Soluble CD14-associated DNA Methylation Sites predict Mortality among Men with Human Immunodeficiency Virus Infection

• Type of Material: Article
• Authors: Boghuma Titanji, Emory University; Zeyuan Wang, Emory University; Junyu Chen, Emory University; Qin Hui, Emory University; Kaku So-Armah, Boston University; Matthew Freiberg, Vanderbilt University; Amy C. Justice, Yale University; Ke Xu, Yale University; Vincent Marconi, Emory University; Yan Sun, Emory University
• Language: English
• Date: 2022-06-21
• Publisher: Wolters Kluwer Health, Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
• Final Published Version (URL): https://doi.org/10.1097%2FQAD.0000000000003279
• Title of Journal or Parent Work: AIDS
• Volume: 36
• Issue: 11
• Start Page: 1563
• End Page: 1571
• Grant/Funding Information: BKT, ZW, QH, VCM and YVS received support from the National Institute of Health (R01DK125187), VCM and YVS received support from Emory CFAR (P30AI050409), Xu received support from the National Institute on Drug Abuse (R01DA042691, R01DA047820, R01DA047063), KS received support from NIH K01HL134147, VACS - NIH NIAAA U24 AA020794, U01 AA020790, U10 AA013566 completed.
• Keywords: inflammation; Epigenome-wide association study; HIV; DNA-methylation; survival
• Research Categories: Health Sciences, Epidemiology

Abstract

Objectives Elevated plasma levels of sCD14 predict all-cause mortality in people with HIV (PWH). Epigenetic regulation plays a key role in infection and inflammation. To reveal the epigenetic relationships between sCD14, immune function and disease progression among PWH, we conducted an epigenome-wide association study (EWAS) of sCD14 and investigated the relationship with mortality. Design and Methods DNA methylation (DNAm) levels of peripheral blood samples from PWH in the Veterans Aging Cohort Study (VACS) were measured using the Illumina Infinium Methylation 450K (n=549) and EPIC (850K) BeadChip (n=526). Adjusted for covariates and multiple testing, we conducted an epigenome-wide discovery, replication, and meta-analysis to identify significant associations with sCD14. We then examined and replicated the relationship between the principal epigenetic sites and survival using Cox regression models. Findings We identified 118 DNAm sites significantly associated with sCD14 in the meta-analysis of 1,075 PWH. The principal associated DNAm sites mapped to genes (e.g., STAT1, PARP9, IFITM1, MX1, and IFIT1) related to inflammation and antiviral response. Adjusting for multiple testing, 10 of 118 sCD14-associated DNAm sites significantly predicted survival time conditional on sCD14 levels. Conclusions The identification of DNAm sites independently predicting survival may improve our understanding of prognosis and potential therapeutic targets among PWH.