Work

Epigenome-Wide Association Study of Biomarkers of Liver Function Identifies Albumin-Associated DNA Methylation Sites Among Male Veterans with HIV

Year: 2022

Type: article

Abstract: Background: Liver disease (LD) is an important cause of morbidity and mortality for people with HIV (PWH). The molecular factors linked with LD in PWH are varied and incompletely characterized. We performed an epigenome-wide association study (EWAS) to identify associations between DNA methylation (DNAm) and biomarkers of liver function—aspartate transaminase, alanine transaminase, albumin, total bilirubin, platelet count, FIB-4 score, and APRI score—in male US veterans with HIV.Methods: Blood samples and clinical data were obtained from 960 HIV-infected male PWH from the Veterans Aging Cohort Study. DNAm was assessed using the Illumina 450K or the EPIC 850K array in two mutually exclusive subsets. We performed a meta-analysis for each DNAm site measured by either platform. We also examined the associations between four measures of DNAm age acceleration (AA) and liver biomarkers.Results: Nine DNAm sites were positively associated with serum albumin in the meta-analysis of the EPIC and 450K EWAS after correcting for multiple testing. Four DNAm sites (cg16936953, cg18942579, cg01409343, and cg12054453), annotated within the TMEM49 and four of the remaining five sites (cg18181703, cg03546163, cg20995564, and cg23966214) annotated to SOCS3, FKBP5, ZEB2, and SAMD14 genes, respectively. The DNAm site, cg12992827, was not annotated to any known coding sequence. No significant associations were detected for the other six liver biomarkers. Higher PhenoAA was significantly associated with lower level of serum albumin (β = -0.007, p-value = 8.6´10-4, CI: -0.011116, -0.002884).Conclusion: We identified epigenetic associations of both individual DNAm sites and DNAm AA with liver function through serum albumin in men with HIV. Further replication analyses in independent cohorts are warranted to confirm the epigenetic mechanisms underlying liver function and LD in PWH.Funding: This work was supported by the following grants: BKT, ML, ZW, JC, 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. Declaration of Interest: V.C.M. has received investigator-initiated research grants (to the institution) and consultation fees from Lilly, Bayer, Gilead Sciences and ViiV. Other coauthors have no conflicts of interest to disclose.Ethical Approval: The VACS study was approved by the respective Institutional Review Boards and Veterans Affairs Research and Development Committees and for participating sites. In this manuscript, the secondary analyses of deidentified data previous collected in the VACS study don’t need additional approval other than the IRB approval for the parent VACS study.

Source: Frontiers in Genetics

DOI: 10.2139/ssrn.4149559