Genetic control of immune proteins linked to TB in people with HIV

Tuberculosis remains a major threat for people with HIV (PWH), but the reasons why some individuals progress from infection to active disease are not fully explained by traditional genetics alone. To explore a different angle, researchers led by corresponding author Johannes Nemeth turned to protein quantitative trait loci, or pQTLs—genetic variants that regulate plasma protein levels—which may bridge genetic differences and immune responses that influence TB progression. The team used samples from the Swiss HIV Cohort Study, selecting 60 PWH who later developed active tuberculosis and 194 matched controls who did not. They measured the circulating proteins in plasma using high-resolution mass spectrometry (dia-PASEF) to produce detailed plasma proteomes for each person. By combining these protein measurements with genetic data, the investigators performed cis-pQTL mapping to find genetic variants located near the genes encoding each protein that were associated with differences in plasma levels. The study design compared genotype-protein relationships separately in the TB progressors and in the matched control group, aiming to uncover genetically anchored proteins that relate specifically to TB progression in PWH.

The analysis focused on cis-pQTLs and on whether these genotype-protein links differed between people who progressed to active TB and those who did not. In the group that progressed to TB, the researchers identified 26 cis-pQTLs linked to 12 proteins; these proteins were uniquely enriched in immune pathways important for infection control, including antigen presentation, complement activation, phagocytosis, and T-cell regulation. By contrast, the control group showed a larger number of cis-pQTLs overall—107 cis-pQTLs linked to 14 targets—but these did not show the same immune-related pattern. Gene Ontology enrichment analysis revealed a striking difference: 46 immune biological processes were enriched among the TB-specific proteins, whereas only a single immune process was enriched in the control group. Among the proteins highlighted as specific to TB progressors were HLA-C, C4B, and CHIT1. Throughout, the study preserved exact analytical approaches: protein quantitative trait loci (pQTLs), cis-pQTL mapping, plasma proteomes quantified via high-resolution mass spectrometry (dia-PASEF), and Gene Ontology enrichment were central tools and terms used in the work.

Taken together, these findings suggest that in people with HIV, TB progression may be linked to the genetic regulation of particular immune proteins rather than to broad host genetic differences alone. The identification of cis-pQTLs tied to immune pathways—and the spotlight on HLA-C, C4B, and CHIT1—provides a set of genetically anchored protein candidates for further investigation. Because the results came from an integrated proteomics and genomics approach, they help connect genetic variation directly to measurable protein changes in the blood, strengthening the case that these proteins are functionally relevant to TB risk. The authors conclude that these candidates support follow-up studies and future biomarker evaluation for TB risk prediction in people with HIV. Importantly, the study frames these findings as associations that now warrant targeted experimental work, replication in other cohorts, and assessment of whether measuring these proteins could improve early identification of PWH at higher risk of progressing to active tuberculosis.