Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease

Abstract

Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.

Plasma stem cell factor levels are associated with risk of cardiovascular disease and death

“…Folkersen et al [48] recently reported similar association between SNPs in the same gene loci on chromosome 20 and plasma SCF with the strongest association found for rs4810479. We identified four SNPs in genes on chromosome 20 that demonstrated genomewide significant association with the plasma level of SCF.…”

“…Three of these were in linkage disequilibrium and regression analysis indicated that the strongest association was with a SNP in the PCIF1 gene. Folkersen et al [48] recently reported similar association between SNPs in the same gene loci on chromosome 20 and plasma SCF with the strongest association found for rs4810479. All four SNPs identified to have genomewide significance with plasma SCF in the present study were significantly associated with plasma SCF also in the study by Folkersson et al with both rs7679 and rs6065904 reaching genomewide significance.…”

Evidence for genetic correlation between human cerebral white matter microstructure and inflammation

“…Genome-wide association (GWA) analyses could identify these genes or variants. There are several GWA studies of FA (Elliott et al, 2017;Lopez et al, 2012;Sprooten et al, 2013Sprooten et al, , 2014 and inflammatory measures (Ahola-Olli et al, 2017;Emilsson et al, 2018;Folkersen et al, 2017;Kim et al, 2012;Larsen et al, 2013;Li et al, 2016;Sun et al, 2018). While these analyses successfully identify loci underlying individual variation in these traits, they fail to identify variants common to both.…”

The Human Plasma Proteome Draft of 2017: Building on the Human Plasma PeptideAtlas from Mass Spectrometry and Complementary Assays

“…One attractive solution is described for coupling multiplexed protein detection with read-out by DNA and to profile more than 90 proteins in a single assay (70, 71); they have been used and applied in extensive sample sets (72, 73). While these proximity extension assays use two binders per target protein, other large scale techniques employ single affinity reagents for high multiplexing capabilities.…”