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


Coll, F; Phelan, J; Hill-Cawthorne, GA; Nair, MB; Mallard, K; Ali, S; Abdallah, AM; Alghamdi, S; Alsomali, M; Ahmed, AO; Portelli, S; Oppong, Y; Alves, A; Bessa, TB; Campino, S; Caws, M; Chatterjee, A; Crampin, AC; Dheda, K; Furnham, N; Glynn, JR; Grandjean, L; Minh Ha, D; Hasan, R; Hasan, Z; Hibberd, ML; Joloba, M; Jones-López, EC; Matsumoto, T; Miranda, A; Moore, DJ; Mocillo, N; Panaiotov, S; Parkhill, J; Penha, C; Perdigão, J; Portugal, I; Rchiad, Z; Robledo, J; Sheen, P; Shesha, NT; Sirgel, FA; Sola, C; Oliveira Sousa, E; Streicher, EM; Helden, PV; Viveiros, M; Warren, RM; McNerney, R; Pain, A; Clark, TG; (2018) Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis. Nature genetics. ISSN 1061-4036 DOI: https://doi.org/10.1038/s41588-017-0029-0

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[img] Text - Accepted Version
Restricted to Repository staff only until 22 July 2018.
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Abstract

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.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Clinical Research
Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Research Centre: Antimicrobial Resistance Centre (AMR)
TB Centre
PubMed ID: 29358649
URI: http://researchonline.lshtm.ac.uk/id/eprint/4646256

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