DNA methylation mediates the effect of cocaine use on HIV severity

Chang Shu,Zuoheng Wang,Dana B Hancock,Amy C Justice,Xinyu Zhang,Ke Xu,Eric O Johnson

doi:10.1186/s13148-020-00934-1

Abstract

BackgroundCocaine use accelerates human immunodeficiency virus (HIV) progression and worsens HIV outcomes. We assessed whether DNA methylation in blood mediates the association between cocaine use and HIV severity in a veteran population.MethodsWe analyzed 1435 HIV-positive participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS-BC). HIV severity was measured by the Veteran Aging Cohort Study (VACS) index. We assessed the effect of cocaine use on VACS index and mortality among the HIV-positive participants. We selected candidate mediators that were associated with both persistent cocaine use and VACS index by epigenome-wide association (EWA) scans at a liberal p value cutoff of 0.001. Mediation analysis of the candidate CpG sites between cocaine’s effect and the VACS index was conducted, and the joint mediation effect of multiple CpGs was estimated. A two-step epigenetic Mendelian randomization (MR) analysis was conducted as validation.ResultsMore frequent cocaine use was significantly associated with a higher VACS index (β = 1.00, p = 2.7E−04), and cocaine use increased the risk of 10-year mortality (hazard ratio = 1.10, p = 0.011) with adjustment for confounding factors. Fifteen candidate mediator CpGs were selected from the EWA scan. Twelve of these CpGs showed significant mediation effects, with each explaining 11.3–29.5% of the variation. The mediation effects for 3 of the 12 CpGs were validated by the two-step epigenetic MR analysis. The joint mediation effect of the 12 CpGs accounted for 47.2% of cocaine’s effect on HIV severity. Genes harboring these 12 CpGs are involved in the antiviral response (IFIT3, IFITM1, NLRC5, PLSCR1, PARP9) and HIV progression (CX3CR1, MX1).ConclusionsWe identified 12 DNA methylation CpG sites that appear to play a mediation role in the association between cocaine use and HIV severity.

Highlights

Cocaine use is common among persons with chronic human immunodeficiency virus (HIV) infection, with prevalence estimates for current or recent use ranging from 5 to 30% [1,2,3,4,5,6], compared with 2% in the US general population [7]
Cocaine use affects HIV severity and mortality among HIV-positive participants We found that among HIV-positive participants, higher cocaine use frequency was associated with increased mortality (p = 0.008, Fig. 2a)
A higher frequency of cocaine use at baseline was significantly associated with a higher Veteran Aging Cohort Study (VACS) index after adjusting for sex, age, race, viral load, CD4 count, and antiviral medication adherence (Table 2)

Summary

Introduction

Cocaine use is common among persons with chronic human immunodeficiency virus (HIV) infection, with prevalence estimates for current or recent use ranging from 5 to 30% [1,2,3,4,5,6], compared with 2% in the US general population [7]. DNA methylation (DNAm) is an important mechanism associated with many environmental exposures such as smoking, alcohol, and drug misuse [16,17,18,19,20,21,22,23,24,25,26] and diseases such as cancer, diabetes, and cardiovascular diseases [27,28,29,30,31,32]. DNAm may play an important mediation role linking environmental exposure and disease outcomes [34,35,36,37,38,39,40] Environmental exposure such as substance use or toxicants can directly or indirectly affect DNA methylatransferases, causing global or site-specific DNAm changes that may lead to disease [41]. We assessed whether DNA methylation in blood mediates the association between cocaine use and HIV severity in a veteran population

Methods

Results

Discussion

Conclusion