The Effect of Tobacco Smoking Differs across Indices of DNA Methylation-Based Aging in an African American Sample: DNA Methylation-Based Indices of Smoking Capture These Effects

Man-Kit Lei,Robert A Philibert,Ronald L Simons,Frederick X Gibbons,Steven R H Beach

doi:10.3390/genes11030311

Abstract

Smoking is one of the leading preventable causes of morbidity and mortality worldwide, prompting interest in its association with DNA methylation-based measures of biological aging. Considerable progress has been made in developing DNA methylation-based measures that correspond to self-reported smoking status. In addition, assessment of DNA methylation-based aging has been expanded to better capture individual differences in risk for morbidity and mortality. Untested to date, however, is whether smoking is similarly related to older and newer indices of DNA methylation-based aging, and whether DNA methylation-based indices of smoking can be used in lieu of self-reported smoking to examine effects on DNA methylation-based aging measures. In the current investigation we examine mediation of the impact of self-reported cigarette consumption on accelerated, intrinsic DNA methylation-based aging using indices designed to predict chronological aging, phenotypic aging, and mortality risk, as well as a newly developed DNA methylation-based measure of telomere length. Using a sample of 500 African American middle aged smokers and non-smokers, we found that a) self-reported cigarette consumption was associated with accelerated intrinsic DNA methylation-based aging on some but not all DNA methylation-based aging indices, b) for those aging outcomes associated with self-reported cigarette consumption, DNA methylation-based indicators of smoking typically accounted for greater variance than did self-reported cigarette consumption, and c) self-reported cigarette consumption effects on DNA methylation-based aging indices typically were fully mediated by DNA methylation-based indicators of smoking (e.g., PACKYRS from GrimAge; or cg05575921 CpG site). Results suggest that when DNA methylation-based indices of smoking are substituted for self-reported assessments of smoking, they will typically fully reflect the varied impact of cigarette smoking on intrinsic, accelerated DNA methylation-based aging.

Highlights

Smoking is a leading preventable cause of mortality and morbidity in the United States, with over400,000 Americans dying prematurely from tobacco consumption each year [1]
Horvath and Haj (2018) [31] report that smoking-related methylation changes did not influence the Horvath [32] or Hannum et al [33] clocks, but was related to “PhenoAge” [29]. These findings suggest that the association of self-reported smoking or DNA methylation-based indices of smoking may differ across different indices of accelerated aging
To provide an alternative assessment of connections between smoking and GRIM, we examine associations with each of the seven subscales of GRIM, i.e., other than DNA methylation-based pack-years (PACKYRS), which were designed to capture specific protein predictors of increased mortality risk and so are not confounded with pack-years assessment: Adrenomedullin (ADM), beta-2 microglobulin (B2M), growth differentiation factor 15 (GDF15), Cystatin C (CystatinC), leptin (Leptin), plasminogen activation inhibitor 1 (PAI1), and tissue inhibitor metalloproteinase 1 (TIMP1)

Summary

Introduction

Smoking is a leading preventable cause of mortality and morbidity in the United States, with over400,000 Americans dying prematurely from tobacco consumption each year [1]. The negative effect of smoking appears to be pronounced among African Americans, with the Centers for Disease Control and Prevention (CDC) reporting that tobacco use is a major contributor to each of the four leading causes of death among African Americans—heart disease, cancer, and stroke and diabetes. Despite smoking fewer cigarettes overall, and beginning to smoke cigarettes at an older age, African Americans are more likely to die from smoking-related diseases than Whites [3,4,5,6], and to experience greater smoking-related morbidity. This background suggests the value of focusing on examining cigarette smoking effects among African Americans

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Results

Conclusion