Methylation patterns linked to blood pressure in people with HIV exposed to antiretroviral therapy reveal neurovascular and immune pathways.

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.