Xu Gao1, Elena Colicino2, Jincheng Shen3, Allan C Just2, Jamaji C Nwanaji-Enwerem4, Cuicui Wang4, Brent Coull5, Xihong Lin5, Pantel Vokonas6, Yinan Zheng7, Lifang Hou7, Joel Schwartz4, Andrea A Baccarelli1. 1. Laboratory of Precision Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, USA. 2. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 3. Department of Population Health Sciences, University of Utah, School of Medicine, Salt Lake City, UT, USA. 4. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 5. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 6. Veterans Affairs Normative Aging Study, Veterans Affairs Boston Healthcare System, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. 7. Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Abstract
BACKGROUND: A 'mortality risk score' (MS) based on ten prominent mortality-related cytosine-phosphate-guanine (CpG) sites was previously associated with all-cause mortality, but has not been verified externally. We aimed to validate the association of MS with mortality and to compare MS with three aging biomarkers: telomere length (TL), DNA methylation age (DNAmAge) and phenotypic age (DNAmPhenoAge) to explore whether MS can serve as a reliable measure of biological aging and mortality. METHODS: Among 534 males aged 55-85 years from the US Normative Aging Study, the MS, DNAmAge and DNAmPhenoAge were derived from blood DNA methylation profiles from the Illumina HumanMethylation450 BeadChip, and TL was measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: A total of 147 participants died during a median follow-up of 9.4 years. The MS showed strong associations with all-cause, cardiovascular disease (CVD) and cancer mortality. After controlling for all potential covariates, participants with high MS (>5 CpG sites with aberrant methylation) had almost 4-fold all-cause mortality (hazard ratio: 3.84, 95% confidence interval: 1.92-7.67) compared with participants with a low MS (0-1 CpG site with aberrant methylation). Similar patterns were observed with respect to CVD and cancer mortality. MS was associated with TL and DNAmPhenoAge acceleration but not with DNAmAge acceleration. Although the MS and DNAmPhenoAge acceleration were independently associated with all-cause mortality, the former exhibited a higher predictive accuracy of mortality than the latter. CONCLUSIONS: MS has the potential to be a prominent predictor of mortality that could enhance survival prediction in clinical settings.
BACKGROUND: A 'mortality risk score' (MS) based on ten prominent mortality-related cytosine-phosphate-guanine (CpG) sites was previously associated with all-cause mortality, but has not been verified externally. We aimed to validate the association of MS with mortality and to compare MS with three aging biomarkers: telomere length (TL), DNA methylation age (DNAmAge) and phenotypic age (DNAmPhenoAge) to explore whether MS can serve as a reliable measure of biological aging and mortality. METHODS: Among 534 males aged 55-85 years from the US Normative Aging Study, the MS, DNAmAge and DNAmPhenoAge were derived from blood DNA methylation profiles from the Illumina HumanMethylation450 BeadChip, and TL was measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: A total of 147 participants died during a median follow-up of 9.4 years. The MS showed strong associations with all-cause, cardiovascular disease (CVD) and cancer mortality. After controlling for all potential covariates, participants with high MS (>5 CpG sites with aberrant methylation) had almost 4-fold all-cause mortality (hazard ratio: 3.84, 95% confidence interval: 1.92-7.67) compared with participants with a low MS (0-1 CpG site with aberrant methylation). Similar patterns were observed with respect to CVD and cancer mortality. MS was associated with TL and DNAmPhenoAge acceleration but not with DNAmAge acceleration. Although the MS and DNAmPhenoAge acceleration were independently associated with all-cause mortality, the former exhibited a higher predictive accuracy of mortality than the latter. CONCLUSIONS: MS has the potential to be a prominent predictor of mortality that could enhance survival prediction in clinical settings.
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