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

Publication ,  Journal Article
Smith, JG; Felix, JF; Morrison, AC; Kalogeropoulos, A; Trompet, S; Wilk, JB; Gidlöf, O; Wang, X; Morley, M; Mendelson, M; Joehanes, R; Shan, X ...
Published in: PLoS Genet
May 2016

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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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

May 2016

Volume

12

Issue

5

Start / End Page

e1006034

Location

United States

Related Subject Headings

  • Receptors, Cytokine
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Humans
  • Heart Failure
  • HEK293 Cells
  • Genotype
  • Genome-Wide Association Study
  • Genetic Variation
 

Citation

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Smith, J. G., Felix, J. F., Morrison, A. C., Kalogeropoulos, A., Trompet, S., Wilk, J. B., … Smith, N. L. (2016). Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. PLoS Genet, 12(5), e1006034. https://doi.org/10.1371/journal.pgen.1006034
Smith, J Gustav, Janine F. Felix, Alanna C. Morrison, Andreas Kalogeropoulos, Stella Trompet, Jemma B. Wilk, Olof Gidlöf, et al. “Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.PLoS Genet 12, no. 5 (May 2016): e1006034. https://doi.org/10.1371/journal.pgen.1006034.
Smith JG, Felix JF, Morrison AC, Kalogeropoulos A, Trompet S, Wilk JB, et al. Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. PLoS Genet. 2016 May;12(5):e1006034.
Smith, J. Gustav, et al. “Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.PLoS Genet, vol. 12, no. 5, May 2016, p. e1006034. Pubmed, doi:10.1371/journal.pgen.1006034.
Smith JG, Felix JF, Morrison AC, Kalogeropoulos A, Trompet S, Wilk JB, Gidlöf O, Wang X, Morley M, Mendelson M, Joehanes R, Ligthart S, Shan X, Bis JC, Wang YA, Sjögren M, Ngwa J, Brandimarto J, Stott DJ, Aguilar D, Rice KM, Sesso HD, Demissie S, Buckley BM, Taylor KD, Ford I, Yao C, Liu C, CHARGE-SCD consortium, EchoGen consortium, QT-IGC consortium, CHARGE-QRS consortium, Sotoodehnia N, van der Harst P, Stricker BHC, Kritchevsky SB, Liu Y, Gaziano JM, Hofman A, Moravec CS, Uitterlinden AG, Kellis M, van Meurs JB, Margulies KB, Dehghan A, Levy D, Olde B, Psaty BM, Cupples LA, Jukema JW, Djousse L, Franco OH, Boerwinkle E, Boyer LA, Newton-Cheh C, Butler J, Vasan RS, Cappola TP, Smith NL. Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. PLoS Genet. 2016 May;12(5):e1006034.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

May 2016

Volume

12

Issue

5

Start / End Page

e1006034

Location

United States

Related Subject Headings

  • Receptors, Cytokine
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Humans
  • Heart Failure
  • HEK293 Cells
  • Genotype
  • Genome-Wide Association Study
  • Genetic Variation