AHRR Methylation is a Significant Predictor of Mortality Risk in Framingham Heart Study

J Insur Med. 2019;48(1):79-89. doi: 10.17849/insm-48-1-1-11.1. Epub 2019 Oct 16.


Background.-The ability to predict mortality is useful to clinicians, policy makers and insurers. At the current time, prediction of future mortality is still an inexact process with some proposing that epigenetic assessments could play a role in improving prognostics. In past work, we and others have shown that DNA methylation status at cg05575921, a well-studied measure of smoking intensity, is also a predictor of mortality. However, the exact extent of that predictive capacity and its independence of other commonly measured mortality risk factors are unknown. Objective.-To determine the capacity of methylation to predict mortality. Method.-We analyzed the relationship of methylation at cg05575921 and cg04987734, a recently described quantitative marker of heavy alcohol consumption, to mortality in the Offspring Cohort of the Framingham Heart Study using proportional hazards survival analysis. Results.-In this group of participants (n = 2278) whose average age was 66 ± 9 years, we found that the inclusion of both cg05575921 and cg04987734 methylation to a base model consisting of age and sex only, or to a model containing 11 commonly used mortality risk factors, improved risk prediction. What is more, prediction accuracy for the base model plus methylation data was increased compared to the base model plus known predictors of mortality (CHD, COPD, or stroke). Conclusion.-Cg05575921, and to a smaller extent cg04987734, are strong predictors of mortality risk in older Americans and that incorporation of DNA methylation assessments to these and other loci may be useful to population scientists, actuaries and policymakers to better understand the relationship of environmental risk factors, such as smoking and drinking, to mortality.

Keywords: AHRR; Alcohol; DNA methylation; Framingham Heart Study Smoking; Methylation; aryl hydrocarbon receptor repressor; cg05575921; digital PCR; epigenetics; smoking; survival.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alcohol Drinking / adverse effects*
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Cardiovascular Diseases / epidemiology
  • DNA Methylation*
  • Epigenesis, Genetic
  • Female
  • Genetic Loci*
  • Humans
  • Longitudinal Studies
  • Male
  • Massachusetts / epidemiology
  • Middle Aged
  • Mortality*
  • Proportional Hazards Models
  • Repressor Proteins / genetics*
  • Risk Factors
  • Smoking / epidemiology


  • AHRR protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Repressor Proteins