Gene-Centric Approach Identifies New and Known Loci for Factor VIII Activity and Von Willebrand Factor Antigen In the Candidate Gene Association Resource (CARe) Consortium

Factor VIII and von Willebrand factor (vWF) are important components of the coagulation system that circulate together in plasma as a non-covalent complex. Increased circulating levels of FVIII activity (FVIII:C) and vWF antigen (vWF:Ag) in the top 25% of the population distribution are common risk factors for venous thromboembolism, the third leading vascular disease. FVIII and vWF are genetically controlled but their genetic determinants are not fully understood. Moreover, data from populations other than European Americans (EAs) are limited. We performed a genetic association study for plasma levels of FVIII:C and vWF:Ag using a gene-centric approach in the cohorts of NHLBI-funded Candidate gene Association Resource (CARe) consortium.

Nearly 50,000 single nucleotide polymorphisms (SNPs) located in about 2,100 candidate genes were genotyped in 18,556 EAs and 4,844 African Americans (AAs) from the Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), Cardiovascular Health Study (CHS), Multi-Ethnic Study of Atherosclerosis (MESA), and Framingham Heart Study (FHS, EAs only). Measurements for FVIII:C and vWF:Ag were inverse normal transformed to normalize trait distribution, and adjusted for age, sex, study site and principal components to account for potential population stratification. Results across studies were combined within each ethnic group by meta-analysis. SNPs with minor allele frequency (MAF)-weighted sample size (MAFxN) < 10 were excluded from individual cohorts before the meta-analysis. The threshold for statistical significance was 2.0×10⁻⁶ after accounting for the number of independent tests.

In EAs, four independent regions were identified with p<2.0×10⁻⁶, characterized by variants from KNG1 (best SNP rs698078, intronic, p= 4.26×10⁻⁷ for FVIII:C), ABO (rs529565, intronic, p<1.0×10⁻¹⁹⁹ for both FVIII:C and vWF:Ag), vWF (rs1063856, missense, p=5.84 ×10⁻¹² for FVIII:C and 1.06 ×10⁻¹⁹ for vWF:Ag), and F8/TMLHE (rs12557310, intronic, p=8.02 ×10⁻¹⁰ for FVIII:C). In AAs, three independent regions emerged, characterized by variants from ABO (rs8176693, intronic, p=2.51 ×10⁻¹¹⁴ for FVIII:C and 1.66 ×10⁻⁸⁹ for vWF:Ag), MET1A (rs2236568, intronic, p=1.69 ×10⁻⁶ for FVIII:C), and vWF (rs2229446, missense, p=1.95 ×10⁻²⁰ for FVIII:C and 1.13 ×10⁻¹⁶ for vWF:Ag). The regions marked by KNG1 and MAT1A have not been previously reported for association with FVIII:C. Notably, the variant rs2229446 in the vWF gene results in an arginine to glutamine substitution at position 2185, is associated with vW disease, and is only present in African, African American, and Asian samples of the HapMap population.

This large, gene-centric genetic association study for FVIII:C and vWF:Ag identified both new and known common loci. These findings expand our understanding of genetic determinants for the common risk factors for thrombosis in both EA and AA populations.

No relevant conflicts of interest to declare.