Genetic variation and natural anticoagulants

Protein C (PC), protein S (PS) and antithrombin (AT) belong to the main anticoagulant pathways that regulate hemostasis and further affect the risk of thrombotic events. Previous epidemiological studies of circulating levels of PC, PS and AT, genetic variation, and risk of venous thromboembolism (VTE) have been limited by small sample sizes and restriction to specific candidate genes only. Utilizing summary results from nine genome-wide association studies (GWAS), we conducted transethnic meta-analyses on AT, PC, and free and total PS. We identified potential novel genome-wide significant signals for AT close to the GCKR, SNX17 and BAZ1B genes in both European ancestry based analysis and transethnic analysis (Transethnic P-value = 4.41e-16, 1.45e-15, 4.01e-09, respectively), but these associations were not observed in African population in our cohorts (P-value = 0.35, 0.55, 0.36, respectively). Signals at GCKR presented significant heterogeneity between ancestries (P-value = 0.017). Also, a genome-wide signal on AT in African American population was found close to the HP gene (Transethnic P-value = 4.37e-26) but was not significant in the European ancestry population (P-value = 0.02). Another novel genome-wide association signal was found close to the ORM1 gene in relation with PS (PS free P-value = 1.16e-19, PS total P-value = 1.03e-15), suggesting possible regulatory mechanisms for PS. We also found a potential genome-wide signal (Transethnic p-value =3.73e-24) at SNX17 for PC, which is in high linkage disequilibrium (LD) with variants in GCKR. Confirmation of these potential novel associations require further analysis in independent populations.