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

Arce Domingo-Relloso; Angela L Riffo-Campos; Naisi Zhao; Guillermo Ayala; Karin Haack; Carlos Manterola; Dorothy A Rhoades; Jason G Umans; M Daniele Fallin; Miguel Herreros-Martinez; Marina Pollan; Eric Boerwinkle; Elizabeth A Platz; Miranda R Jones; Jan Bressler; Roby Joehanes; Calen P Ryan; Juan R Gonzalez; Daniel Levy; Daniel W Belsky; Shelley A Cole; Dominique S Michaud; Ana Navas-Acien; Maria Tellez-Plaza

doi:10.1016/j.jaccao.2024.07.014

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

JACC CardioOncol. 2024 Sep 10;6(5):731-742. doi: 10.1016/j.jaccao.2024.07.014. eCollection 2024 Oct.

Authors

Arce Domingo-Relloso^{1

2

3}, Angela L Riffo-Campos^{4

5

6}, Naisi Zhao⁷, Guillermo Ayala⁵, Karin Haack⁸, Carlos Manterola⁴, Dorothy A Rhoades⁹, Jason G Umans¹⁰, M Daniele Fallin¹¹, Miguel Herreros-Martinez¹², Marina Pollan³, Eric Boerwinkle^{13

14}, Elizabeth A Platz¹⁵, Miranda R Jones¹⁵, Jan Bressler¹³, Roby Joehanes^{16

17}, Calen P Ryan¹⁸, Juan R Gonzalez¹⁹, Daniel Levy^{16

17}, Daniel W Belsky²⁰, Shelley A Cole⁸, Dominique S Michaud⁷, Ana Navas-Acien¹, Maria Tellez-Plaza^{2

3}

Affiliations

¹ Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York, USA.
² Integrative Epidemiology Group, National Center for Epidemiology, Instituto de Salud Carlos III, Madrid, Spain.
³ Department of Chronic Disease Epidemiology, National Center for Epidemiology, Instituto de Salud Carlos III, Madrid, Spain.
⁴ Universidad de La Frontera, Ph.D. Program in Medical Sciences; and Millennium Nucleus on Sociomedicine (SocioMed), Temuco, Chile.
⁵ Department of Computer Science, Universidad de Valencia, Valencia, Spain.
⁶ Center for Cancer Prevention and Control, Santiago, Chile.
⁷ Department of Public Health & Community Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA.
⁸ Population Health Program, Texas Biomedical Research Institute, San Antonio, Texas, USA.
⁹ Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
¹⁰ MedStar Health Research Institute, Washington, DC, USA.
¹¹ Emory University Rollins School of Public Health, Atlanta, Georgia, USA.
¹² Department of Bioinformatics, INCLIVA Biomedical Research Institute, Valencia, Spain.
¹³ The University of Texas Health Science Center at Houston, Houston, Texas, USA.
¹⁴ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
¹⁵ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
¹⁶ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
¹⁷ Framingham Heart Study, Framingham, Massachusetts, USA.
¹⁸ Columbia Aging Center, Columbia University Mailman School of Public Health, New York, New York, USA.
¹⁹ Bioinformatics and Genetic Epidemiology Unit, Instituto de Salud Global, Barcelona, Spain.
²⁰ Department of Epidemiology, Columbia University Mailman School of Public Health, New York, New York, USA.

Abstract

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.

Keywords: DNA methylation; cancer; cardio-oncology; cardiovascular disease; multicohort.