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. 2022 Sep 14;75(5):768-776.
doi: 10.1093/cid/ciab1067.

Whole Genome Sequencing Assessing Impact of Diabetes Mellitus on Tuberculosis Mutations and Type of Recurrence in India

Vidya Mave  1   2   3 , Liang Chen  4 , Uma Devi Ranganathan  5 , Dileep Kadam  6 , Vijay Vishwanathan  7 , Rahul Lokhande  6 , Siva Kumar S  5 , Anju Kagal  6 , Neeta N Pradhan  1   3 , Shri Vijay Bala Yogendra Shivakumar  3 , Mandar S Paradkar  1   3 , Sona Deshmukh  1   3 , Jeffrey A Tornheim  2 , Hardy Kornfeld  8 , Maha Farhat  9 , Amita Gupta  2 , Chandrasekaran Padmapriyadarsini  5 , Nikhil Gupte  1   2   3 , Jonathan E Golub  2 , Barun Mathema  10 , Barry N Kreiswirth  4
Affiliations

Whole Genome Sequencing Assessing Impact of Diabetes Mellitus on Tuberculosis Mutations and Type of Recurrence in India

Vidya Mave et al. Clin Infect Dis. .

Abstract

Background: Evidence describing the impact of diabetes mellitus (DM) on the recurrence and mutation rate of Mycobacterium tuberculosis (Mtb) is limited.

Methods: This study was nested in 3 cohort studies of tuberculosis (TB) patients with and without DM in India. Paired Mtb isolates recovered at baseline and treatment failure/recurrence underwent whole genome sequencing. We compared acquisition of single-nucleotide polymorphisms (SNPs), TB drug resistance mutations, and type of recurrence (endogenous reactivation [<8 SNPs] or exogenous reinfection [≥8 SNPs]) by DM status.

Results: Of 1633 enrolled in the 3 parent cohorts, 236 (14.5%) had microbiologically confirmed TB treatment failure/recurrence; 76 Mtb isolate pairs were available for sequencing (22 in TB-DM and 54 in TB-only). The SNP acquisition rate was overall was 0.43 (95% confidence interval [CI], .25-.64) per 1 person-year (PY); 0.77 (95% CI, .40-1.35) per 1 PY, and 0.44 (95% CI, .19-.86) per 1 PY at treatment failure and recurrence, respectively. Significant difference in SNP rates by DM status was seen at recurrence (0.21 [95% CI, .04-.61]) per 1 PY for TB-only vs 1.28 (95% CI, .41-2.98) per 1 PY for TB-DM; P = .02). No significant difference in SNP rates by DM status was observed at treatment failure. Acquired TB drug resistance was seen in 4 of 18 (22%) in TB-DM vs 4 of 45 (9%) in TB-only (P = .21). Thirteen (17%) participants had exogenous reinfection; the reinfection rate at recurrence was 25% (3/12) for TB-DM vs 17% (4/24) in TB-only (P = .66).

Conclusions: Considerable intrahost Mtb mutation rates were present at recurrence among patients with DM in India. One-fourth of patients with DM had exogenous reinfection at recurrence.

Keywords: India; diabetes mellitus; drug resistance and recurrence; tuberculosis; whole genome sequencing.

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Conflict of interest statement

Potential conflicts of interest. V. V., S. K. S., U. D. R., S. V. B. Y. S., D. K., A. K., R. L., M. S. P., N. G., V. M., N. N. P., and C. P. report joint funding for the RePORT India Consortium, by DBT, government of India; Indian Council of Medical Research; NIH, USA; NIAID, USA; Office of AIDS Research, USA; and CRDF Global, USA. H. K. reports grants or contracts: 1 R01 HL152078-01A1 (NIH), W81XWH2110029 (Department of Defense), 1U01AI134585-02 (NIH), 1 R01 AI153152-01A1 (NIH), DAA3-20-67038-1 (CRDF Global), 1 R01 HL153162-01A1 (NIH), DAA9-19-65378-1 (CRDF Global); royalties or licenses from Boston University Technology Development: IL-16; consulting fees from Parexel International; payment or honoraria from Chungnam National University, Korea; US patent 5,766,866 (Lymphocyte chemoattractant factor and uses thereof, 1998), US patent 5,965,120 (Lymphocyte chemoattractant factor and uses thereof, 1999), US patent 5,807,549 (Lymphocyte chemoattractant factor and uses thereof), US patent 5,976,522 (Lymphocyte chemoattractant factor and uses thereof, 1999), US patent 5,807,712 (DNA encoding lymphocyte chemoattractant factor and uses thereof, 1998); and data safety and monitoring board SinoCelltech protocol SCTA01-A301. R. L. reports grants or contracts from the Byramjee-Jeejeebhoy Government Medical College–Johns Hopkins University HIV-TB Program funded by the Fogarty International Center, NIH. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Study flowchart. Abbreviations: BJGMC JHU CRS, Byramjee-Jeejeebhoy Government Medical College–Johns Hopkins University Clinical Research Site; C-TRIUMPh, Cohort for Tuberculosis Research by the Indo-US Medical Partnership; EDOTS, Effects of Diabetes on TB Severity; MVDRC, Professor M. Vishwanathan Diabetes Research Center; NIRT, National Institute for Research in Tuberculosis; QC, quality control; TB, tuberculosis; TB-DM, Impact of Diabetes Mellitus on TB Treatment Outcomes.
Figure 2.
Figure 2.
Lineage of Mycobacterium tuberculosis strains isolated at baseline and tuberculosis treatment failure or recurrence in India.
Figure 3.
Figure 3.
Phylogenetic reconstruction of 76 paired Mycobacterium tuberculosis strains showing clustering of isolates, with participant origin in Chennai or Pune, India, as well as presence of drug resistance mutations. Color schemes depict lineages. Abbreviation: MDR, multidrug-resistant.
See this image and copyright information in PMC

References

    1. World Health Organization. Global tuberculosis report 2019. Available at: https://www.who.int/publications/i/item/9789241565714. Accessed 3 January 2022.
    1. Cadena AM, Fortune SM, Flynn JL.. Heterogeneity in tuberculosis. Nat Rev Immunol 2017; 17:691–702. - PMC - PubMed
    1. McGrath M, Gey van Pittius NC, van Helden PD, Warren RM, Warner DF.. Mutation rate and the emergence of drug resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 2014; 69:292–302. - PubMed
    1. Ford CB, Shah RR, Maeda MK, et al. Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nat Genet 2013; 45:784–90. - PMC - PubMed
    1. Müller B, Borrell S, Rose G, Gagneux S.. The heterogeneous evolution of multidrug-resistant Mycobacterium tuberculosis. Trends Genet 2013; 29:160–9. - PMC - PubMed

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