Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 197, Issue 9, Pages 1198-1208Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201711-2340OC
Keywords
tuberculosis; gene expression; biomarkers
Categories
Funding
- Bill and Melinda Gates Foundation [OPP1065330, OPP1023483, OPP1055806]
- GC6-74 grant [37772]
- NIH [R01AI087915, U01AI115619, N01AI095383/AI070022]
- Strategic Health Innovation Partnerships (SHIP) Unit of the South African Medical Research Council
- South African Department of Science and Technology
- Carnegie Corporation of New York
- South African National Research Foundation
- Claude Leon Foundation
- Columbia University-Southern African Fogarty AIDS International Training and Research Program (AITRP) through the Fogarty International Center, NIH grant [D43 TW000231]
- TBVAC Horizon (Tuberculosis Vaccine Initiative under the European Commission's Horizon research and innovation program) [643381]
- MRC [MC_UP_A900_1122, MC_U190071468] Funding Source: UKRI
- Bill and Melinda Gates Foundation [OPP1055806, OPP1065330, OPP1023483] Funding Source: Bill and Melinda Gates Foundation
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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-alpha 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.
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