title: Associations Between Common and Rare Exonic Genetic Variants and Serum Levels of 20 Cardiovascular-Related Proteins: The Tromsø Study.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  As 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.
  
  
  CONCLUSIONS
  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 disease and physiological phenotypes.
authors.affiliation: From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady's Children's Hospital, San Diego, La Jolla, CA (E.N.S., H.M., K.A.F.); Institute for Genomic Medicine, University of California, San Diego, La Jolla (K.A.F.); Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) (E.N.S., S.K.B., I.N., E.B.M., J.-B.H., K.A.F.), Department of Community Medicine (T.W., I.N.), and Brain and Circulation Research Group, Department of Clinical Medicine (E.B.M.), UiT The Arctic University of Norway; and Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., J.-B.H.).
authors.forename: Terry
authors.initials: T
authors.lastname: Solomon
authors.affiliation: From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady's Children's Hospital, San Diego, La Jolla, CA (E.N.S., H.M., K.A.F.); Institute for Genomic Medicine, University of California, San Diego, La Jolla (K.A.F.); Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) (E.N.S., S.K.B., I.N., E.B.M., J.-B.H., K.A.F.), Department of Community Medicine (T.W., I.N.), and Brain and Circulation Research Group, Department of Clinical Medicine (E.B.M.), UiT The Arctic University of Norway; and Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., J.-B.H.).
authors.forename: Erin N
authors.initials: EN
authors.lastname: Smith
authors.affiliation: From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady's Children's Hospital, San Diego, La Jolla, CA (E.N.S., H.M., K.A.F.); Institute for Genomic Medicine, University of California, San Diego, La Jolla (K.A.F.); Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) (E.N.S., S.K.B., I.N., E.B.M., J.-B.H., K.A.F.), Department of Community Medicine (T.W., I.N.), and Brain and Circulation Research Group, Department of Clinical Medicine (E.B.M.), UiT The Arctic University of Norway; and Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., J.-B.H.).
authors.forename: Hiroko
authors.initials: H
authors.lastname: Matsui
authors.affiliation: From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady's Children's Hospital, San Diego, La Jolla, CA (E.N.S., H.M., K.A.F.); Institute for Genomic Medicine, University of California, San Diego, La Jolla (K.A.F.); Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) (E.N.S., S.K.B., I.N., E.B.M., J.-B.H., K.A.F.), Department of Community Medicine (T.W., I.N.), and Brain and Circulation Research Group, Department of Clinical Medicine (E.B.M.), UiT The Arctic University of Norway; and Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., J.-B.H.).
authors.forename: Sigrid K
authors.initials: SK
authors.lastname: Braekkan
authors.affiliation: From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady's Children's Hospital, San Diego, La Jolla, CA (E.N.S., H.M., K.A.F.); Institute for Genomic Medicine, University of California, San Diego, La Jolla (K.A.F.); Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) (E.N.S., S.K.B., I.N., E.B.M., J.-B.H., K.A.F.), Department of Community Medicine (T.W., I.N.), and Brain and Circulation Research Group, Department of Clinical Medicine (E.B.M.), UiT The Arctic University of Norway; and Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., J.-B.H.).
authors.forename: Tom
authors.initials: T
authors.lastname: Wilsgaard
authors.affiliation: From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady's Children's Hospital, San Diego, La Jolla, CA (E.N.S., H.M., K.A.F.); Institute for Genomic Medicine, University of California, San Diego, La Jolla (K.A.F.); Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) (E.N.S., S.K.B., I.N., E.B.M., J.-B.H., K.A.F.), Department of Community Medicine (T.W., I.N.), and Brain and Circulation Research Group, Department of Clinical Medicine (E.B.M.), UiT The Arctic University of Norway; and Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., J.-B.H.).
authors.forename: Inger
authors.initials: I
authors.lastname: Njølstad
authors.affiliation: From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady's Children's Hospital, San Diego, La Jolla, CA (E.N.S., H.M., K.A.F.); Institute for Genomic Medicine, University of California, San Diego, La Jolla (K.A.F.); Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) (E.N.S., S.K.B., I.N., E.B.M., J.-B.H., K.A.F.), Department of Community Medicine (T.W., I.N.), and Brain and Circulation Research Group, Department of Clinical Medicine (E.B.M.), UiT The Arctic University of Norway; and Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., J.-B.H.).
authors.forename: Ellisiv B
authors.initials: EB
authors.lastname: Mathiesen
authors.affiliation: From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady's Children's Hospital, San Diego, La Jolla, CA (E.N.S., H.M., K.A.F.); Institute for Genomic Medicine, University of California, San Diego, La Jolla (K.A.F.); Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) (E.N.S., S.K.B., I.N., E.B.M., J.-B.H., K.A.F.), Department of Community Medicine (T.W., I.N.), and Brain and Circulation Research Group, Department of Clinical Medicine (E.B.M.), UiT The Arctic University of Norway; and Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., J.-B.H.).
authors.forename: John-Bjarne
authors.initials: JB
authors.lastname: Hansen
authors.affiliation: From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady's Children's Hospital, San Diego, La Jolla, CA (E.N.S., H.M., K.A.F.); Institute for Genomic Medicine, University of California, San Diego, La Jolla (K.A.F.); Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) (E.N.S., S.K.B., I.N., E.B.M., J.-B.H., K.A.F.), Department of Community Medicine (T.W., I.N.), and Brain and Circulation Research Group, Department of Clinical Medicine (E.B.M.), UiT The Arctic University of Norway; and Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., J.-B.H.). kafrazer@ucsd.edu.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frazer
mesh_terms: D001798:Blood Proteins / Q000235:genetics*; D016022:Case-Control Studies; D019295:Computational Biology; D030541:Databases, Genetic; D005091:Exons; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D009664:Norway; D010641:Phenotype; D011446:Prospective Studies; D011498:Protein Precursors / Q000378:metabolism; D040641:Quantitative Trait Loci; D012307:Risk Factors; D054556:Venous Thromboembolism / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*
chemical_list: D001798:Blood Proteins; D005819:Genetic Markers; D011498:Protein Precursors; D020097:Natriuretic Peptide, Brain
keywords: biomarker; coronary artery disease; exome; human; protein; venous thromboembolism