Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California.
J Thromb Haemost. 2020 Jun;18(6):1335-1347. doi: 10.1111/jth.14741. Epub 2020 Feb 20.
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.
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.
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.
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.
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.
前瞻性研究表明，较高的因子 VIII（FVIII）水平是冠心病（CHD）和中风的独立危险因素。然而，包括基因和表观遗传因素对 FVIII 变异的影响在内的有限信息，特别是在非洲裔美国人（AA）中，他们的 FVIII 水平高于欧洲人。
我们在基于社区的杰克逊心脏研究中测量了约 3400 名 AA 中的 FVIII 水平，并评估了 FVIII 的遗传、表观遗传和流行病学相关性，以及心血管疾病（CVD）事件的发生情况。
我们评估了 FVIII 与 CVD 危险因素以及 CHD、中风、心力衰竭和死亡率事件的相关性。我们还评估了与 TOPMed 全基因组测序数据和全基因组甲基化阵列的相关性。
我们的结果证实了 FVIII 与 AA 中 CHD 事件和总死亡率的发生风险之间的关联；死亡率的关联在很大程度上独立于传统的危险因素。我们还证明了 FVIII 与心力衰竭的发生有关，与 B 型利钠肽无关。两个基因组区域与 FVIII 强烈相关（ABO 和 VWF）。VWF 上的索引变体仅存在于非洲裔个体中，与先前报道的欧洲 VWF 关联信号不同。全基因组关联分析显示，ABO 区域的几个 CpG 位点与 FVIII 存在显著相关性。然而，在调整 ABO 遗传变异后，ABO CpG 位点不再显著。
需要更大的 AA 样本量来发现 FVIII 表型变异的其他遗传和表观遗传因素，这可能对 CVD 健康差异有影响。
