Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis
Authors: 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, Gerhard Walzl, Gillian F. Black, Gian van der Spuy, Kim Stanley, Magdalena Kriel, Nelita Du Plessis, Nonhlanhla Nene, Teri Roberts, Leanie Kleynhans, Andrea Gutschmidt, Bronwyn Smith, Nonhlanhla Nene, Andre G. Loxton, Novel N. Chegou, Gerhardus Tromp, David Tabb, Tom H. M. Ottenhoff, Michel R. Klein, Marielle C. Haks, Kees L. M. C. Franken, Annemieke Geluk, Krista E. van Meijgaarden, Simone A. Joosten, W. Henry Boom, Bonnie Thiel, Harriet Mayanja-Kizza, Moses Joloba, Sarah Zalwango, Mary Nsereko, Brenda Okwera, Hussein Kisingo, Stefan H. E. Kaufmann, Shreemanta K. Parida, Robert Golinski, Jeroen Maertzdorf, January Weiner, 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, Sara Suliman, Thomas J. Scriba, Hassan Mahomed, E. Jane Hughes, Nicole Bilek, Mzwandile Erasmus, Onke Xasa, Ashley Veldsman, Katrina Downing, Michelle Fisher, Adam Penn-Nicholson, Humphrey Mulenga, Brian Abel, Mark Bowmaker, Benjamin Kagina, William Kwong Chung, Willem A. Hanekom, 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, Rawleigh Howe, Adane Mihret, Abraham Aseffa, Yonas Bekele, Rachel Iwnetu, Mesfin Tafesse, Lawrence Yamuah, Martin Ota, Jayne Sutherland, Philip Hill, Richard Adegbola, Tumani Corrah, Martin Antonio, Toyin Togun, Ifedayo Adetifa, Simon Donkor, Peter Andersen, Ida Rosenkrands, Mark Doherty, Karin Weldingh, Gary Schoolnik, Gregory Dolganov, Tran Van, Fazlin Kafaar, Leslie Workman, Humphrey Mulenga, Thomas J. Scriba, E. Jane Hughes, Nicole Bilek, Mzwandile Erasmus, Onke Xasa, Ashley Veldsman, Yolundi Cloete, Deborah Abrahams, Sizulu Moyo, Sebastian Gelderbloem, Michele Tameris, Hennie Geldenhuys, Willem Hanekom, Gregory Hussey, Rodney Ehrlich, Suzanne Verver, Larry Geiter
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

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-α 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.