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Response by Aragam et al to Letter Regarding Article, “Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery”

2019; Lippincott Williams & Wilkins; Volume: 140; Issue: 1 Linguagem: Inglês

10.1161/circulationaha.119.040940

1524-4539

Krishna G. Aragam, Mark Chaffin, Patrick T. Ellinor, Sekar Kathiresan, Steven A. Lubitz,

Genomics and Rare Diseases

HomeCirculationVol. 140, No. 1Response by Aragam et al to Letter Regarding Article, “Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Aragam et al to Letter Regarding Article, “Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery” Krishna G. Aragam, MD, MS, Mark Chaffin, MS, Patrick T. Ellinor, MD, PhD, Sekar Kathiresan, MD and Steven A. Lubitz, MD, MPH Krishna G. AragamKrishna G. Aragam Cardiovascular Disease Initiative, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (K.G.A., M.C., P.T.E., S.K., S.A.L.). Center for Genomic Medicine, Massachusetts General Hospital, Boston (K.G.A., S.K.). Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (K.G.A., P.T.E., S.A.L.). Search for more papers by this author , Mark ChaffinMark Chaffin Cardiovascular Disease Initiative, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (K.G.A., M.C., P.T.E., S.K., S.A.L.). Search for more papers by this author , Patrick T. EllinorPatrick T. Ellinor Cardiovascular Disease Initiative, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (K.G.A., M.C., P.T.E., S.K., S.A.L.). Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (K.G.A., P.T.E., S.A.L.). Search for more papers by this author , Sekar KathiresanSekar Kathiresan Cardiovascular Disease Initiative, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (K.G.A., M.C., P.T.E., S.K., S.A.L.). Center for Genomic Medicine, Massachusetts General Hospital, Boston (K.G.A., S.K.). Search for more papers by this author and Steven A. LubitzSteven A. Lubitz Cardiovascular Disease Initiative, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (K.G.A., M.C., P.T.E., S.K., S.A.L.). Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (K.G.A., P.T.E., S.A.L.). Search for more papers by this author Originally published1 Jul 2019https://doi.org/10.1161/CIRCULATIONAHA.119.040940Circulation. 2019;140:e7–e8In Response:We thank Drs Feldman, Gerhard, and Cheung for their interest in our phenotype-driven analysis of common, complex heart failure in the UK Biobank.1 Indeed, our observation that both rare and common variation at BAG3 associates with a nonischemic dilated cardiomyopathy phenotype within a single biobank corroborates prior reports and confirms BAG3 as an important nonischemic dilated cardiomyopathy susceptibility locus worthy of further interrogation. We agree, however, that careful consideration of the specific BAG3 variants analyzed is critical to our understanding of disease biology and for precise functional characterization of this locus to inform potential therapeutic development.The authors aptly note that the Pro209Leu BAG3 variant (rs121918312) is a rare missense variant that often induces a myopathic syndrome, although a dilated cardiomyopathy has not been described to our knowledge, and is generally incompatible with survival to adulthood.2–4 However, our analysis of rare variants was limited to those truncating, premature stop, canonical splice, or frameshift mutations predicted to lead to loss of protein function, and did not include any missense mutations such as the Pro209Leu variant. We have now probed for the Pro209Leu missense variant at BAG3 among the ≈390 000 UK Biobank participants in our genetic analysis (all age >40 years), and identified only five mutation carriers, none with a nonischemic dilated cardiomyopathy phenotype.We again thank the authors for highlighting this interesting mutation at BAG3, which was not directly addressed in our manuscript. Forthcoming whole-exome sequencing data in all 500 000 UK Biobank participants should permit more robust rare variant analyses in this large, richly phenotyped biobank population to further our understanding of BAG3 and other cardiomyopathy loci.DisclosuresDr Aragam is supported by an award from the American Heart Association Institute for Precision Cardiovascular Medicine (17IFUNP33840012). Dr Ellinor is supported by the Foundation Leducq (14CVD01) and by awards from the National Heart, Lung, and Blood Institute (RO1HL092577, R01HL128914, K24HL105780). Dr Kathiresan is supported by an Ofer and Shelly Nemirovsky Research Scholar Award from Massachusetts General Hospital, and by awards from the National Heart, Lung, and Blood Institute (RO1 HL127564), and the National Human Genome Research Institute (5UM1HG008895). Dr Lubitz is supported by National Institutes of Health grant 1R01HL139731 and American Heart Association grant 18SFRN34250007. Dr Lubitz receives sponsored research support from Bristol-Myers Squibb/Pfizer, Bayer HealthCare, and Boehringer Ingelheim, and has consulted for Abbott, Quest Diagnostics, and Bristol-Myers Squibb/Pfizer. The other author reports no conflicts.References1. Aragam KG, Chaffin M, Levinson RT, McDermott G, Choi SH, Shoemaker MB, Haas ME, Weng LC, Lindsay ME, Smith JG, Newton-Cheh C, Roden DM, London B, Wells QS, Ellinor PT, Kathiresan S, Lubitz SA. Phenotypic refinement of heart failure in a national biobank facilitates genetic discovery.Circulation. 2019; 139:489–501. doi: 10.1016/CIRCULATIONAHA.118.035774LinkGoogle Scholar2. Finsterer J, Zarrouk-Mahjoub S. BAG3-related myofibrillar myopathy requiring heart transplantation for restrictive cardiomyopathy.Mol Genet Metab Rep. 2018; 15:65–66. doi: 10.1016/j.ymgmr.2018.02.002CrossrefMedlineGoogle Scholar3. Arimura T, Ishikawa T, Nunoda S, Kawai S, Kimura A. Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes.Hum Mutat. 2011; 32:1481–1491. doi: 10.1002/humu.21603CrossrefMedlineGoogle Scholar4. Selcen D, Muntoni F, Burton BK, Pegoraro E, Sewry C, Bite AV, Engel AG. 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Liu Y, Chang X, Glessner J, Qu H, Tian L, Li D, Nguyen K, Sleiman P and Hakonarson H (2019) Association of Rare Recurrent Copy Number Variants With Congenital Heart Defects Based on Next-Generation Sequencing Data From Family Trios, Frontiers in Genetics, 10.3389/fgene.2019.00819, 10 Chen H, Zhuo C and Zheng L (2022) Assessing Causal Associations of Atopic Dermatitis With Heart Failure and Other Cardiovascular Outcomes: A Mendelian Randomization Study, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2022.868850, 9 July 2, 2019Vol 140, Issue 1 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.040940PMID: 31549875 Originally publishedJuly 1, 2019 PDF download Advertisement SubjectsHeart Failure