Genes shape blood responses during TB and treatment

Tuberculosis (TB) remains a major global health challenge, and scientists are still learning how a patient’s own genes influence the immune response to active disease and to anti-TB treatment (ATT). Understanding which genetic differences change how immune genes turn on or off during illness and therapy can help explain why people respond differently to infection and drugs. In work led by David E. MacHugh, researchers filled an important gap: until now there had been no genome-wide in vivo response expression quantitative trait loci (reQTL) studies for active TB and ATT. To tackle this, they collected longitudinal peripheral blood RNA-seq data from n = 48 patients with active TB as they went through ATT. Rather than relying on separate DNA testing, the team called sequence variants directly from these transcriptomes and then imputed missing variants using a multi-ancestry reference panel. This approach let them study how genetic differences in the patients relate to changes in gene expression over the course of disease and treatment, all from blood RNA data.

The team associated the called and imputed variants with the expression levels of nearby genes to map genetic control of gene activity. Using these methods on the longitudinal peripheral blood RNA-seq sets, they identified thousands of cis-eQTL and hundreds of reQTL, describing genetic variants that influence baseline gene expression and variants that change their influence during disease or treatment. They also used deconvolution of the bulk RNA-seq data to estimate changing cell type proportions in blood over the course of ATT, and found significant changes in those proportions during treatment. By combining the variant-to-gene associations with the deconvolved cell information, the researchers identified the putative cell type specific nature of many cis-eQTL, suggesting that some genetic effects act through particular immune cell types. All of these findings come from analyses tied directly to peripheral blood RNA-seq and the imputation approach using a multi-ancestry reference panel.

Taken together, these results shed light on the immunogenetics of TB disease and treatment while offering a practical framework for future work. The discovery of thousands of cis-eQTL and hundreds of reQTL shows that genetic variation has widespread effects on blood gene expression in active TB and that some effects change with treatment. Demonstrating significant shifts in blood cell composition during ATT and linking genetic effects to putative cell types helps clarify mechanisms by which host genetics can shape immune responses. Importantly, the study shows it is possible to obtain both variant calls and expression relationships from RNA-seq alone, which could lower barriers for other studies where DNA data are not available. By providing methods and a proof of principle, the work supports more detailed investigations into how host genetics influence TB outcomes and may guide development of biomarkers or tailored approaches to therapy in the future.