Epigenome-Wide and Methylation Risk Score Analysis of Body Mass Index Among People with HIV.

Background/Objectives: People with HIV (PWH) on antiretroviral therapy (ART) often gain weight, which increases their risk of type 2 diabetes and cardiovascular disease. The role of DNA methylation (DNAm) markers in obesity among PWH is understudied. This research explores the relationship between body mass index (BMI) and epigenetic patterns to better understand and manage obesity-related risks in PWH. Methods: We conducted an epigenome-wide association study (EWAS) on 892 African American male PWH from the Veterans Aging Cohort Study, examining BMI associations with DNAm using linear mixed models, adjusting for covariates, including soluble CD14. We compared our results with BMI-associated DNAm markers from non-HIV individuals and developed a methylation risk score (MRS) for BMI using machine learning and a cross-validation approach. Results: We identified four epigenome-wide significant CpG sites, including one in the RAP1B gene, indicating shared and unique BMI-related epigenetic markers between PWH and non-HIV individuals. The constructed BMI MRS explained approximately 19% of the BMI variance in PWH. Conclusions: DNAm markers and MRS are significantly linked to BMI in PWH, suggesting shared and distinct molecular mechanisms with non-HIV populations. These insights could lead to targeted interventions to reduce cardiometabolic disease risks in PWH under ART.