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

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Author
Smith, J. Gustav
Felix, Janine F.
Morrison, Alanna C.
Kalogeropoulos, Andreas
Trompet, Stella
Wilk, Jemma B.
Gidlöf, Olof
Wang, Xinchen
Morley, Michael
Mendelson, Michael
Joehanes, Roby
Ligthart, Symen
Shan, Xiaoyin
Bis, Joshua C.
Wang, Ying A.
Sjögren, Marketa
Ngwa, Julius
Brandimarto, Jeffrey
Stott, David J.
Aguilar, David
Rice, Kenneth M.
Demissie, Serkalem
Buckley, Brendan M.
Taylor, Kent D.
Ford, Ian
Yao, Chen
Liu, Chunyu
Sotoodehnia, Nona
van der Harst, Pim
Stricker, Bruno H. Ch.
Kritchevsky, Stephen B.
Liu, Yongmei
Hofman, Albert
Moravec, Christine S.
Uitterlinden, André G.
Kellis, Manolis
van Meurs, Joyce B.
Margulies, Kenneth B.
Dehghan, Abbas
Levy, Daniel
Olde, Björn
Psaty, Bruce M.
Cupples, L. Adrienne
Jukema, J. Wouter
Franco, Oscar H.
Boerwinkle, Eric
Boyer, Laurie A.
Butler, Javed
Vasan, Ramachandran S.
Cappola, Thomas P.
Smith, Nicholas L.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1371/journal.pgen.1006034Metadata
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Smith, J. G., J. F. Felix, A. C. Morrison, A. Kalogeropoulos, S. Trompet, J. B. Wilk, O. Gidlöf, et al. 2016. “Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.” PLoS Genetics 12 (5): e1006034. doi:10.1371/journal.pgen.1006034. http://dx.doi.org/10.1371/journal.pgen.1006034.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858216/pdf/Terms of Use
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