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

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Bibtex

@article{d6e1c5908d73413d980e0fa453c577f5,
title = "Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure",
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.",
author = "Gustav Smith and Felix, {Janine F.} and Morrison, {Alanna C.} and Andreas Kalogeropoulos and Stella Trompet and Wilk, {Jemma B.} and Olof Gidl{\"o}f and Xinchen Wang and Michael Morley and Michael Mendelson and Roby Joehanes and Symen Ligthart and Xiaoyin Shan and Bis, {Joshua C.} and Wang, {Ying A.} and Marketa Sj{\"o}gren and Julius Ngwa and Jeffrey Brandimarto and Stott, {David J.} and David Aguilar and Rice, {Kenneth M.} and Sesso, {Howard D.} and Serkalem Demissie and Buckley, {Brendan M.} and Taylor, {Kent D.} and Ian Ford and Chen Yao and Chunyu Liu and Nona Sotoodehnia and {van der Harst}, Pim and Stricker, {Bruno H Ch} and Kritchevsky, {Stephen B.} and Yongmei Liu and Gaziano, {J. Michael} and Albert Hofman and Moravec, {Christine S.} and Uitterlinden, {Andr{\'e} G.} and Manolis Kellis and {van Meurs}, {Joyce B.} and Margulies, {Kenneth B.} and Abbas Dehghan and Daniel Levy and Bj{\"o}rn Olde and Psaty, {Bruce M.} and Cupples, {L. Adrienne} and Jukema, {J. Wouter} and Luc Djousse and Franco, {Oscar H.} and Eric Boerwinkle and Boyer, {Laurie A.} and Christopher Newton-Cheh and Javed Butler and Vasan, {Ramachandran S.} and Cappola, {Thomas P.} and Smith, {Nicholas L.}",
year = "2016",
month = "5",
day = "1",
doi = "10.1371/journal.pgen.1006034",
language = "English",
volume = "12",
journal = "PLoS Genetics",
issn = "1553-7404",
publisher = "Public Library of Science",
number = "5",

}