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Repurposing: Efficient use of excess PLCO biospecimens to investigate DNA methylation patterns and cardiovascular disease mortality risk

Principal Investigator

Name
Jason Wong

Degrees
Sc.D

Institution
National Heart Lung and Blood Institute

Position Title
Tenure-track Investigator

Email
jason.wong@nih.gov

About this CDAS Project

Study
PLCO (Learn more about this study)

Project ID
2026-8083

Initial CDAS Request Approval
Jun 25, 2026

Title
Repurposing: Efficient use of excess PLCO biospecimens to investigate DNA methylation patterns and cardiovascular disease mortality risk

Summary
This project is in response to the request for proposals (“Upcoming PLCO Sample Culling and Opportunity for Repurposing”) issued on September 2nd, 2025. As chief of the Laboratory of Genomic Instability and Cardiopulmonary Outcomes (LoGICO) at the National Heart Lung and Blood Institute (NHLBI), I lead epidemiologic studies to understand how chemical compounds in the air and consumer products influence the risk of cardiovascular and non-malignant lung diseases through pathways involving genomic instability. LoGICO’s efforts are focused on identifying omics biomarkers that capture in unison environmental exposures, disease risk, and genomic instability. DNA methylation is an omics biomarker of interest that fulfill these criteria, and supports disease prevention efforts by helping identify higher-risk populations that might benefit from exposure reduction.

Leveraging excess whole blood or leukocyte biospecimens from PLCO, I propose a nested case-control study to agnostically investigate associations between DNA methylation markers and cardiovascular disease (CVD) mortality risk. A previous study conducted in PLCO identified 17,793 CVD deaths (8788 in the control arm and 9005 in the screening arm) during an 19-year prospective follow-up (DOI: 10.1038/s41598-024-78252-2). In a subset of CVD mortality cases without prior CVD at baseline and 1:2 age- and sex- matched controls, all with available whole blood or leukocyte samples, I plan to conduct an epigenomic scan using Illumina’s newest Methylation Screening Array (270K). This chip has distinct and important advantages over previous 850K EPIC arrays, including: 1) being half the cost, 2) requiring only 50 ng of genomic DNA, which is important for population studies with precious samples, 3) having efficient and intelligently-designed probes which have been previously found to respond to hazardous exposures, and 4) being able to interrogate 123,776 new methylation sites. The DNA methylation assays will be conducted by TruDiagnostic (Lexington, Kentucky). In addition to the agnostic approach, I plan to focus attention on a priori DNA methylation patterns that have be previously linked to air and chemical exposures deposited in EWAS Catalogue (https://ewascatalog.org/) and from deep literature search. Further, I will examine heterogeneity in these analyses by sex, age groups, and socioeconomic status to potentially support targeted interventions for high-risk populations, in alignment with the HHS/NIH’s core mission to reduce the burden of chronic diseases among Americans.

At the NHLBI-Division of Intramural Research (DIR), I have access to the new centralized Biospecimen Core (Director Coleen Damcott), which has been in operation since 2024. Currently, the Biospecimen Core has enthusiastic support from the DIR office of the director and has indefinite storage capacity going forward into FY26. My laboratory and NHLBI/DIR Biospecimen Core have already made material transfer arrangements to house nearly 50,000 biospecimens from NCI’s Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (PI: Dr. Demetrius Albanes) and the NIEHS Agricultural Lung Health Study’s metagenomic samples (PI: Dale Sandler / Stephanie London (retired)) that were slated for culling. Both the intramural NHLBI/DIR Biospecimen Core and NCI Frederick BioProcessing Laboratory use similar BSI systems and storage procedures, thus continued storage of excess PLCO samples here would be beneficial economically and for consistency.

Aims

1) Agnostically investigate the prospective associations between DNA methylation markers measured using the state-of-the-art Illumina Methylation Screening Array (MSA; 270K) and cardiovascular disease (CVD) mortality risk. In addition to the agnostic approach, I plan to focus attention on a priori DNA methylation patterns that have be previously linked to air and chemical exposures deposited in EWAS Catalogue (https://ewascatalog.org/) and identified with a deep literature search.

2) Determine if the identified associations between DNA methylation markers and CVD mortality risk differ by specific cardiovascular outcomes including heart failure, atrial fibrillation, myocardial infarction, ischemic heart disease, hypertension, and stroke.

3) Determine if the identified associations between DNA methylation patterns and CVD mortality risk show heterogeneity by sex, age groups, smoking status, adiposity, and socioeconomic status.