Integrated multiomic scores for cardiovascular disease prediction across multiancestral populations
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Background Genomic, epigenomic, and proteomic data capture complementary aspects of cardiovascular disease biology, but the value of integrating these data for predicting multiple cardiovascular disease outcomes across ancestry groups remains uncertain. Methods We derived disease-specific proteomic scores using 999 plasma proteins in 50,673 UK Biobank participants and validated them in 9,358 participants from the Prospective Urban and Rural Epidemiological (PURE) study. In PURE, we integrated these proteomic scores with 2,279 polygenic scores and 479 DNA methylation scores to develop 4 multiomic scores (MEGASCOREs) for myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), and cardiovascular mortality. Associations with incident cardiovascular disease, discrimination, calibration, and performance across ancestry groups were evaluated in PURE and 2 additional cohorts. Results In pooled analyses, each standard deviation increase in the corresponding MEGASCORE was associated with MI (hazard ratio [HR], 2.13; 95% CI, 1.86-2.43), AF (HR, 1.94; 95% CI, 1.68-2.24), HF (HR, 3.33; 95% CI, 2.75-4.05), and cardiovascular mortality (HR, 3.28; 95% CI, 2.33-4.61). MEGASCOREs improved discrimination compared with clinical models, with strongest improvements for HF and cardiovascular mortality. MEGASCORE CV-Death had a higher area under the receiver operating characteristic curve (AUC) than SCORE2 for cardiovascular mortality (0.83 [95% CI, 0.82-0.85] vs. 0.78 [95% CI, 0.77-0.80]). Its discrimination was also higher than that of SCORE2 across all 4 ancestry groups, with better calibration across non-European ancestry groups. MEGASCOREs remained associated with cardiovascular outcomes among participants without conventional cardiovascular risk factors. Conclusions Integrated multiomic MEGASCOREs were associated with multiple cardiovascular outcomes and provided prognostic information beyond conventional clinical variables in PURE. Clinical Perspective What is new? We developed 4 cardiovascular disease-specific multiomic scores integrating proteomic signatures, polygenic scores, and DNA methylation scores to characterize risk of MI, AF, HF, and cardiovascular mortality. The MEGASCOREs were associated with incident cardiovascular disease outcomes and provided prognostic information beyond conventional clinical risk factors. MEGASCOREs showed consistent risk stratification across ancestry and remained associated with risk among participants without conventional cardiovascular risk factors. What are the clinical implications? Integrated multiomic scores may complement conventional cardiovascular risk assessment by capturing molecular information not fully represented by clinical variables. Molecular risk profiling may help identify individuals with elevated cardiovascular risk despite having no conventional risk factors. Assessment of clinical utility, evaluation of implementation and cost-effectiveness are needed before MEGASCOREs can inform preventive treatment decisions.
Source: medRxiv
Authors: Pascal B. Meyre, Michael Chong, Marie Pigeyre, Shihong Mao, Michael Kamal, Shrikant Bangdiwala, Roya Kelishadi, Annika Rosengren, Fernando Lanas, Afzalhussein Yusufali, Rita Yusuf, Jephat Chifamba, Patricio Lopez-Jaramillo, Marc Evans M. Abat, Alvaro Avezum, Karen Yeates, Maria Luz Diaz, Hassan Mir, Bernard Keavney, Sonia S. Anand, Koon Teo, Sumathy Rangarajan, Philip Joseph, Hertzel Gerstein, Salim Yusuf, Guillaume Paré
Institutions: University of Basel, University Hospital of Basel, Population Health Research Institute, McMaster University, Isfahan University of Medical Sciences, Sahlgrenska University Hospital, University of Gothenburg, Universidad de La Frontera, BRAC, BRAC University, University of Zimbabwe, Universidad De Santander, Philippine General Hospital, Hospital Alemão Oswaldo Cruz, Queen's University, Estudios Clínicos Latinoamérica, Instituto Cardiovascular de Rosario, University of Ottawa, Ottawa Heart Institute, Manchester Academic Health Science Centre, University of Manchester, Manchester University NHS Foundation Trust, Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: AstraZeneca, GlaxoSmithKline, Sanofi, Departamento Administrativo de Ciencia, Tecnología e Innovación (COLCIENCIAS), Public Health Agency of Canada, Ontario Ministry of Health and Long-Term Care, South Africa Netherlands research Programme on Alternatives in Development, Forskningsrådet för Arbetsliv och Socialvetenskap, AFA Försäkring, Vetenskapsrådet, North-West University, Universidad de La Frontera, Servier, Independent University, Bangladesh, Canadian Institutes of Health Research, Medical Research Council
Awards: G6259304196, G8884921450
OpenAlex ID: W7224091431