DNA Methylation Markers of Type 2 Diabetes among HIV-infected and Uninfected Individuals Open Access

Abstract

Type 2 Diabetes Mellitus (T2DM) has been increasingly diagnosed in HIV/AIDS patients in the United States, resulting in an approximately 3.8% difference in prevalence between HIV positive and HIV negative individuals in 2009-2010. HIV infection and/or HIV treatment could result in epigenetic modification of the T2DM-related loci in the human genome, affecting the risk of developing this disease. In this study, we investigated differential DNA methylation associated with T2DM in both HIV positive and negative populations using data from the Veterans Aging Cohort Study (VACS). We conducted association analyses to replicate five previously reported CpG sites associated with T2DM and to discover novel loci associated with T2DM in HIV positive individuals. DNA methylation level was modeled as a function of T2DM status, controlling for HIV-infection status, current smoking status, chronological age, BMI, and cell type proportions in all study participants and with stratification by HIV-infection status. Interaction effects were assessed between T2DM status and HIV-infection status. Among reported T2DM-associated CpG sites, cg1963031 in TXNIP, cg18181703 in SOCS3, and cg09152259 in PROC were negatively associated with T2DM in the HIV positive individuals, suggesting T2DM status is associated with hypomethylation of these CpG sites. Three novel sites, cg1231141 in ADAMTS2 (p-value = 6.76´10^-7), cg19534769 in HGFAC (p-value = 2.09´10^-6), and cg13163919 in TLE3 (p-value = 4.48´10^-6) showed suggestive statistical significance in the epigenome-wide association analysis among HIV positive individuals. The T2DM-HIV interaction was associated with cg17862404 in TSC22D1 with suggestive statistical significance (interaction p-value = 9.87´10^-7). Though further validation is warranted, our study identified novel T2DM-associated CpG sites in people living with HIV and suggested modification by HIV-infection. The identified epigenetic associations with T2DM have implications in inflammation, pancreatic β-cell function, and T2DM pathogenesis.

Key words: epigenome; DNA methylation; HIV; Type 2 Diabetes

Table of Contents

Chapter I: Background and Significance................................... 1

Genetic research on Type 2 Diabetes......................................... 2

Epigenetic research on Type 2 Diabetes.................................... 5

Epigenetic research on HIV...................................................... 7

Addressing the Gap: The intersection between Type 2 Diabetes and HIV........................................................................................... 9

 

Chapter II: Manuscript............................................................ 11

Abstract................................................................................... 11

Introduction............................................................................. 12

Methods................................................................................... 14

VACS Data.......................................................................... 14

Phenotypes and Data Analysis............................................ 15

DNA Methylation Assessment and Data Analysis.............. 15

Results...................................................................................... 17

Discussion................................................................................ 21

Tables....................................................................................... 26

Figures..................................................................................... 29

 

Chapter III: Summary, Public Health Implications, and Future Directions................................................................................... 37

Summary of Results............................................................... 37

Public Health Implications and Possible Future Directions....40

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology
Keyword	Type 2 Diabetes DNA methylation HIV epigenome
Committee Chair / Thesis Advisor	Sun, Yan, Emory University
Committee Members	Marconi, Vince, Emory University
Partnering Agencies	Does not apply (no collaborating organization)

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