Combined Effects of Thrombosis Pathway Gene Variants Predict Cardiovascular Events

Kirsi Auro,Kati Kristiansson,Kari Kuulasmaa,Leena Peltonen,Kaisa Silander,Veikko Salomaa,Mervi Alanne,Markus Perola,David B Allison

doi:10.1371/journal.pgen.0030120

Kirsi Auro, Kati Kristiansson + Show 7 more

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https://doi.org/10.1371/journal.pgen.0030120

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Abstract

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.

Highlights

The genetic basis of complex diseases like coronary heart disease and ischemic stroke probably consists of several predisposing risk factors that can interact with environmental factors to produce the disease phenotype
As in other complex diseases, the genetic risk is thought to consist of several genetic variants and their possible interactions
Our study explores the role in cardiovascular disease of four thrombosis genes: coagulation factor V, intercellular adhesion molecule 1, protein C, and thrombomodulin

Summary

Introduction

The genetic basis of complex diseases like coronary heart disease and ischemic stroke probably consists of several predisposing risk factors that can interact with environmental factors to produce the disease phenotype To address such polygenic structure is a challenge likely requiring simultaneous analysis of several risk factors, including genetic variants, in large study samples rich in phenotypes. Gene– gene and gene–environment interaction studies have recently attempted to answer this challenge by analyzing the interacting relations of putative risk loci [1,2,3,4,5] The majority of these studies, use two to three genetic markers, failing to address the physiological entities or the underlying complex genetic profiles. Whether THBD gene variants act as independent CVD risk factors remains unclear [15]

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