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Author Notes:

E-mail: gustav.smith@med.lu.se

Conceived and designed the experiments: JGS JFF ACM RSV NLS.

Performed the experiments: JGS JFF OG XW MMo RJ BO.

Analyzed the data: JGS JFF OG XW MMe RJ BO.

Wrote the paper: JGS.

Data collection and analysis in the participating genome-wide association and functional studies: ARIC study: ACM DA EB. CHARGE-SCD/ CHARGE-QRS study: NS PvdH. CHS study: JCB KMR KDT BMP NLS. Functional enhancer annotation and siRNA knockdown: JGS OG XW MK BO LAB CNC. Health ABC: AK SBK YL JBu. FHS: MMe RJ YAW JN SD CY CL DL LAC RSV. MAGNet: MMo XS JBr CSM KBM TPC. MDC/MPP: JGS MS. PHS: JBW HDS JMG LD. PROSPER: ST DJS BMB IF JWJ. RS: JFF SL BHCS AH AGU JBvM AD OHF. QT-IGC: CNC.

A detailed list of acknowledgments is provided in the Supplementary Materials.

The authors have declared that no competing interests exist.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Research Funding:

Support for research reported in this article is listed in the full article, arranged by study.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • RISK
  • Cardiology
  • Heart failure
  • DNA methylation
  • Gene expression
  • Death rates
  • Genome-wide association studies
  • Genetic loci
  • Blood
  • Chromosomes

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

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Journal Title:

PLoS Genetics


Volume 12, Number 5


, Pages e1006034-e1006034

Type of Work:

Article | Final Publisher PDF


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.

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