Hemostatic factors and their causal role in coronary heart disease and ischemic stroke
Background: High levels of hemostatic factors including fibrinogen, factor VII (FVII), von Willerbrand factors (vWF), and factor VIII (FVIII) can increase the risk of coronary heart disease (CHD) and ischemic stroke (IS). A Mendelian randomization (MR) approach is used to examine the causality of the association of hemostatic factors with CHD and IS.^ Methods: This analysis involved 10,893 European ancestry (EA) and 3,856 African ancestry (AA) individuals from the Atherosclerosis Risk in Communities (ARIC) study. Common and rare variants from HumanExome BeadChip (exome chip) data were selected as genetic instruments. With each hemostatic factor, genetic instruments meeting MR assumptions were combined into unweighted single genetic score. Well-established genetic variants in the FGB and F7 genes were also used as instruments for the analyses with fibrinogen and FVII. Hemostatic factor levels were measured with the blood samples collected at the baseline exam and standardized in the analyses. Incident CHD and IS events are those occurring until December 31, 2011. Direct association between genetic scores and CHD or IS using Cox regression was used as the main approach for causal inference, where a significance indicated causality. Two-stage Cox instrumental variable (IV) regression was employed for estimating causal effect size of hemostatic factors on CHD or IS risk.^ Results: Evidence of causality was found between FVII and IS in EA. Using rs6046 in the F7 gene as the genetic instrument, the direct Cox regression was significant with pgene-IS = 0.047; and the two-stage Cox IV regression resulted in a causal hazard ratio HR FVII-IS = 1.36 (95% CI: 1.01, 1.83), which indicated that the hazard of IS was raised 1.36 times with each 1-SD increase in FVII level. vWF was a significant causal predictor for both CHD and IS among AA when using single genetic score, with pgene-CHD = 0.011 and pgene-IS = 0.028, and HRvWF-CHD = 1.63 (95% CI: 1.12, 2.39) and HRvWF-IS = 1.74 (95% CI: 1.06, 2.85). Evidence of causality was observed between FVIII and IS among EA using single genetic score, pgene-IS = 0.033 and HRFVIII-IS = 2.49 (95% CI: 1.07, 5.76). No evidence of causality was found for fibrinogen with either CHD or IS among both EA and AA.^ Conclusions: This study supports a race-specific causal role for FVII and FVIII in increasing IS risk in EA and the causal role for vWF in increasing CHD and IS risk in AA. This study does not support a causal role for fibrinogen in relation to either CHD or IS.^
Vu, Khanh N, "Hemostatic factors and their causal role in coronary heart disease and ischemic stroke" (2015). Texas Medical Center Dissertations (via ProQuest). AAI3721349.