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Epigenomes of Human Hearts Reveal New Genetic Variants Relevant for Cardiac Disease and Phenotype.
Tan, Wilson Lek Wen; Anene-Nzelu, Chukwuemeka George; Wong, Eleanor; Lee, Chang Jie Mick; Tan, Hui San; Tang, Sze Jing; Perrin, Arnaud; Wu, Kan Xing; Zheng, Wenhao; Ashburn, Robert John; Pan, Bangfen; Lee, May Yin; Autio, Matias Ilmari; Morley, Michael P; Tam, Wai Leong; Cheung, Christine; Margulies, Kenneth B; Chen, Leilei; Cappola, Thomas P; Loh, Marie; Chambers, John; Prabhakar, Shyam; Foo, Roger S Y.
Afiliação
  • Tan WLW; From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.).
  • Anene-Nzelu CG; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Wong E; From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.).
  • Lee CJM; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Tan HS; From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.).
  • Tang SJ; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Perrin A; From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.).
  • Wu KX; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Zheng W; From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.).
  • Ashburn RJ; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Pan B; Cancer Science Institute of Singapore, National University of Singapore (S.J.T., W.L.T., L.C.).
  • Lee MY; From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.).
  • Autio MI; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Morley MP; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (K.X.W., C.C., M.L., J.C.).
  • Tam WL; From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.).
  • Cheung C; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Margulies KB; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Chen L; From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.).
  • Cappola TP; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Loh M; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Chambers J; From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.).
  • Prabhakar S; Genome Institute of Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., R.J.A., B.P., L.M.Y., M.I.A., W.L.T., S.P., R.S.Y.F.).
  • Foo RSY; Cardiovascular Institute, Perlman School of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (M.P.M., K.B.M., T.P.C.).
Circ Res ; 127(6): 761-777, 2020 08 28.
Article em En | MEDLINE | ID: mdl-32529949
ABSTRACT
RATIONALE Identifying genetic markers for heterogeneous complex diseases such as heart failure is challenging and requires prohibitively large cohort sizes in genome-wide association studies to meet the stringent threshold of genome-wide statistical significance. On the other hand, chromatin quantitative trait loci, elucidated by direct epigenetic profiling of specific human tissues, may contribute toward prioritizing subthreshold variants for disease association.

OBJECTIVE:

Here, we captured noncoding genetic variants by performing epigenetic profiling for enhancer H3K27ac chromatin immunoprecipitation followed by sequencing in 70 human control and end-stage failing hearts. METHODS AND

RESULTS:

We have mapped a comprehensive catalog of 47 321 putative human heart enhancers and promoters. Three thousand eight hundred ninety-seven differential acetylation peaks (FDR [false discovery rate], 5%) pointed to pathways altered in heart failure. To identify cardiac histone acetylation quantitative trait loci (haQTLs), we regressed out confounding factors including heart failure disease status and used the G-SCI (Genotype-independent Signal Correlation and Imbalance) test1 to call out 1680 haQTLs (FDR, 10%). RNA sequencing performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression quantitative trait loci), either in cis (180) or through long-range interactions (81), identified by Hi-C (high-throughput chromatin conformation assay) and HiChIP (high-throughput protein centric chromatin) performed on a subset of hearts. Furthermore, a concordant relationship between the gain or disruption of TF (transcription factor)-binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalization of haQTLs with the subthreshold loci of heart-related genome-wide association studies datasets.

CONCLUSIONS:

Disease and phenotype association for 62 unique loci are now implicated. These loci may indeed mediate their effect through modification of enhancer H3K27 acetylation enrichment and their corresponding gene expression differences (bioRxiv https//doi.org/10.1101/536763). Graphical Abstract A graphical abstract is available for this article.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Variação Genética / Histonas / Epigenoma / Insuficiência Cardíaca Tipo de estudo: Diagnostic_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Circ Res Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Variação Genética / Histonas / Epigenoma / Insuficiência Cardíaca Tipo de estudo: Diagnostic_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Circ Res Ano de publicação: 2020 Tipo de documento: Article