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Esslinger, U.B.* ; Garnier, S.* ; Korniat, A.* ; Proust, C.* ; Kararigas, G.* ; Müller-Nurasyid, M. ; Empana, J.* ; Morley, M.P.* ; Perret, C.* ; Stark, K.* ; Bick, A.G.* ; Prasad, S.K.* ; Kriebel, J. ; Li, J.* ; Tiret, L.* ; Strauch, K. ; O'Regan, D.P.* ; Marguiles, K.B.* ; Seidman, J.G.* ; Boutouyrie, P.* ; Lacolley, P.* ; Jouven, X.* ; Hengstenberg, C.* ; Komajda, M.* ; Hakonarson, H.H.* ; Isnard, R.* ; Arbustini, E.* ; Grallert, H. ; Cook, S.A.* ; Seidman, C.E.* ; Regitz-Zagrosek, V.* ; Cappola, T.P.* ; Charron, P.* ; Cambien, F.* ; Villard, E.*

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy.

PLoS ONE 12:e0172995 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Aims Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. Conclusion We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Skeletal-muscles; Common Variants; Heart-failure; P19cl6 Cells; Protein; Mutations; Hspb7; Fhod3; Differentiation; Architecture
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 1932-6203
Journal PLoS ONE
Quellenangaben Volume: 12, Issue: 3, Pages: , Article Number: e0172995 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place Lawrence, Kan.
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
90000 - German Center for Diabetes Research
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504100-001
G-504091-002
G-501900-402
PubMed ID 28296976
DOI 10.1371/journal.pone.0172995
WOS ID WOS:000396311700021
Scopus ID 85015292949
Erfassungsdatum 2017-04-26
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