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

TitleDiscovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.
Publication TypeJournal Article
Year of Publication2016
AuthorsJ Smith G, 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, Sotoodehnia N, van der Harst P, Stricker B CH, Kritchevsky SB, Liu Y, J Gaziano M, Hofman A, Moravec CS, Uitterlinden AG, Kellis M, van Meurs JB, Margulies KB, Dehghan A, Levy D, Olde B, Psaty BM, L Cupples A, J Jukema W, Djoussé L, Franco OH, Boerwinkle E, Boyer LA, Newton-Cheh C, Butler J, Vasan RS, Cappola TP
Secondary AuthorsSmith NL
Corporate AuthorsCHARGE-SCD consortium, ECHOGen Consortium, QT-IGC consortium, CHARGE-QRS consortium
JournalPLoS Genet
Volume12
Issue5
Paginatione1006034
Date Published2016 05
ISSN1553-7404
KeywordsAfrican Americans, Alleles, Basic Helix-Loop-Helix Transcription Factors, Chromosomes, Human, Pair 5, DNA Methylation, Female, Gene Expression Regulation, Gene Knockdown Techniques, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Heart Failure, HEK293 Cells, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Cytokine
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.

DOI10.1371/journal.pgen.1006034
Alternate JournalPLoS Genet
PubMed ID27149122
PubMed Central IDPMC4858216
Grant ListHHSN268201100008C / HL / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
N01HC55020 / HL / NHLBI NIH HHS / United States
R01 HG008155 / HG / NHGRI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
T32 EY022303 / EY / NEI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
R01 HL093328 / HL / NHLBI NIH HHS / United States
R01 HL105993 / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
R01 HL077477 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 AG032098 / AG / NIA NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States