Coagulation Factors and the Risk of Ischemic Heart Disease: A Mendelian Randomization Study

Coagulation plays a role in ischemic heart disease (IHD). However, which coagulation factors are targets of intervention is unclear. We assessed how genetically predicted vWF (von Willebrand factor), ETP (endogenous thrombin potential), FVIII (factor VIII), d-dimer, tPA (tissue-type plasminogen activator), and PAI (plasminogen activator inhibitor)-1 affected IHD. We similarly estimated effects on lipids to determine whether any associations were independent of lipids.

Separate sample instrumental variable analysis with genetic instruments, that is, Mendelian randomization, was used to obtain unconfounded estimates of effects on IHD using extensively genotyped studies of coronary artery disease/myocardial infarction, CARDIoGRAMplusC4D Metabochip (64 374 cases, 130 681 controls) and CARDIoGRAMplusC4D 1000 Genomes (60 801 cases, 123 504 controls), and on lipids using the Global Lipids Genetics Consortium Results (n=196 475). Genetically predicted ETP was positively associated with IHD (odds ratio, 1.05 per log-transformed SD; 95% confidence interval, 1.03-1.07) based on 15 single-nucleotide polymorphisms, as were vWF (odds ratio, 1.05 per SD; 95% confidence interval, 1.02-1.08) and FVIII (odds ratio, 1.06 per SD; 95% confidence interval, 1.03-1.09) based on 16 and 6 single-nucleotide polymorphisms, respectively, but the latter associations were null after considering pleiotropy. vWF and FVIII were associated with higher LDL (low-density lipoprotein) cholesterol, but not after considering pleiotropy. Genetically predicted d-dimer, tPA, and PAI-1 were not clearly associated with IHD or lipids based on 3, 3, and 5 single-nucleotide polymorphisms, respectively.

ETP may affect IHD. Assessing the role of its drivers in more precisely phenotyped studies of IHD could be worthwhile.