Population genomics in peripartum cardiomyopathy

Massachusetts General Hospital, Boston MA

Investigators

Abstract

PROJECT SUMMARY Peripartum cardiomyopathy (PPCM) is a form of heart failure characterized by left ventricular dysfunction that occurs during late pregnancy or shortly after delivery. This condition causes a sudden weakening of the heart muscle, leading to clinical heart failure and significant reductions in both quality and quantity of life. PPCM remains a leading cause of maternal mortality, accounting for nearly a quarter of all deaths in the late postpartum period. Despite its severe impact, the exact cause of PPCM is unknown, and it often arises in women without identifiable clinical risk factors. Additionally, PPCM disproportionately affects women of self-identified Black race and African descent, even after adjusting for ancestry-specific cardiac risk factors and socioeconomic disparities. Recent studies have linked rare ("monogenic") variants associated with dilated cardiomyopathy (DCM), such as truncating mutations in TTN, to PPCM in about 15% of cases. Moreover, polygenic risk scores (PRS), which aggregate common genetic variants associated with DCM, have shown relevance to PPCM in a broader subset of cases. Notably, we recently identified a common African ancestry-specific loss-of-function mutation in CD36 that accounts for a significant portion of DCM risk in AFR populations. However, it remains unclear: (1) How combining monogenic and polygenic factors could enhance prediction and early detection of PPCM; and (2) The extent to which CD36 variation explains the increased PPCM risk observed in AFR individuals. This proposal aims to expand genomic investigation into PPCM by leveraging the national PPCM- Registry (~470 participants, 40% of AFR ancestry) alongside additional recruitment and biobank data. We will combine data from existing biobanks, where genetic data are available but phenotyping of PPCM is required, and from newly recruited PPCM cases, where detailed phenotyping is available, but genetic data generation is needed. This expanded dataset will provide added power for testing a priori hypotheses and discovering novel PPCM associations, facilitating a more comprehensive understanding of genetic risk in PPCM. Our study aims to: (1) Expand the PPCM-Registry and create a larger, consolidated genetic dataset by integrating genetic and phenotypic data across biobanks and recruited cohorts; this will involve generating new genetic data where needed and standardizing phenotypic data across cohorts to support discovery in this rare condition. (2) Evaluate monogenic and polygenic risk factors for left ventricular dysfunction in all PPCM-Registry participants to understand the combined effect of rare and common variants on PPCM risk. (3) Characterize African ancestry-specific risk for PPCM, focusing on the contribution of the CD36 loss-of-function variant to PPCM incidence among AFR participants, with additional analysis of its impact on observed disparities in PPCM risk. Through this comprehensive approach, we aim to advance understanding of the genomic underpinnings of PPCM to enhance prediction, early detection, prevention, and management of this serious cardiovascular condition, while addressing significant disparities in risk.