Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis

Abstract

Rationale: Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with Mycobacterium tuberculosis and progression to disease.Objectives: We investigated biosignatures with predictive ability for incident TB.Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated. Measurements and Main Results:A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. Post hoc meta-analysis identified a single gene pair, C1QC/TRAV27 (complement C1q C-chain / T-cell receptor-a variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events.Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs.

Latent tuberculosis infection: Opportunities and challenges

“…More recently, a four-transcript blood signature [upregulation of growth arrest-specific 6 (GAS6) and septin 4 (SEPT4) and downregulation of cluster of differentiation 1C (CD1C) and B lymphocyte kinase (BLK) proto-oncogene] was validated to predict progression to TB in recently exposed household contacts in diverse African populations. 52…”

Concise whole blood transcriptional signatures for incipient tuberculosis: A systematic review and patient-level pooled meta-analysis

“…Four signature discovery datasets included HIV-infected and -uninfected participants 11,13,29,30 , one was discovered in an exclusively HIV-infected population for the purpose of active case finding 31 , while the remainder were discovered in HIV-negative populations. Four signatures were discovered with the intention of diagnosis of incipient TB [16][17][18] , with the remaining 13 discovered for diagnosis of active TB disease. Of these, five 11,14,28,32,33 targeted discrimination of TB from other diseases in addition to discriminating people who were healthy or with LTBI.…”

“…The eight signatures that achieved equivalent performance were discovered with the primary intention of diagnosis of incipient TB [16][17][18] , or differentiating active TB from people who are healthy or with LTBI 12,13,30,37 .…”

“…More recently, perturbation in the transcriptome has been found to predate the diagnosis of TB 14,[16][17][18] , suggesting that transcriptional signatures may offer an opportunity to diagnose incipient TB and potentially fulfil the WHO TPP. However, independent validation of each signature is still limited.…”

Addressing diversity in tuberculosis using multidimensional approaches

“…A South African treatment cohort from the Catalysis TB-Biomarker study identified a disease signature that with high precision at 1-4 weeks of treatment discriminates subsequent treatment failures at 24 weeks from treatment success [37]. Four-gene risk signatures have now been derived that also identify incipient or subclinical disease, that are more amenable to translation into a fieldfriendly assay [38]. Other studies have investigated circulating miRNA [39,40] rather than RNA transcripts in blood cells, and subsequent studies have identified clinically useful sets of miRNAs that correlate with treatment outcome at an excellent accuracy, or that predict progression to disease [41].…”