Protein Quantitative Trait Loci Identify Genetically Regulated Immune Proteins Associated with Tuberculosis Progression in People with HIV

Background: Host genetics alone explains limited susceptibility to tuberculosis (TB), particularly in people with HIV (PWH). Protein quantitative trait loci (pQTLs), genetic variants that regulate plasma protein levels, may bridge genetic and immunological mechanisms underlying TB progression. Methods: We conducted cis-pQTL mapping in 60 PWH who progressed to active TB and 194 matched controls from the Swiss HIV Cohort Study. Plasma proteomes were quantified via high-resolution mass spectrometry (dia-PASEF), and genotype-protein associations were analyzed separately in TB and control groups. Results: TB progressors harbored 26 cis-pQTLs linked to 12 proteins uniquely enriched in immune pathways (antigen presentation, complement activation, phagocytosis, and T-cell regulation). Controls showed 107 cis-pQTLs linked to 14 targets. Gene Ontology enrichment revealed 46 immune biological processes in TB versus only 1 in controls, with HLA-C, C4B, and CHIT1 as key TB-specific proteins. Conclusions: Integrating proteomics with genomics suggests differential regulation of immune proteins associated with TB progression in PWH. hese genetically anchored protein candidates support follow-up studies and future biomarker evaluation for TB risk prediction.