1. Four-gene pan-African blood signature predicts progression to tuberculosis
- Author
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Sara Suliman, Ethan G. Thompson, Jayne Sutherland, January Weiner, Martin O. C. Ota, Smitha Shankar, Adam Penn-Nicholson, Bonnie Thiel, Mzwandile Erasmus, Jeroen Maertzdorf, Fergal J. Duffy, Philip C. Hill, E. Jane Hughes, Kim Stanley, Katrina Downing, Michelle L. Fisher, Joe Valvo, Shreemanta K. Parida, Gian van der Spuy, Gerard Tromp, Ifedayo M. O. Adetifa, Simon Donkor, Rawleigh Howe, Harriet Mayanja-Kizza, W. Henry Boom, Hazel M. Dockrell, Tom H. M. Ottenhoff, Mark Hatherill, Alan Aderem, Willem A. Hanekom, Thomas J. Scriba, Stefan H. E. Kaufmann, Daniel E. Zak, Gerhard Walzl, Gillian F. Black, Magdalena Kriel, Nelita Du Plessis, Nonhlanhla Nene, Teri Roberts, Leanie Kleynhans, Andrea Gutschmidt, Bronwyn Smith, Andre G. Loxton, Novel N. Chegou, Gerhardus Tromp, David Tabb, Michel R. Klein, Marielle C. Haks, Kees L. M. C. Franken, Annemieke Geluk, Krista E. van Meijgaarden, Simone A. Joosten, Moses Joloba, Sarah Zalwango, Mary Nsereko, Brenda Okwera, Hussein Kisingo, Robert Golinski, Marc Jacobson, Hazel Dockrell, Steven Smith, Patricia Gorak-Stolinska, Yun-Gyoung Hur, Maeve Lalor, Ji-Sook Lee, Amelia C. Crampin, Neil French, Bagrey Ngwira, Anne Ben-Smith, Kate Watkins, Lyn Ambrose, Felanji Simukonda, Hazzie Mvula, Femia Chilongo, Jacky Saul, Keith Branson, Hassan Mahomed, Nicole Bilek, Onke Xasa, Ashley Veldsman, Michelle Fisher, Humphrey Mulenga, Brian Abel, Mark Bowmaker, Benjamin Kagina, William Kwong Chung, Jerry Sadoff, Donata Sizemore, S. Ramachandran, Lew Barker, Michael Brennan, Frank Weichold, Stefanie Muller, Larry Geiter, Desta Kassa, Almaz Abebe, Tsehayenesh Mesele, Belete Tegbaru, Debbie van Baarle, Frank Miedema, Adane Mihret, Abraham Aseffa, Yonas Bekele, Rachel Iwnetu, Mesfin Tafesse, Lawrence Yamuah, Martin Ota, Philip Hill, Richard Adegbola, Tumani Corrah, Martin Antonio, Toyin Togun, Ifedayo Adetifa, Peter Andersen, Ida Rosenkrands, Mark Doherty, Karin Weldingh, Gary Schoolnik, Gregory Dolganov, Tran Van, Fazlin Kafaar, Leslie Workman, Yolundi Cloete, Deborah Abrahams, Sizulu Moyo, Sebastian Gelderbloem, Michele Tameris, Hennie Geldenhuys, Willem Hanekom, Gregory Hussey, Rodney Ehrlich, Suzanne Verver, Graduate School, APH - Methodology, and APH - Global Health
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Tuberculosis ,Respiratory System ,Disease ,Critical Care and Intensive Care Medicine ,Medical and Health Sciences ,Mycobacterium tuberculosis ,03 medical and health sciences ,The ACS cohort study team ,0302 clinical medicine ,Rare Diseases ,Clinical Research ,Internal medicine ,medicine ,Genetics ,2.1 Biological and endogenous factors ,030212 general & internal medicine ,Aetiology ,Index case ,Gene ,screening and diagnosis ,biology ,GC6-74 cohort study team ,Pan african ,business.industry ,Risk of infection ,Prevention ,biomarkers ,medicine.disease ,biology.organism_classification ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,030104 developmental biology ,Infectious Diseases ,Emerging Infectious Diseases ,Good Health and Well Being ,tuberculosis ,Cohort ,gene expression ,HIV/AIDS ,Gene expression ,business ,Infection ,Biomarkers ,4.2 Evaluation of markers and technologies - 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 bio-signatures 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.
- Published
- 2018