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

Research output: Contribution to journalJournal articlepeer-review

  • Lasse Folkersen
  • Eric Fauman
  • Maria Sabater-Lleal
  • Rona J Strawbridge
  • Mattias Frånberg
  • Bengt Sennblad
  • Damiano Baldassarre
  • Fabrizio Veglia
  • Steve E Humphries
  • Rainer Rauramaa
  • Ulf de Faire
  • Andries J Smit
  • Philippe Giral
  • Sudhir Kurl
  • Elmo Mannarino
  • Stefan Enroth
  • Åsa Johansson
  • Sofia Bosdotter Enroth
  • Stefan Gustafsson
  • Lars Lind
  • Cecilia M Lindgren
  • Andrew P Morris
  • Vilmantas Giedraitis
  • Angela Silveira
  • Anders Franco-Cereceda
  • Elena Tremoli
  • Ulf Gyllensten
  • Erik Ingelsson
  • Per Eriksson
  • Daniel Ziemek
  • Anders Hamsten
  • Anders Mälarstig

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.

Original languageEnglish
Article numbere1006706
JournalP L o S Genetics
Volume13
Issue number4
Number of pages21
ISSN1553-7390
DOIs
Publication statusPublished - Apr 2017
Externally publishedYes

    Research areas

  • Journal Article

ID: 177047769