Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

Research output: Contribution to journalArticle

Abstract

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

Details

Authors
  • Janine F. Felix
  • Alanna C. Morrison
  • Andreas Kalogeropoulos
  • Stella Trompet
  • Jemma B. Wilk
  • Xinchen Wang
  • Michael Morley
  • Michael Mendelson
  • Roby Joehanes
  • Symen Ligthart
  • Xiaoyin Shan
  • Joshua C. Bis
  • Ying A. Wang
  • Julius Ngwa
  • Jeffrey Brandimarto
  • David J. Stott
  • David Aguilar
  • Kenneth M. Rice
  • Howard D. Sesso
  • Serkalem Demissie
  • Brendan M. Buckley
  • Kent D. Taylor
  • Ian Ford
  • Chen Yao
  • Chunyu Liu
  • Nona Sotoodehnia
  • Pim van der Harst
  • Bruno H Ch Stricker
  • Stephen B. Kritchevsky
  • Yongmei Liu
  • J. Michael Gaziano
  • Albert Hofman
  • Christine S. Moravec
  • André G. Uitterlinden
  • Manolis Kellis
  • Joyce B. van Meurs
  • Kenneth B. Margulies
  • Abbas Dehghan
  • Daniel Levy
  • Bruce M. Psaty
  • L. Adrienne Cupples
  • J. Wouter Jukema
  • Luc Djousse
  • Oscar H. Franco
  • Eric Boerwinkle
  • Laurie A. Boyer
  • Christopher Newton-Cheh
  • Javed Butler
  • Ramachandran S. Vasan
  • Thomas P. Cappola
  • Nicholas L. Smith
Organisations
External organisations
  • University of Texas
  • Emory Clinic
  • Leiden University Medical Centre
  • Brigham and Women's Hospital / Harvard Medical School
  • Massachusetts Institute of Technology
  • University of Pennsylvania
  • Boston Children's Hospital
  • National Heart Lung and Blood Institute
  • Erasmus University Medical Center
  • University of Washington
  • Novartis Institutes for BioMedical Research, Inc.
  • Boston University
  • University of Glasgow
  • Baylor College of Medicine
  • University College Cork
  • University of California, Los Angeles
  • University of Groningen
  • Wake Forest University
  • Cleveland Clinic Foundation
  • Kaiser Permanente Research Institute
  • Interuniversity Cardiology Institute of the Netherlands
  • Massachusetts General Hospital
  • Veterans Health Administration Office of Research and Development
  • Seattle Epidemiologic Research and Information Center
  • Broad Institute
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems
Original languageEnglish
Article numbere1006034
JournalPLoS Genetics
Volume12
Issue number5
Publication statusPublished - 2016 May 1
Publication categoryResearch
Peer-reviewedYes