Effects of Smoking-related DNA Methylation on Coronary Flow Reserve Pubblico

Abstract

Background: Smoking is a major risk factor for cardiovascular disease, which is a leading cause of death in the United States. Smoking has been shown to affect human health through changes of epigenetics such as DNA methylation. Previous publications suggested that smoking-related DNA methylation might mediate the effect of smoking on cardiovascular function, and the smoking-related DNA methylation markers could potentially improve the prediction of cardiovascular diseases.

Methods: Genome-wide DNA methylation data of peripheral blood (218 male twins) were utilized to investigate the associations between smoking, DNA methylation and coronary flow reserve (CFR), which is a parameter that reflects the coronary vasodilator capacity by showing the status of pericardial coronary arteries and the microvascular coronary circulation. An epigenome-wide association analysis was conducted to identify the smoking-related DNA methylation markers, which were further investigated in a linear mixed effect model, adjusting for age, body mass index, cell types (granulocytes, monocytes, natural killer cells, B cells, CD4+ and CD8+ T cells) and treating Beadchip and pair as random effects. Then, smoking was additionally controlled in the model to study the role of DNA methylation as a mediator in the effect of smoking on cardiovascular function. Furthermore, twin-specific models were performed to assess within-twin and between-twin effects.

Results: We successfully replicated 50 smoking-related CpG sites, which were reported 3 or more times in previous publications. 15 of the 50 markers were significantly associated with CFR (p< 0.05) in linear mixed effect model, adjusting for age, body mass index, cell types (granulocytes, monocytes, natural killer cells, B cells, CD4+ and CD8+ T cells) and treating Beadchip and pair as random effects. After additional adjustment for smoking, cg21121843 in huntingtin (HTT) gene on Chromosome 4 remained associated with CFR (p=0.046).

Conclusions: Our findings suggest that smoking-related DNA methylation sites of peripheral blood cells are associated with CFR but may not directly mediate the effects of smoking on cardiovascular function.

Table of Contents

BACKGROUND….………………………..………………………….......1

METHODS…………...………………………………………………….…...5

Data source…………………………………………………................5

DNA methylation methods……..……………..………............5

Phenotypic measurements……….…………………….............6

Statistical analysis………………………...………….................7

RESULTS………..…………………………………………………..……...10

DISCUSSION………………...…………………………………………...12

STRENGTHS & WEAKNESSES…….……..……………………….15

FUTURE DIRECTIONS……….………………………………………….16

REFERENCES…….………...……………………………………………..17

TABLES…………………………………………..….………………………..23

FIGURES……...………………………………….………………………...27

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology
Parola chiave	Smoking DNA Methylation Coronary Flow Reserve
Committee Chair / Thesis Advisor	Sun, Yan, Emory University
Partnering Agencies	Emory University schools, faculty or affiliated programs

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