Identification of Genetic Variants Linking Protein C and Lipoprotein Metabolism: The ARIC Study (Atherosclerosis Risk in Communities)

James S. Pankow, Weihong Tang, Nathan Pankratz, Weihua Guan, Lu Chen Weng, Mary Cushman, Eric Boerwinkle, Aarossn R. Folsom

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)589-597
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume37
Issue number3
DOIs
StatePublished - Mar 1 2017

Bibliographical note

Funding Information:
National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100

Publisher Copyright:
© 2017 American Heart Association, Inc.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • cholesterol, HDL
  • cholesterol, LDL
  • genetic association studies
  • protein C
  • triglycerides

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