Identification of Genetic Variants Linking Protein C and Lipoprotein Metabolism

Abstract

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.

The role of haematological traits in risk of ischaemic stroke and its subtypes

“…From our systematic literature review of haematological traits we obtained published GWAS summary statistics for 36 blood cell traits and 49 haemostasis traits from 27 publications involving over 375 000 individuals (Supplementary Table 1) (Barbalic et al , 2010; Johnson et al , 2010; Smith et al , 2010, 2011; Athanasiadis et al , 2011; Lovely et al , 2011; Paré et al , 2011; Edelstein et al , 2012; Huang et al , 2012, 2014; Oudot-Mellakh et al , 2012; de la Morena-Barrio et al , 2013; Williams et al , 2013; Ma et al , 2014; Rocanin-Arjo et al , 2014; de Vries et al , 2015, 2016; Tang et al , 2015; Astle et al , 2016; van Loon et al , 2016; Dennis et al , 2017; Pankow et al , 2017; Sennblad et al , 2017; Kanai et al , 2018; Olson et al , 2018; Stanne et al , 2018; Sun et al , 2018). Figures 2 and 3 summarize the direction and magnitude of the association estimates for each haematological trait with each stroke subtype, with stronger associations indicated by darker colours (red in the positive direction and blue in the negative direction) and asterisks to indicate the level of statistical significance.…”

Evaluation of the relationship between plasma lipids and abdominal aortic aneurysm: A Mendelian randomization study

“…Detailed information on GWAS genotyping, quality control and imputation can be found elsewhere. [ 24 ] Imputation quality for the SNPs included in this study was good (quality score = 0.84–1.0 with a mean of 0.99). Additionally, 10 principal components of population stratification based on the GWAS data were generated by EIGENSTRAT[ 25 ] to reflect the population structure of the ARIC participants.…”

Recent Advances in the Genetics of Atherothrombotic Disease and Its Determinants

“…In contrast, a Mendelian randomization experiment in 10 778 white and 3190 black participants in the ARIC study (Atherosclerosis Risk in Communities) found that variants in the CELSR2-PSRC1-SORT1 region on chromosome 1 influenced circulating protein C levels, thus indicating a possible genetic link between lipoprotein metabolism and hemostasis. 13 Finally, a Mendelian randomization experiment by Coassin et al 14 found that genetic determinants of low HDL-C (high-density lipoprotein cholesterol) levels were not associated with worsened renal function (ie, estimated glomerular filtration rate), thus demonstrating that the relationship was not causal in nature.…”