| Title: | Polygenic Susceptibility in Peripartum, Alcohol-Induced, and Cancer Therapy-Related Cardiomyopathies |
| Journal: | JAMA Cardiology |
| Published: | 1 Nov 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41032333/ |
| DOI: | https://doi.org/10.1001/jamacardio.2025.3248 |
| URL: | https://pure.amsterdamumc.nl/en/publications/8af3f06b-5a84-4539-b1fb-eaaed7e1c887 |
Publication 19083
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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.</p>
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.</p>
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.</p>
Exposures: DCM polygenic risk score and DCM monogenic variants.</p>
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.</p>
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.</p>
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.</p>
16 Keywords
- Adult
- Cardiomyopathies
- Cardiomyopathy, Dilated
- Female
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- Multifactorial Inheritance
- Neoplasms
- Peripartum Period
- Pregnancy
- Pregnancy Complications, Cardiovascular
- Puerperal Disorders
- Retrospective Studies
- Risk Factors
21 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
1 Application
| Application ID | Title |
|---|---|
| 17488 | Understanding the Genetic Basis of Cardiac Arrhythmias |
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