Fibrinogen plasma levels modify the association between the factor XIII Val34Leu variant and risk of coronary artery disease: the EPIC-Norfolk prospective population study

BACKGROUND: The factor (F) XIII Val34Leu variant has been implicated in coronary artery disease (CAD). In vitro evidence suggests an interaction between this variant and fibrinogen concentrations in determining thrombus structure. OBJECTIVES: To test whether this interaction is relevant in influencing coronary risk in apparently healthy individuals. METHODS: In an 8-year prospective population study of 25 663 men and women, we compared 898 apparently healthy men and women developing incident CAD with 1580 matched controls. RESULTS: Overall, the FXIII Val34Leu variant was not associated with the risk of future CAD. However, a significant interaction existed between the Val34Leu variant and fibrinogen levels for the risk of future CAD (P = 0.004). Among people in the lowest tertile of fibrinogen concentrations, LeuLeu carriers had an odds ratio (OR) of 2.88 (95% confidence interval; CI 1.24-6.74) compared to wild-type individuals (P for linearity = 0.003). By contrast, among those in the highest fibrinogen tertile, LeuLeu carriers were had a lower risk than wild-type individuals (OR 0.47, 95% CI 0.18-1.17, P for linearity = 0.1). CONCLUSIONS: Our results suggest that a significant gene-covariate interaction exists between the FXIII Val34Leu variant and fibrinogen levels. Relationships between genotype and disease risk may be altered by biological covariates. Simplistic paradigms of gene or biomarker associations are unlikely to fully characterize disease risk in populations