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

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

  • Authors: 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
  • Publication Year: 2018
  • Journal: Nature Genetics
  • Link: https://www.nature.com/articles/s41588-017-0029-0%20

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.

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About GHTM

GHTM is a R&D Unit that brings together researchers with a track record in Tropical Medicine and International & Global Health. It aims at strengthening Portugal's role as a leading partner in the development and implementation of a global health research agenda. Our evidence-based interventions contribute to the promotion of equity in health and to improve the health of populations.

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