Multicohort Epigenome-Wide Association Study of All-Cause Cardiovascular Disease and Cancer Incidence: A Cardio-Oncology Approach.

Background

Emerging evidence reveals a complex relationship between cardiovascular disease (CVD) and cancer, which share common risk factors and biological pathways.

Objectives

The aim of this study was to evaluate common epigenetic signatures for CVD and cancer incidence in 3 ethnically diverse cohorts: Native Americans from the SHS (Strong Heart Study), European Americans from the FHS (Framingham Heart Study), and European Americans and African Americans from the ARIC (Atherosclerosis Risk In Communities) study.

Methods

A 2-stage strategy was used that included first conducting untargeted epigenome-wide association studies for each cohort and then running targeted models in the union set of identified differentially methylated positions (DMPs). We also explored potential molecular pathways by conducting a bioinformatics analysis.

Results

Common DMPs were identified across all populations. In a subsequent meta-analysis, 3 and 1 of those DMPs were statistically significant for CVD only and both cancer and CVD, respectively. No meta-analyzed DMPs were statistically significant for cancer only. The enrichment analysis pointed to interconnected biological pathways involved in cancer and CVD. In the DrugBank database, elements related to 1-carbon metabolism and cancer and CVD medications were identified as potential drugs for target gene products. In an additional analysis restricted to the 950 SHS participants who developed incident CVD, the C index for incident cancer increased from 0.618 (95% CI: 0.570-0.672) to 0.971 (95% CI: 0.963-0.978) when adjusting the models for the combined cancer and CVD DMPs identified in the other cohorts.

Conclusions

These results point to molecular pathways and potential treatments for precision prevention of CVD and cancer. Screening based on common epigenetic signatures of incident CVD and cancer may help identify patients with newly diagnosed CVD at increased cancer risk.

Informations de copyright

© 2024 The Authors.

Déclaration de conflit d'intérêts

This work was supported by grants from the National Heart, Lung, and Blood Institute (under contracts 75N92019D00027, 75N92019D00028, 75N92019D00029, and 75N92019D00030) and previous grants (R01HL090863, R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319 and cooperative agreements U01HL41642, U01HL41652, U01HL41654, U01HL65520, and U01HL65521); by the National Institute of Health Sciences (R01ES021367, R01ES025216, P42ES033719, and P30ES009089); by the Spanish Funds for Research in Health Sciences, Instituto de Salud Carlos III, cofunded by European Regional Development Funds (PI22CIII/00029, PI15/00071 and CP12/03080); and the by Spanish Agency for Research (PID2023-147163OB-C22, PID2019-108973RB-C21 and PID2020-117114GB-I00 from Ministerio de Ciencia e Innovación) by “Ministerio de Ciencia e Innovación,” Maria Zambrano grant ZA21-063, funded by the Ministry of Universities of the Government of Spain, financed by the European Union, NextGeneration EU, to Dr Riffo-Campos; ANID–Millennium Science Initiative Program—NCS2021_013 and ANID FONDAP 152220002 (CECAN) and a fellowship from the “La Caixa” Foundation (ID 100010434), code LCF/BQ/DR19/11740016. The ARIC study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, under contracts 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. Funding was also supported by grants 5RC2HL102419 and R01NS087541. Studies on cancer in ARIC are also supported by the National Cancer Institute (U01 CA164975). Cancer data were provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health, with funding from the State of Maryland and the Maryland Cigarette Restitution Fund. The collection and availability of cancer registry data are also supported by cooperative agreement NU58DP007114, funded by the Centers for Disease Control and Prevention. The FHS is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, and a National Institutes of Health Director’s Challenge Award (Daniel Levy, principal investigator). Dr Belsky is a fellow of the CIFAR CBD Network. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the Centers for Disease Control and Prevention, the U.S. Department of Health and Human Services, or Instituto de Salud Carlos III. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.