Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis

Autor: Nicholas Furnham, Mridul Nair, Theolis Costa Barbosa Bessa, Miguel Viveiros, Christophe Sola, Isabel Portugal, Robert M Warren, Moses Joloba, Jody Phelan, Maxine Caws, Saad Alghamdi, Zahra Hasan, Nora Mocillo, Rumina Hasan, Francesc Coll, Dang Minh Ha, Patricia Sheen, Edward C. Jones-López, Jaime Robledo, Tomoshige Matsumoto, Judith R. Glynn, Elizabeth M. Streicher, Nashwa Talaat Shesha, Arnab Pain, Adriana Alves, Louis Grandjean, Yaa Oppong, Mona Alsomali, Paul D. van Helden, Taane G. Clark, Shahjahan Ali, Anirvan Chatterjee, Martin L. Hibberd, Stephanie Portelli, Anabela Miranda, Kim Mallard, Abdallah O Ahmed, F. A. Sirgel, Carlos Penha, David Moore, Keertan Dheda, Abdallah M. Abdallah, Erivelton de Oliveira Sousa, Julian Parkhill, João Perdigão, Stefan Panaiotov, Zineb Rchiad, Grant A. Hill-Cawthorne, Amelia C. Crampin, Susana Campino, Ruth McNerney
Přispěvatelé: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine (LSHTM), King Abdullah University of Science and Technology (KAUST), Sydney Emerging Infectious Diseases and Biosecurity Institute (SEIB), The University of Sydney, King Abdullah Univ Sci & Technol, Phys Sci & Engn Div, Thuwal 23955, Makkah, Saudi Arabia, Umm Al-Qura University, Genome Institute of Singapore (GIS), Makerere University College of Health Sciences, Department of Clinical Research and Development, Osaka Prefectural Hospital Organization, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino-city, National Center of Infectious and Parasitic Diseases, National Center of Infectious and Parasitic Diseases [Sofia, Bulgarie] (NCIPD), The Wellcome Trust Sanger Institute [Cambridge], Faculdade de Farmácia da Universidade de Lisboa, Division of Physical Sciences and Engineering (KAUST) (KAUST), Corporacion para Investigaciones Biologicas (CIB), Universidad Peruana Cayetano Heredia (UPCH), Universidade de Lisboa (ULISBOA), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP), Liverpool School of Tropical Medicine (LSTM), Universidade de Lisboa = University of Lisbon (ULISBOA)
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Nature Genetics
Nature Genetics, Nature Publishing Group, 2018, 50, pp.307-316. ⟨10.1038/s41588-017-0029-0⟩
Nature Genetics, 2018, 50, pp.307-316. ⟨10.1038/s41588-017-0029-0⟩
ISSN: 1061-4036
1546-1718
DOI: 10.1038/s41588-017-0029-0⟩
Popis: International audience; To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 $Mycobacterium\ tuberculosis$ clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps ($drrA$ and $Rv2688c$) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.
Databáze: OpenAIRE
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