GENOME-WIDE DNA METHYLATION PATTERNS ASSOCIATED WITH BLOOD PRESSURE TRAITS IN PEOPLE WITH HIV

Samson Okello: Genome-wide DNA Methylation Patterns of Blood Pressure Traits in People with HIV (Under the direction of Kari E. North)Background: Hypertension is a major contributor to cardiovascular disease among people with HIV (PWH), yet its molecular mechanisms remain poorly defined. DNA methylation (DNAm) may play a role in hypertension development and progression, particularly among PWH exposed to antiretroviral therapy (ART).Methods: We conducted cross-sectional and longitudinal methylome-wide association studies (MWAS) of blood pressure (BP) traits in PWH exposed to ART from the MACS/WIHS Combined Cohort Study (MWCCS). The cross-sectional analysis included 1,131 participants (739 women, 392 men; mean age, 43 years) to identify differentially methylated positions (DMPs) and regions (DMRs) associated with systolic BP (SBP), diastolic BP (DBP), and hypertension.The longitudinal analysis included 1,658 observations (median follow-up, 2.8 years) to identify changes in DNAm associated with temporal changes in SBP and DBP using linear mixed effects models.Results: Cross-sectional analyses identified 59 and 60 DMPs associated with SBP and DBP, respectively (FDR < 0.05), enriched in vascular, metabolic, and immune pathways. A total of 204 DMPs were associated with hypertension, including a top hypermethylated locus near GSE1 (odds ratio = 0.014, 95% CI: 0.013, 0.015, p = 1.32×10-16). We also identified 23 DMRs for DBP and 136 for hypertension, including regions neighboring CTBP1, BAZ2A, and LMNTD1. Longitudinal analyses revealed dynamic DNAm changes associated with change in BP , including eight DMPs related to SBP and three related to DBP. Key nearby genes included ALOX15B, PTPRN2, EBF4, NKX2-2, and THRB. Functional enrichment analyses implicatedimmune, metabolic, renal, and vascular pathways, with several DMR-associated genes (CD151, CNR2, MAEA) linked to antihypertensive drug response.Conclusion: Our findings reveal both stable and dynamic epigenetic loci associated with BP regulation in PWH exposed to ART, implicating neurovascular, renometabolic, and immune-regulatory pathways in HIV-associated hypertension. Together, these results provide novel insights into the epigenetic architecture of BP traits and suggest potential mechanisms underlyinghypertension and cardiovascular risk among PWH.