Gene expression in cord blood and tuberculosis in early childhood: A nested case-control study in a South African birth cohort.

Abstract

Transcriptomic profiling of adult tuberculosis patients has become increasingly common, predominantly for diagnostic and risk prediction purposes. However few studies have evaluated signatures in children, particularly in identifying those at risk for developing TB disease. We investigated the relationship between gene expression obtained from umbilical cord blood and both tuberculin skin test conversion as well as incident tuberculosis disease through the first 5 years of life. We conducted a nested case-control study in the Drakenstein Child Health Study, a longitudinal, population-based birth cohort in South Africa. We applied transcriptome-wide screens to umbilical cord blood samples from neonates born to a subset of selected mothers (n=131). Signatures identifying tuberculin conversion and risk of subsequent tuberculosis disease were identified from genome wide analysis of RNA expression. Gene expression signatures revealed clear differences predictive of tuberculin conversion (n=26) and tuberculosis disease (n=10); 114 genes were associated with tuberculin conversion and 30 genes were associated with the progression to tuberculosis disease among children with early infection. Co-expression network analysis revealed six modules associated with risk of tuberculosis infection or disease, including a module associated with neutrophil activation in immune response (p<0.0001) and defense response to bacterium (p<0.0001). These findings suggest multiple detectable differences in gene expression at birth which were associated with risk of tuberculosis infection or disease throughout early childhood. Such measures may provide novel insights into tuberculosis pathogenesis and susceptibility.