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

Author:
  • Gustav Smith
  • Janine F. Felix
  • Alanna C. Morrison
  • Andreas Kalogeropoulos
  • Stella Trompet
  • Jemma B. Wilk
  • Olof Gidlöf
  • Xinchen Wang
  • Michael Morley
  • Michael Mendelson
  • Roby Joehanes
  • Symen Ligthart
  • Xiaoyin Shan
  • Joshua C. Bis
  • Ying A. Wang
  • Marketa Sjögren
  • 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
  • Björn Olde
  • 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
Publishing year: 2016-05-01
Language: English
Publication/Series: PLoS Genetics
Volume: 12
Issue: 5
Document type: Journal article
Publisher: Public Library of Science

Abstract english

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.

Keywords

  • Cardiac and Cardiovascular Systems

Other

Published
  • Heart Failure and Mechanical Support
  • ISSN: 1553-7390
E-mail: gustav.smith [at] med.lu.se

Associate professor

Cardiology

+46 46 17 26 33

D1232C

32

Research project participant

Cardiovascular Epigenetics

32

Research project participant

Heart Failure and Mechanical Support

32

Project manager

Molecular Epidemiology and Cardiology

+46 46 17 26 33

32

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