Associations Between Common and Rare Exonic Genetic Variants and Serum Levels of 20 Cardiovascular-Related Proteins: The Tromsø Study.

• Main Authors: Solomon, Terry, Smith, Erin N, Matsui, Hiroko, Braekkan, Sigrid K, INVENT Consortium, Wilsgaard, Tom, Njølstad, Inger, Mathiesen, Ellisiv B, Hansen, John-Bjarne, Frazer, Kelly A
• Format: Article in Journal/Newspaper
• Language: unknown
• Published: eScholarship, University of California 2016
• Subjects: INVENT Consortium; Humans; Genetic Predisposition to Disease; Natriuretic Peptide; Brain; Blood Proteins; Protein Precursors; Genetic Markers; Risk Factors; Case-Control Studies; Prospective Studies; Computational Biology; Gene Frequency; Phenotype; Quantitative Trait Loci; Exons; Databases; Genetic; Norway; Venous Thromboembolism; Genetic Variation; Genome-Wide Association Study; biomarker; coronary artery disease; exome; human; protein; Genetics; Cardiovascular; Biotechnology; 1.1 Normal biological development and functioning; Underpinning research; 2.1 Biological and endogenous factors; Aetiology; Good Health and Well Being; Medical Biotechnology; Cardiorespiratory Medicine and Haematology; Cardiovascular System & Hematology; Tromsø
• Online Access: https://escholarship.org/uc/item/94p1748g

BackgroundGenetic 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.Methods and resultsAs part of a larger case-control study of venous thromboembolism, 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 6 are novel (ie, not previously reported); 7 associations with rare variants in cis, of which 4 are novel; and 6 associations in trans. Of the 20 proteins, 15 were associated with single sites and 7 with rare variants. cis-pQTLs for kallikrein and F12 also show trans associations for proteins (uPAR, kininogen) known to be cleaved by kallikrein and with NTproBNP. We experimentally demonstrate that kallikrein can cleave proBNP (NTproBNP precursor) in vitro. Nine of the pQTLs have previously identified associations with 17 disease and physiological phenotypes.ConclusionsWe have identified cis and trans genetic variation associated with the serum levels of 20 proteins and utilized these pQTLs to study molecular mechanisms underlying disease and physiological phenotypes.