Methylation patterns linked to blood pressure in people with HIV exposed to ART reveal neurovascular and immune pathways: The MACS/WIHS Combined Cohort Study

Background: Hypertension is a leading contributor to cardiovascular disease in people with HIV (PWH), yet its underlying molecular mechanisms remain poorly understood. Methods: We conducted a cross-sectional methylome-wide association study (MWAS) of blood pressure (BP) and arterial hypertension in 1131 PWH (739 women, 392 men; mean age 43 years) in the MACS/WIHS Combined Study (MWCCS), to identify differentially methylated positions (DMPs) and regions (DMRs) associated with SBP, DBP, and hypertension. Results: We identified 59 DMPs associated with SBP and 60 associated with DBP [false discovery rate (FDR) P < 0.05], enriched in vascular, metabolic, and immune pathways. Top DMPs near ATP8B2 gene [3.8% DNA methylation (DNAm) per SD change in SBP], MIR378E gene (− 9.5% DNAm per SD change in SBP), SNORA114 gene (5.2% DNAm per SD change in DBP), and ANXA11 gene (− 7.9% DNAm per SD change in DBP). A total of 204 DMPs were associated with hypertension, including a top hypermethylated DMP near GSE1 gene [odds ratio = 0.014, 95% confidence interval (CI) 0.013–0.015, P = 1.32e -16 ] per 1% increase in DNAm. Gene enrichment analysis showed associations with BP-relevant tissues including kidney, brain, vasculature, and adipose tissue. We found 23 DMRs associated with DBP, including a 19-DMP region in CTBP1 gene, and 136 DMRs associated with hypertension, the largest spanning BAZ2A and LMNTD1 genes. Conclusion: We identified HIV/antiretroviral therapy (ART)-specific and shared epigenetic loci associated with BP traits, implicating neurovascular, renometabolic, and immune-regulatory pathways in HIV/ART-related hypertension.