Abstract P252: A Gene-centric Association Study of Venous Thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology Study

Abstract

Objective: Venous thromboembolism (VTE) is a common disease associated with a high mortality rate. A few variants in genes for factor V (FV Leiden), prothrombin, antithrombin, proteins C and S, and blood groups have been documented to confer VTE risk, but other genetic determinants for VTE likely exist. Methods: We performed an association study for VTE using a gene-centric approach in the Longitudinal Investigation of Thromboembolism Etiology (LITE) Study, which comprises the Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts. A total of 280 VTE cases were ascertained in 9,827 participants of European ancestry in ARIC and 136 cases in 3,952 participants in CHS. The average follow-up time was 16 and 10 years in ARIC and CHS, respectively. Nearly 50,000 single nucleotide polymorphisms (SNPs) located in 2,100 candidate genes were genotyped by the Candidate gene Association Resource (CARe) gene chip. In each study, the association between each SNP and VTE was assessed with an additive genetic model using Cox proportional-hazards regression adjusted for age, sex, and field center. Data from ARIC and CHS were meta-analyzed using inverse-variance, fixed-effects models. SNPs with minor allele frequency < 1% or extreme p-values from Hardy-Weinberg disequilibrium test were excluded. Results: After adjusting for multiple testing, the thresholds for statistical significance and suggestive associations were set at 2.0x10−6 and 2.0x10−4, respectively. Four SNPs at the factor V gene locus exceeded the statistical significance threshold, with the top SNP being FV Leiden (rs6025, hazard ratio=3.01, p=9.7x10−17). Five SNPs showed suggestive associations with VTE (hazard ratios =1.29∼1.66), including those from the cholesteryl ester transfer protein (1 SNP), carboxypeptidase E (1 SNP), ABO (2 SNPs), and estrogen receptor 2 (1 SNP) genes. Conclusions: Among these genes, the FV Leiden variant and ABO are involved in coagulation and their associations with VTE have been previously confirmed. The other three genes have no known involvement in coagulation or hemostasis and thus, if replicated in future studies, may represent novel pathways.