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Phenotypic Refineme...
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Aragam, Krishna G.Massachusetts General Hospital,Broad Institute
(författare)
Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery
- Artikel/kapitelEngelska2019
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Nummerbeteckningar
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LIBRIS-ID:oai:lup.lub.lu.se:0481d2e3-3e5d-43cb-9138-09fec8497e0c
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https://lup.lub.lu.se/record/0481d2e3-3e5d-43cb-9138-09fec8497e0cURI
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https://doi.org/10.1161/CIRCULATIONAHA.118.035774DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:art swepub-publicationtype
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Ämneskategori:ref swepub-contenttype
Anmärkningar
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Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery. Methods: We defined all-cause HF among 488 010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30 201). Results: We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (P<1×10 -6 ), the majority linked to upstream HF risk factors, ie, coronary artery disease (CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation (PITX2). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy (BAG3, CLCNKA-ZBTB17). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated BAG3 as a disease susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%; odds ratio,12.03; P=3.62×10 -5 ). Conclusions: We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk facto rs and that are associated with subclinical left ventricular dysfunction.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Chaffin, MarkBroad Institute
(författare)
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Levinson, Rebecca T.Vanderbilt University Medical Center
(författare)
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McDermott, GregoryMassachusetts General Hospital
(författare)
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Choi, Seung HoanBroad Institute
(författare)
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Shoemaker, M. BenjaminVanderbilt University Medical Center
(författare)
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Haas, Mary E.Massachusetts General Hospital,Broad Institute
(författare)
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Weng, Lu ChenBroad Institute,Massachusetts General Hospital
(författare)
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Lindsay, Mark E.Massachusetts General Hospital
(författare)
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Smith, J. GustavLund University,Lunds universitet,Cardiovascular Epigenetics,Forskargrupper vid Lunds universitet,Lund University Research Groups,Broad Institute(Swepub:lu)med-gvs
(författare)
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Newton-Cheh, ChristopherBroad Institute,Massachusetts General Hospital
(författare)
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Roden, Dan M.Broad Institute,Vanderbilt University Medical Center
(författare)
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London, BarryUniversity of Iowa
(författare)
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Wells, Quinn S.Vanderbilt University Medical Center
(författare)
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Ellinor, Patrick T.Massachusetts General Hospital,Broad Institute
(författare)
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Kathiresan, SekarBroad Institute,Massachusetts General Hospital
(författare)
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Lubitz, Steven A.Broad Institute,Massachusetts General Hospital
(författare)
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Massachusetts General HospitalBroad Institute
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Circulation139:4, s. 489-5010009-7322
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Aragam, Krishna ...
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Chaffin, Mark
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Levinson, Rebecc ...
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McDermott, Grego ...
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Choi, Seung Hoan
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Shoemaker, M. Be ...
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visa fler...
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Haas, Mary E.
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Weng, Lu Chen
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Lindsay, Mark E.
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Smith, J. Gustav
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Newton-Cheh, Chr ...
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Roden, Dan M.
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London, Barry
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Wells, Quinn S.
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Ellinor, Patrick ...
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Kathiresan, Seka ...
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Lubitz, Steven A ...
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Kardiologi
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Medicinsk geneti ...
- Artiklar i publikationen
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Circulation
- Av lärosätet
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Lunds universitet