DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Mortality in heart failure. The EFO term heart failure, mortality was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: heart failure, mortality

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2020-05-06

SPECIES:

AUTHORS:

JG Smith, JF Felix, AC Morrison, A Kalogeropoulos, S Trompet, JB Wilk, O Gidlöf, X Wang, M Morley, M Mendelson, R Joehanes, S Ligthart, X Shan, JC Bis, YA Wang, M Sjögren, J Ngwa, J Brandimarto, DJ Stott, D Aguilar, KM Rice, HD Sesso, S Demissie, BM Buckley, KD Taylor, I Ford, C Yao, C Liu, N Sotoodehnia, P van der Harst, BH Stricker, SB Kritchevsky, Y Liu, JM Gaziano, A Hofman, CS Moravec, AG Uitterlinden, M Kellis, JB van Meurs, KB Margulies, A Dehghan, D Levy, B Olde, BM Psaty, LA Cupples, JW Jukema, L Djousse, OH Franco, E Boerwinkle, LA Boyer, C Newton-Cheh, J Butler, RS Vasan, TP Cappola, NL Smith

TITLE:

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

JOURNAL:

PLoS genetics May 2016, Vol 12, pp. e1006034

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. PUBMED: 27149122
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