Coagulation factor VIII: Relationship to cardiovascular disease risk and whole genome sequence and epigenome‐wide analysis in African Americans

• Published in: Journal of thrombosis and haemostasis 2020-06, Vol.18 (6), p.1335-1347
• Main Authors: Raffield, Laura M., Lu, Ake T., Szeto, Mindy D., Little, Amarise, Grinde, Kelsey E., Shaw, Jessica, Auer, Paul L., Cushman, Mary, Horvath, Steve, Irvin, Marguerite R., Lange, Ethan M., Lange, Leslie A., Nickerson, Deborah A., Thornton, Timothy A., Wilson, James G., Wheeler, Marsha M., Zakai, Neil A., Reiner, Alex P.
• Format: Article
• Language: English
• Subjects: African American; African Americans; Association analysis; Black or African American - genetics; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - diagnosis; Cardiovascular Diseases - genetics; coagulation; Coagulation factor VIII; Coagulation factors; Congestive heart failure; Coronary artery disease; CpG islands; Cross-Sectional Studies; DNA methylation; Epidemiology; Epigenetics; Epigenome; factor VIII; Factor VIII - genetics; Genetic diversity; Genomes; genome‐wide association studies; Health risk assessment; Heart failure; Humans; Mortality; Nucleotide sequence; Phenotypic variations; Prospective Studies; Risk factors; thrombosis; von Willebrand Factor - genetics; Whole genome sequencing
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.14741

Background Prospective studies have suggested higher factor VIII (FVIII) levels are an independent risk factor for coronary heart disease (CHD) and stroke. However, limited information, including on genetic and epigenetic contributors to FVIII variation, is available specifically among African Americans (AAs), who have higher FVIII levels than Europeans. Objectives We measured FVIII levels in ~3400 AAs from the community‐based Jackson Heart Study and assessed genetic, epigenetic, and epidemiological correlates of FVIII, as well as incident cardiovascular disease (CVD) associations. Methods We assessed cross‐sectional associations of FVIII with CVD risk factors as well as incident CHD, stroke, heart failure, and mortality associations. We additionally assessed associations with TOPMed whole genome sequencing data and an epigenome‐wide methylation array. Results Our results confirmed associations between FVIII and risk of incident CHD events and total mortality in AAs; mortality associations were largely independent of traditional risk factors. We also demonstrate an association of FVIII with incident heart failure, independent of B‐type natriuretic peptide. Two genomic regions were strongly associated with FVIII (ABO and VWF). The index variant at VWF is specific to individuals of African descent and is distinct from the previously reported European VWF association signal. Epigenome‐wide association analysis showed significant FVIII associations with several CpG sites in the ABO region. However, after adjusting for ABO genetic variants, ABO CpG sites were not significant. Conclusions Larger sample sizes of AAs will be required to discover additional genetic and epigenetic contributors to FVIII phenotypic variation, which may have consequences for CVD health disparities.