Identification of Genetic Variants Linking Protein C and Lipoprotein Metabolism: The ARIC Study (Atherosclerosis Risk in Communities). Issue 3 (March 2017) - Pankow, James S.
Abstract : Objective—: Previous studies have identified common genetic variants in 4 chromosomal regions that together account for 14% to 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 ⩽10 778 European and 3190 black participants aged 45 to 64 years. Analyses included >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 whites and PROC and PROCR-EDEM2 regions in blacks, confirming earlier findings. In a novel finding, the low-density lipoprotein cholesterol–lowering allele of rs12740374, located in the CELSR2–PSRC1–SORT1 region, was associated with lower protein C level in both whites and blacks, 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 low-density lipoprotein cholesterol, influence protein C levels. Conclusions—: Discovery of variants influencing circulating protein C levels in the CELSR2–PSRC1–SORT1 region may indicate a novel genetic link between lipoprotein metabolism and hemostasis. Abstract : Supplemental Digital Content is available in the text.