Whole genome sequencing analysis to evaluate the influence of T2DM on polymorphisms associated with drug resistance in M. tuberculosis

Abstract

BackgroundType 2 diabetes mellitus (T2DM) has been associated with treatment failure, and the development of drug resistance in tuberculosis (TB). Also, whole-genome sequencing has provided a better understanding and allowed the growth of knowledge about polymorphisms in genes associated with drug resistance. Considering the above, this study analyzes genome sequences to evaluate the influence of type 2 diabetes mellitus in the development of mutations related to tuberculosis drug resistance. M. tuberculosis isolates from individuals with (n=74), and without (n=74) type 2 diabetes mellitus was recovered from online repositories, and further analyzed. ResultsThe results showed the presence of 591 SNPs with similar proportions between diabetics, and non-diabetics individuals (48.2% vs. 51.7%), but with no significant relationship. A greater number of mutations associated with rifampicin resistance was observed in the T2DM-TB individuals (19.3% vs. 12.5%), and the exclusive presence of rpoBQ432L, rpoBQ432P, rpoBS441L, and rpoBH445L variants. While these variants are not private to T2DM-TB cases they are globally rare highlighting a potential role of T2DM. The phylogenetic analysis showed 12 sublineages, being 4.1.1.3, and 4.1.2.1 the most prevalent in T2DM-TB individuals but not differing from those most prevalent in their geographic location. Four clonal complexes were found, however, no significant relationship with T2DM was observed. Samples size and potential sampling biases prevented us to look for significant associations. ConclusionsThe occurrence of globally rare rifampicin variants identified only in isolates from individuals with T2DM could be due to the hyperglycemic environment within the host. Therefore, further studies about the dynamics of SNPs’ generation associated with antibiotic resistance in patients with diabetes mellitus are necessary.

Mutational Dynamics Related to Antibiotic Resistance in M. tuberculosis Isolates from Serial Samples of Patients with Tuberculosis and Type 2 Diabetes Mellitus

“…It has been reported that rifampicin-resistant M. tuberculosis strains isolated from HIV-coinfected patients carry more resistance-conferring mutations in rpoB and are associated with low fitness in the absence of the drug [28]. It has recently been described that some specific variations are associated with T2DM in DNA reparation genes in M. tuberculosis [29]; however, no differences have been described in the polymorphisms observed in canonical genes related to antibiotic resistance in individuals with the binomial TB-T2DM [30], suggesting that the high frequency of resistance observed in individuals with T2DM may be due to the rapid and early occurrence of variants in the resistance genes that allow rapid development [31]. The present study therefore aimed to evaluate the influence of T2DM in the dynamics of polymorphism generation related to the development of antibiotic resistance in M. tuberculosis.…”