Common Genetic Determinants of Coagulation and Fibrinolysis

Family studies indicate a major contribution of additive genetic factors in determining risk for thrombosis. The proteins involved in coagulation, fibrinolysis and platelet function are candidate genes for thrombosis and many gene variants in these candidates have been associated with risk for venous and/or arterial thrombosis. Recent technological advances have enabled identification of genetic variants in putative regulatory regions. In particular, linkage analysis in twin- and family-based studies and genome-wide association studies (GWAS) have identified novel factors associated with hemostasis and thrombosis phenotypes. These studies support contributions of many genetic variants, with minor individual effect sizes. However, additively the significant single-nucleotide polymorphisms (SNPs) identified to date account for only a minor proportion of variance (or risk) despite the strong genetic component estimated for many phenotypes in twin and family studies. Population stratification and poorly defined phenotypes may partly account for this missing heritable component. However, it is likely that new approaches for data analysis will enable evaluation of the combined effects of multiple genes and environmental factors to reveal additional genetic factors modestly contributing to intermediate and disease phenotypes. The impact of these discoveries on clinical practice remains uncertain.