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.
Samson Okello (Fri,) studied this question.