Dimitri J Maamari,Kiran J Biddinger,Sean J Jurgens,Joel T Rämö,Liam Gaziano,Alice Zheng,Saketh P Challa,Dolphurs Hayes,Carlos A Gongora,Seung Hoan Choi,Kyong-Mi Chang,Philip S Tsao,Zoltan Arany,Paaladinesh Thavendiranathan,Jennifer E Huffman,Akl C Fahed,Amy A Sarma,Tomas G Neilan,Amit V Khera,Patrick T Ellinor,Krishna G Aragam
{"title":"Polygenic Susceptibility in Peripartum, Alcohol-Induced, and Cancer Therapy-Related Cardiomyopathies.","authors":"Dimitri J Maamari,Kiran J Biddinger,Sean J Jurgens,Joel T Rämö,Liam Gaziano,Alice Zheng,Saketh P Challa,Dolphurs Hayes,Carlos A Gongora,Seung Hoan Choi,Kyong-Mi Chang,Philip S Tsao,Zoltan Arany,Paaladinesh Thavendiranathan,Jennifer E Huffman,Akl C Fahed,Amy A Sarma,Tomas G Neilan,Amit V Khera,Patrick T Ellinor,Krishna G Aragam","doi":"10.1001/jamacardio.2025.3248","DOIUrl":null,"url":null,"abstract":"Importance\r\nRare monogenic variants linked to nonischemic dilated cardiomyopathy (DCM) are enriched among individuals with secondary cardiomyopathies, such as peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-related (CCM) cardiomyopathies. However, it remains unclear whether a polygenic predisposition to DCM also contributes to these conditions.\r\n\r\nObjective\r\nTo assess the association of a DCM polygenic score with PPCM, ACM, and CCM, and to evaluate the contributions of monogenic and polygenic susceptibilities to these secondary cardiomyopathies.\r\n\r\nDesign, Setting, and Participants\r\nThis was a retrospective genetic association analysis of data from the Mass General Brigham (MGB) Biobank (n = 42 137, 2008-2025), with replication in the UK Biobank (n = 295 160, 2005-2010), FinnGen (n = 417 950, 2017-2025), and the Veterans Affairs Million Veteran Program (n = 516 066, 2011-2025). In MGB Biobank, medical records were reviewed to ascertain secondary cardiomyopathy cases and antecedent clinical risk factors.\r\n\r\nExposures\r\nDCM polygenic risk score and DCM monogenic variants.\r\n\r\nMain Outcomes and Measures\r\nThe primary outcomes were the association of the DCM polygenic risk score with PPCM, ACM, and CCM and the prevalence of monogenic variants and a high polygenic score among individuals with cardiomyopathy.\r\n\r\nResults\r\nThe mean (SD) age in the MGB Biobank was 55.7 (17.0) years at enrollment, and 24 551 (58.3%) were female. Across the 4 study cohorts, 3414 individuals with secondary cardiomyopathy were identified, including 70 with PPCM, 2281 with ACM, and 1063 with CCM. The DCM polygenic score was associated with PPCM (odds ratio [OR], 1.82 per SD; 95% CI, 1.43-2.30), ACM (OR, 1.56; 95% CI,1.34-1.82), and CCM (OR, 1.64; 95% CI,1.24-2.15) (all with P < .001). Monogenic variants were enriched but present in 7 of 113 individuals with medical record-reviewed cardiomyopathy in MGB, while 66 had a high polygenic score, which conferred an approximately 3-fold increased odds of cardiomyopathy. Most individuals with cardiomyopathy lacked antecedent clinical risk factors.\r\n\r\nConclusions and Relevance\r\nIn this cohort study, individuals with PPCM, ACM, and CCM were enriched for monogenic DCM variants and a high DCM polygenic score, suggesting a shared genetic susceptibility influenced by distinct environmental precipitants. These findings support a shared genetic architecture between secondary cardiomyopathies and DCM, although additional work with larger numbers of individuals with cardiomyopathy is needed to confirm these findings.","PeriodicalId":14657,"journal":{"name":"JAMA cardiology","volume":"78 1","pages":""},"PeriodicalIF":14.1000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JAMA cardiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1001/jamacardio.2025.3248","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Importance
Rare monogenic variants linked to nonischemic dilated cardiomyopathy (DCM) are enriched among individuals with secondary cardiomyopathies, such as peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-related (CCM) cardiomyopathies. However, it remains unclear whether a polygenic predisposition to DCM also contributes to these conditions.
Objective
To assess the association of a DCM polygenic score with PPCM, ACM, and CCM, and to evaluate the contributions of monogenic and polygenic susceptibilities to these secondary cardiomyopathies.
Design, Setting, and Participants
This was a retrospective genetic association analysis of data from the Mass General Brigham (MGB) Biobank (n = 42 137, 2008-2025), with replication in the UK Biobank (n = 295 160, 2005-2010), FinnGen (n = 417 950, 2017-2025), and the Veterans Affairs Million Veteran Program (n = 516 066, 2011-2025). In MGB Biobank, medical records were reviewed to ascertain secondary cardiomyopathy cases and antecedent clinical risk factors.
Exposures
DCM polygenic risk score and DCM monogenic variants.
Main Outcomes and Measures
The primary outcomes were the association of the DCM polygenic risk score with PPCM, ACM, and CCM and the prevalence of monogenic variants and a high polygenic score among individuals with cardiomyopathy.
Results
The mean (SD) age in the MGB Biobank was 55.7 (17.0) years at enrollment, and 24 551 (58.3%) were female. Across the 4 study cohorts, 3414 individuals with secondary cardiomyopathy were identified, including 70 with PPCM, 2281 with ACM, and 1063 with CCM. The DCM polygenic score was associated with PPCM (odds ratio [OR], 1.82 per SD; 95% CI, 1.43-2.30), ACM (OR, 1.56; 95% CI,1.34-1.82), and CCM (OR, 1.64; 95% CI,1.24-2.15) (all with P < .001). Monogenic variants were enriched but present in 7 of 113 individuals with medical record-reviewed cardiomyopathy in MGB, while 66 had a high polygenic score, which conferred an approximately 3-fold increased odds of cardiomyopathy. Most individuals with cardiomyopathy lacked antecedent clinical risk factors.
Conclusions and Relevance
In this cohort study, individuals with PPCM, ACM, and CCM were enriched for monogenic DCM variants and a high DCM polygenic score, suggesting a shared genetic susceptibility influenced by distinct environmental precipitants. These findings support a shared genetic architecture between secondary cardiomyopathies and DCM, although additional work with larger numbers of individuals with cardiomyopathy is needed to confirm these findings.
JAMA cardiologyMedicine-Cardiology and Cardiovascular Medicine
CiteScore
45.80
自引率
1.70%
发文量
264
期刊介绍:
JAMA Cardiology, an international peer-reviewed journal, serves as the premier publication for clinical investigators, clinicians, and trainees in cardiovascular medicine worldwide. As a member of the JAMA Network, it aligns with a consortium of peer-reviewed general medical and specialty publications.
Published online weekly, every Wednesday, and in 12 print/online issues annually, JAMA Cardiology attracts over 4.3 million annual article views and downloads. Research articles become freely accessible online 12 months post-publication without any author fees. Moreover, the online version is readily accessible to institutions in developing countries through the World Health Organization's HINARI program.
Positioned at the intersection of clinical investigation, actionable clinical science, and clinical practice, JAMA Cardiology prioritizes traditional and evolving cardiovascular medicine, alongside evidence-based health policy. It places particular emphasis on health equity, especially when grounded in original science, as a top editorial priority.