Factor VIII (FVIII) functions as a cofactor for factor IXa in the contact coagulation pathway and circulates in a protective complex with von Willebrand factor (VWF). Plasma FVIII activity is strongly influenced by environmental and genetic factors through VWF-dependent and -independent mechanisms. SNPs of the coding and promoter sequence in the FVIII gene have been extensively studied for effects on FVIII synthesis, secretion and activity, but impacts of non-disease causing intronic SNPs remain largely unknown. We analyzed FVIII SNPs and FVIII activity in 10,434 healthy Americans of European (EA) or African (AA) descents in the Atherosclerosis Risk in Communities study. Among covariates, age, race, diabetes and ABO contributed 2.2%, 3.5%, 4% and 10.7% to FVIII inter-subject variation, respectively. Four intronic FVIII SNPs associated with FVIII activity and eight with FVIII-VWF ratio in a gender- and race-dependent manner. The FVIII haplotypes AT and GCTTTT also associated with FVIII activity. Seven VWF SNPs were associated with FVIII activity in EA subjects, but no FVIII SNPs were associated with VWF antigen. These data demonstrate that intronic SNPs could directly or indirectly influence inter-subject variation of FVIII activity. Further investigation may reveal novel mechanisms of regulating FVIII expression and activity.
