| Autor: |
Maamari, Dimitri J, Biddinger, Kiran J, Jurgens, Sean J, Gaziano, Liam, Rämö, Joel T, Gongora, Carlos A, Hayes, Dolphurs, Choi, Seung H, Sarma, Amy, Neilan, Tomas G, Khera, Amit V, Ellinor, Patrick T, Aragam, Krishna G |
| Zdroj: |
Circulation (Ovid); November 2022, Vol. 146 Issue: Supplement 1 pA15276-A15276, 1p |
| Abstrakt: |
Introduction:Rare (monogenic) variants linked to dilated cardiomyopathy (DCM) are enriched among individuals with peripartum (PPCM), alcoholic (ACM), and chemotherapy-induced cardiomyopathies (CCM), but are present in <15% of cases. Whether a common-variant (polygenic) susceptibility to DCM is also shared across these secondary cardiomyopathies is unknown.Methods:Cases of DCM, PPCM, ACM, and CCM were adjudicated using hospital billing codes only (in UK Biobank), or with additional chart reviews conducted by 2 medical doctors blinded to the genetic data (in Mass General Brigham [MGB] Biobank). A DCM polygenic score predicated on imaging-based measures of left ventricular structure and function was tested for association with each condition. In a subset of MGB Biobank participants with whole exome sequencing data, we determined the proportion of cases with a monogenic variant and/or a high (≥90thpercentile) polygenic score.Results:In MGB Biobank (n=30,837) and UK Biobank (n=304,687), 193 cases of PPCM (n=18), ACM (n=127) or CCM (n=48) were identified. A DCM polygenic score comprising 2.3 million common genetic variants associated comparably with DCM and all three secondary cardiomyopathies (meta-analyzed p<0.001 for all) (Figure). Among chart-validated phenotypes in MGB Biobank, cases had higher median polygenic score percentiles than controls (Controls=50; DCM=68; PPCM=86; ACM=70; CCM=59), and a high polygenic score conferred 3.3-fold odds of any secondary cardiomyopathy (p<0.001). In the whole exome sequencing subset (N=21,378; n=65 secondary cardiomyopathy cases), 9.2% of secondary cardiomyopathy cases harbored a monogenic variant, while 21.5% had a high polygenic score (including 1.5% who had both).Conclusion:Individuals with PPCM, ACM, and CCM are enriched for a high DCM polygenic score, further suggesting that these conditions arise from unique, extrinsic insults acting in the context of a common, underlying genetic susceptibility. |
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