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

Coll, Francesc, Phelan, Jody, Hill-Cawthorne, Grant A, Nair, Mridul B, Mallard, Kim, Ali, Shahjahan, Abdallah, Abdallah M, Alghamdi, Saad, Alsomali, Mona, Ahmed, Abdallah O, Portelli, Stephanie, Oppong, Yaa, Alves, Adriana, Bessa, Theolis Barbosa, Campino, Susana, Caws, Maxine ORCID: https://orcid.org/0000-0002-9109-350X, Chatterjee, Anirvan, Crampin, Amelia C, Dheda, Keertan, Furnham, Nicholas, Glynn, Judith R, Grandjean, Louis, Minh Ha, Dang, Hasan, Rumina, Hasan, Zahra, Hibberd, Martin L, Joloba, Moses, Jones-López, Edward C, Matsumoto, Tomoshige, Miranda, Anabela, Moore, David J, Mocillo, Nora, Panaiotov, Stefan, Parkhill, Julian, Penha, Carlos, Perdigão, João, Portugal, Isabel, Rchiad, Zineb, Robledo, Jaime, Sheen, Patricia, Shesha, Nashwa Talaat, Sirgel, Frik A, Sola, Christophe, Oliveira Sousa, Erivelton, Streicher, Elizabeth M, Helden, Paul Van, Viveiros, Miguel, Warren, Robert M, McNerney, Ruth, Pain, Arnab and Clark, Taane G (2018) 'Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis.'. Nature Genetics, Vol 50, Issue 2, pp. 307-316.

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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
Subjects:	QW Microbiology and Immunology > Bacteria > QW 125 Actinibacteria, Actinomycetales. WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General) WF Respiratory System > Tuberculosis > WF 360 Drug therapy
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1038/s41588-017-0029-0
Depositing User:	Julie Franco
Date Deposited:	30 Jan 2018 12:19
Last Modified:	12 Sep 2018 08:46
URI:	https://archive.lstmed.ac.uk/id/eprint/8156

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