Genetic Variation Within the Anticoagulant, Procoagulant, Fibrinolytic and Innate Immunity Pathways As Risk Factors for Venous Thromboembolism

Overview

Journal J Thromb Haemost

Publisher Elsevier

Specialty Hematology

Date 2011 Apr 6

PMID 21463476

Citations 41

Authors

J A Heit

J M Cunningham

T M Petterson

S M Armasu

D N Rider

M de Andrade

Affiliations

Soon will be listed here.

Abstract

Background: Venous thromboembolism (VTE) is highly heritable (estimated heritability [h(2)]=0.62) and likely to be a result of multigenic action.

Objective: To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE.

Methods: Non-Hispanic adults of European ancestry with objectively-diagnosed VTE, and age- and sex- matched controls, were genotyped for 13 031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n=12296 SNPs) were performed with plink using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke.

Results: Among 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including factor (F) V Leiden, prothrombin G20210A, ABO non-O blood type, and a novel association with ABO rs2519093 (OR=1.68, P-value=8.08×10(-16) ) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among FV Leiden non-carriers; F5, F11, KLKB1 and GFRA1 in those with ABO non-O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among prothrombin G20210A non-carriers. The ABO rs2519093 population-attributable risk (PAR) exceeded that of FV Leiden and prothrombin G20210A, and the joint PAR of FV Leiden, prothrombin G20210A, ABO non-O and ABO rs2519093 was 0.40.

Conclusions: Anticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non-Hispanic adults of European ancestry.

Citing Articles

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Whole-Exome Sequencing in a Family with an Unexplained Tendency for Venous Thromboembolism: Multicomponent Prediction of Low-Frequency Variant Deleteriousness and of Individual Protein Interaction.

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Factor XI, a potential target for anticoagulation therapy for venous thromboembolism.

Li T, Liu J, Wu W Front Cardiovasc Med. 2022; 9:975767.

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