SNPs in Genes Related to DNA Damage Repair in Mycobacterium Tuberculosis: Their Association with Type 2 Diabetes Mellitus and Drug Resistance

Abstract

Genes related to DNA damage repair in Mycobacterium tuberculosis are critical for survival and genomic diversification. The aim of this study is to compare the presence of SNPs in genes related to DNA damage repair in sensitive and drug-resistant M. tuberculosis genomes isolated from patients with and without type 2 diabetes mellitus (T2DM). We collected 399 M. tuberculosis L4 genomes from several public repositories; 224 genomes belonging to hosts without T2DM, of which 123 (54.9%) had drug sensitive tuberculosis (TB) and 101 (45.1%) had drug resistance (DR)-TB; and 175 genomes from individuals with T2DM, of which 100 (57.1%) had drug sensitive TB and 75 (42.9%) had DR-TB. The presence of SNPs in the coding regions of 65 genes related to DNA damage repair was analyzed and compared with the resistance profile and the presence/absence of T2DM in the host. The results show the phylogenetic relationships of some SNPS and L4 sub-lineages, as well as differences in the distribution of SNPs present in DNA damage repair-related genes related to the resistance profile of the infecting strain and the presence of T2DM in the host. Given these differences, it was possible to generate two discriminant functions to distinguish between drug sensitive and drug resistant genomes, as well as patients with or without T2DM.

SNPs in genes related to the repair of damage to DNA in clinical isolates of M. tuberculosis: A transversal and longitudinal approach

“…Although none of the SNPs with low allele frequency showed significant associations with DR, the allelic variation in MutY (4030721, Ala 77Pro) and RuvB (2923293, Arg314Pro) present in different sublineages could suggest a homoplasy event. Although RuvB is a protein involved in the resolution of branched DNA structures [ 34 ], our previous observations suggest that the occurrence of SNPs in RuvB is more frequent in the presence of DMT2 in the host [ 35 ]. On the other hand, recent research has shown that some mutations in MutY abrogate its functions generating a hypermutagenic phenotype, with increased survival and rapid acquisition of resistance mutations for rifampicin and ciprofloxacin [ 12 , 36 ].…”

Sarcopenia and Tuberculosis: Is There Any Connection?

“…Another significant tool could be the use of Mendelian randomization (MR), which is a highly efficient method that allows researchers to identify a causal relationship between phenotypes (diseases) and estimates of causal effects, thus overcoming the limitations of observational studies [45]. To perform such an analysis and to establish a possible connection between sarcopenia and TB, a list of DNA polymorphisms, known as single-nucleotide polymorphisms (SNPs), which are associated with these diseases could be utilized and investigated [46,47]. As a result, in order to further clarify the association between the entities of TB infection and sarcopenia in the future, it may be appropriate to carry out MR using previously known genetic tools.…”

SNPs in genes related to the repair of damage to DNA in clinical isolates ofM. tuberculosis: a transversal and longitudinal approach

“…Although none of the SNPs with low allele frequency showed significant associations with DR, the allelic variation in MutY (4030721, Ala 77Pro) and RuvB (2923293, Arg314Pro) present in different sublineages could suggest a homoplasy event. Although RuvB is a protein involved in the resolution of branched DNA structures[32], our previous observations suggest that the occurrence of SNPs in RuvB is more frequent in the presence of DMT2 in the host [33]. On the other hand, recent research has shown that some mutations in MutY abrogate its functions generating a hypermutagenic phenotype, with increased survival and rapid acquisition of resistance mutations for rifampicin and ciprofloxacin [11,34].…”