考虑到这些基因在分子水平上的相互作用，探索其遗传效应的合理方法是对所有四个基因进行基因特异性分析，以说明它们可能的相互作用。该研究将分类树与经典的遗传分析相结合，涵盖了所有已知的常见基因变异。结果表明，这四个基因中的变异单独或以各种等位基因组合的形式导致疾病风险。
The genetic background of complex diseases is proposed to consist of several low-penetrance risk loci. Addressing this complexity likely requires both large sample size and simultaneous analysis of different predisposing variants. We investigated the role of four thrombosis genes: coagulation factor V (F5), intercellular adhesion molecule 1 (ICAM1), protein C (PROC), and thrombomodulin (THBD) in cardiovascular diseases. Single allelic gene variants and their pair-wise combinations were analyzed in two independently sampled population cohorts from Finland. From among 14,140 FINRISK participants (FINRISK-92, n = 5,999 and FINRISK-97, n = 8,141), we selected for genotyping a sample of 2,222, including 528 incident cardiovascular disease (CVD) cases and random subcohorts totaling 786. To cover all known common haplotypes (>10%), 54 single nucleotide polymorphisms (SNPs) were genotyped. Classification-tree analysis identified 11 SNPs that were further analyzed in Cox's proportional hazard model as single variants and pair-wise combinations. Multiple testing was controlled by use of two independent cohorts and with false-discovery rate. Several CVD risk variants were identified: In women, the combination of F5 rs7542281 × THBD rs1042580, together with three single F5 SNPs, was associated with CVD events. Among men, PROC rs1041296, when combined with either ICAM1 rs5030341 or F5 rs2269648, was associated with total mortality. As a single variant, PROC rs1401296, together with the F5 Leiden mutation, was associated with ischemic stroke events. Our strategy to combine the classification-tree analysis with more traditional genetic models was successful in identifying SNPs—acting either in combination or as single variants—predisposing to CVD, and produced consistent results in two independent cohorts. These results suggest that variants in these four thrombosis genes contribute to arterial cardiovascular events at population level. The genetic background of cardiovascular diseases is still largely unknown. As in other complex diseases, the genetic risk is thought to consist of several genetic variants and their possible interactions. Elucidation of the genetic component of any complex trait most likely requires simultaneous examination of various genes in large and well-characterized study samples. Our study explores the role in cardiovascular disease of four thrombosis genes: coagulation factor V, intercellular adhesion molecule 1, protein C, and thrombomodulin. These genes form a physiological pathway that is part of the coagulation cascade. Their defects, such as the Leiden mutation in factor V gene, predispose to venous thrombosis, making them tempting candidates for involvement with cardiovascular events. Given the interactions of these genes at the molecular level, a logical way to explore their genetic effects is simultanous rather than gene-specific analysis of all the four genes, aiming to illustrate their possible interplay. The study setting combines classification trees with classic genetic analyses and covers all known common variants of the genes. The results imply that the variants in these four genes contribute to disease risk either alone or in various allelic combinations.
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影响因子：
15.8
作者：
Weedon MN;McCarthy MI;Hitman G;Walker M;Groves CJ;Zeggini E;Rayner NW;Shields B;Owen KR;Hattersley AT;Frayling TM
通讯作者：
Frayling TM
影响因子：
4.5
作者：
Komulainen K;Alanne M;Auro K;Kilpikari R;Pajukanta P;Saarela J;Ellonen P;Salminen K;Kulathinal S;Kuulasmaa K;Silander K;Salomaa V;Perola M;Peltonen L
通讯作者：
Peltonen L
影响因子：
0.9
作者：
Silander, K;Komulainen, K;Saarela, J
通讯作者：
Saarela, J
DOI：
10.1161/01.atv.0000208365.45200.41
发表时间：
2006-04-01
影响因子：
8.7
作者：
Auro, K;Komulainen, K;Salomaa, V
通讯作者：
Salomaa, V
影响因子：
7.7
作者：
Evans, A;Salomaa, V;Kuulasmaa, K
通讯作者：
Kuulasmaa, K