-Genetic variation can be used to study causal relationships between biomarkers and diseases. Here, we identify new common and rare genetic variants associated with cardiovascular-related protein levels (protein quantitative trait loci, pQTLs). We functionally annotate these pQTLs, predict and experimentally confirm a novel molecular interaction and determine which pQTLs are associated with diseases and physiological phenotypes.
-As part of a larger case/control study of VTE, serum levels of 51 proteins implicated in cardiovascular diseases were measured in 330 individuals from the Tromsø Study. Exonic genetic variation near each protein's respective gene (cis) was identified using sequencing and arrays. Using single site and gene-based tests, we identified 27 genetic associations between pQTLs and the serum levels of 20 proteins: 14 associated with common variation in cis, of which six are novel (i.e. not previously reported); seven associations with rare variants in cis, of which four are novel; and six associations in trans Of the 20 proteins, 15 were associated with single sites and seven with rare variants. cis-pQTLs for kallikrein and F12 also show trans associations for proteins (uPAR, kininogen) known to be cleaved by kallikrein as well as with NTproBNP. We experimentally demonstrate that kallikrein can cleave proBNP (NTproBNP precursor) in vitro Nine of the pQTLs have previously identified associations with 17 diseases and/or physiological phenotypes.
-We have identified cis and trans genetic variation associated with the serum levels of 20 proteins and utilized these pQTLs to study molecular mechanisms underlying diseases and/or physiological phenotypes.