Objective
Previous studies have identified common genetic variants in four chromosomal regions that together account for 14–15% of the variance in circulating levels of protein C. To further characterize the genetic architecture of protein C, we obtained denser coverage at some loci, extended investigation of protein C to low frequency and rare variants, and searched for new associations in genes known to influence protein C.
Approach and Results
Genetic associations with protein C antigen level were evaluated in up to 10,778 European and 3,190 African American participants ages 45–64 years. Analyses included up to 26 million autosomal variants available after imputation to the 1000 Genomes reference panel along with additional low frequency and rare variants directly genotyped using the Illumina ITMAT-Broad-CARe chip and Illumina HumanExome BeadChip.
Genome-wide significant associations (P<5×10−8) were found for common variants in the GCKR, PROC, BAZ1B, and PROCR-EDEM2 regions in European Americans and PROC and PROCR-EDEM2 regions in African Americans, confirming earlier findings. In a novel finding, the LDL cholesterol-lowering allele of rs12740374, located in the CELSR2/PSRC1/SORT1 region, was associated with lower protein C level in both European and African Americans, reaching genome-wide significance in a meta-analysis combining results from both groups (P=1.4 × 10−9). To further investigate a possible link between lipid metabolism and protein C level, we conducted Mendelian randomization analyses using 185 lipid-related genetic variants as instrumental variables. The results indicated that triglycerides, and possibly LDL-C, influence protein C levels.
Conclusions
Discovery of variants influencing circulating protein C levels in CELSR2/PSRC1/SORT1 region may indicate a novel genetic link between lipoprotein metabolism and hemostasis.