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Coagulation factor VIII: Relationship to cardiovascular disease risk and whole genome sequence and epigenome-wide
Laura M Raffield1, Ake T Lu2, Mindy D Szeto3
1Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
Insights
Higher factor VIII (FVIII) levels increase risk for coronary heart disease (CHD) and stroke in African Americans (AAs). Genetic factors in ABO and VWF regions influence FVIII levels, impacting cardiovascular disease (CVD) disparities.
Area of Science:
- Cardiovascular Genetics
- Hematology
- Population Health
Background:
- Elevated factor VIII (FVIII) levels are linked to increased risk of coronary heart disease (CHD) and stroke.
- Limited data exists on genetic and epigenetic factors influencing FVIII levels in African Americans (AAs), a population with higher baseline FVIII compared to Europeans.
Purpose of the Study:
- To investigate genetic, epigenetic, and epidemiological correlates of FVIII levels in a large cohort of African Americans.
- To assess the association of FVIII levels with incident cardiovascular disease (CVD), including CHD, stroke, and heart failure, and mortality in AAs.
Main Methods:
- Measured FVIII levels in approximately 3400 AAs from the Jackson Heart Study.
- Utilized whole genome sequencing data (TOPMed) and an epigenome-wide methylation array to analyze genetic and epigenetic associations.
- Assessed cross-sectional and incident associations with CVD risk factors, clinical outcomes, and mortality.
Main Results:
- Confirmed associations between FVIII levels and incident CHD events and total mortality in AAs, largely independent of traditional risk factors.
- Demonstrated an association between FVIII and incident heart failure, independent of B-type natriuretic peptide.
- Identified two genomic regions, ABO and VWF, strongly associated with FVIII; a VWF variant was specific to individuals of African descent.
Conclusions:
- FVIII levels are associated with increased risk of CVD events and mortality in African Americans.
- Genetic variants in the ABO and VWF regions are significant contributors to FVIII variation in AAs.
- Further research with larger AA cohorts is needed to uncover additional genetic and epigenetic factors influencing FVIII and address CVD health disparities.
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.
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