Genome-wide association study of untargeted plasma metabolomic profiles identifies host genetic regulation in people with HIV

People with human immunodeficiency virus (PWH) exhibit accelerated aging and a higher prevalence of aging-related conditions, despite effective antiretroviral therapy. The biological mechanisms involved remain incompletely understood. Integrating genomic and metabolomic profiling may help uncover genes and pathways contributing to aging-related disease in this population. Using a genome-wide association study framework and untargeted metabolomic profiling, we searched for associations between human genetic variants and the plasma concentrations of 1,930 putative metabolites in 1,244 individuals enrolled in the Swiss HIV Cohort Study. We performed an expression quantitative trait locus (eQTL) colocalization analysis to explore biological links between genetic variants and metabolites and used Mendelian randomization to search for causal relationships between metabolites and aging-related diseases. We identified 27 metabolites significantly associated with 12 genetic loci, including genes encoding the metabolic enzymes NAT8 and FUT2; 10 associations had been previously reported in general-population studies, of which eight were replicated in our analysis. The colocalization analyses provided evidence for a large overlap between genetic regulation of mRNA expression and metabolite levels, while Mendelian randomization suggested several causal effects. Our study uncovered genetic-metabolic associations observed in PWH and explored their biological relevance. These findings highlight the potential of integrated multi-omics profiling to deepen mechanistic understanding and inform future precision approaches to comorbidity management in this population.