Heterogeneous Gene Expression Patterns of Tuberculosis-Diabetes Interaction in Diverse Cohorts

Background. Diabetes mellitus (DM) increases tuberculosis (TB) severity. We previously reported baseline blood microarray data in a South Indian pulmonary TB cohort with or without DM, finding no qualitative or quantitative differences in immune pathway gene expression. To extend those observations, we compared baseline and longitudinal blood gene expression in TB patients from South India and Brazil. Methods. Adults with pulmonary TB, with or without DM, were enrolled at two sites in India and one site in Brazil. Blood RNA sequencing (RNAseq) was performed at baseline and treatment months 2 and 6. Differentially expressed genes (DEGs) and pathway activation were compared by group and site. Comparison was also made with published RNAseq data from the TANDEM study South African and Romanian cohorts. Findings. No consistent pattern of DEGs discriminated TB from TBDM in India or Brazil. Pathway analysis also showed little commonality between sites, although a shared profile of complement activation and matrix degradation was identified in TBDM. Indian participants showed marked longitudinal changes in DEGs and pathways at 2 and 6 months of treatment, whereas these were stable in Brazilian participants. High variability in gene expression was observed between sites at baseline and during treatment. Interpretation. DM exacerbates matrix degradation in TB but is not associated with major immune gene expression or pathway differences compared to TB without DM. Comparison between cohorts in India, Brazil, Romania, and South Africa revealed an unexpectedly high degree of site-specific variation that may reflect population differences in TB pathobiology. Gene expression analysis on subjects TB-infected with and without diabetes from different locations.