Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism.

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.

• Authors: J A Heit, J M Cunningham, T M Petterson, S M Armasu, D N Rider, M DE Andrade
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 9 Issue 6 Pg. 1133-42 (Jun 2011) ISSN: 1538-7836 [Electronic] England
• PMID: 21463476 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 International Society on Thrombosis and Haemostasis.

Topics

• Adult
• Aged
• Blood Coagulation (genetics)
• Disease Susceptibility
• Female
• Fibrinolysis (genetics)
• Genetic Variation
• Genotype
• Hemostasis (genetics)
• Humans
• Immunity, Innate (genetics)
• Linkage Disequilibrium
• Male
• Middle Aged
• Risk Factors
• Venous Thromboembolism (etiology)