Epigenome-wide association study of biomarkers of liver function identifies albumin-associated DNA methylation sites among male veterans with HIV

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 United States 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.