Protein C is an environmentally modifiable anticoagulant, which protects against venous thrombosis, whether it also protects against ischaemic heart disease is unclear, based on observational studies and relatively small genetic studies. It was our study aim to clarify the role of protein C in ischaemic heart disease. The risk of coronary artery disease/myocardial infarction (CAD/MI) was assessed according to genetically predicted protein C in very large studies. Associations with lipids and diabetes were similarly assessed to rule out effects via traditional cardiovascular disease risk factors. Separate sample instrumental variable analysis with genetic instruments (Mendelian randomisation) was used to obtain an unconfounded estimate of the association of protein C (based on (rs867186 (PROCR), rs3746429 (EDEM2), rs7580658 (inter/PROC)) with CAD/MI in an extensively genotyped case (n=64374)-control (n=130681) study, CARDIoGRAMplusC4D. Associations with lipids and diabetes were similarly assessed using the Global Lipids Genetics Consortium Results (n=196,475) and the DIAbetes Genetics Replication And Meta-analysis case (n=34,380)-control (n=114,981) study. Genetically predicted protein C was negatively associated with CAD/MI, odds ratio (OR) 0.85 µg/ml, 95 % confidence interval 0.80 to 0.90, but had no such negative association with lipids or diabetes. Results were similar for the SNP rs867186 functionally relevant to protein C, and including additional potentially pleiotropic SNPs (rs1260326 (GCKR), rs17145713 (BAZ1B) and rs4321325 (CYP27C1)). In conclusion, protein C may protect against CAD/MI. Whether environmental or dietary items that raise protein C protect against ischaemic cardiovascular disease by that mechanism should be investigated.
Keywords: Mendelian randomisation analysis; Protein C; coagulation; heart diseases; lipids.