الملخص الإنجليزي
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis which
has a high impact in endemic countries, with an estimated average 1.5 million death per
year. TB is a curable disease, three lines of treatment are available, but the emergence of
drug resistance represents a major challenge to management and control. The present
study investigates mutations in putative isoniazid (INH) resistance genes, katG, InhA and
InhA promotor and ahpC, in a population sample of isoniazid-sensitive (INHS
) and
resistant (INHR) Mycobacterium tuberculosis in Oman.
A Hundred M. tuberculosis isolates, INHS
(n=57) and INHR
(n=43) were collected from
nationals (n=32) and expatriates' patients (n=68) from foreign countries. Mutations were
identified by amplifying and DNA sequencing of the whole size of each gene. The most
polymorphic gene was KatG (11 alleles), followed by InhA and its promoter (6 alleles)
and ahpC (3 alleles). Mutations affecting katG, the InhA promoter and open reading frame
and ahpC were found in, 71.4%, 30.2% and 4.65% of INHR
isolates, respectively, and in
61%, 0%, and 3.5% of INHS
strains, respectively. The frequency of mutations in KatG
(P<0.01) and InhA (P<0.01) were significantly linked to the INH resistance profile,
however, ahpC mutations were not. The common KatG mutation 315T was associated
with INHR
, while multiple mutations in the examined genes were associated with
increased probability of INH resistance. Multi-locus haplotypes carrying KatG 463L plus
KatG 315T existed at a significantly higher prevalence among INHR
isolates than
haplotypes-carrying KatG 315T alone, suggests a cumulative effect of mutations and a
role of epistasis in stabilizing INH resistance.
Mutations of the above genes were distributed evenly among M. tuberculosis isolates
causing pulmonary and extra-pulmonary. There was no difference in the proportion of
mutations among M. tuberculosis causing pulmonary TB (54/83, 65%) compared to those
causing extra-pulmonary TB (11/17, 64%).
Multi-locus haplotypes of KatG, InhA and ahpC were shared between Omanis and
expatriates, with no significant differences. Genetic differentiation analysis, including
spoligo loci, demonstrated close genetic background of M. tuberculosis isolates infecting
Omanis and expatriates; this suggests a possible circulation of drug resistance strains
between the two groups. The M. tuberculosis isolates examined in the presents study
belong to 9 Spoligo-families with variable response to INH. The frequent spoligotypes
were CAS (26 %), EAI (25%), Beijing (17%), and T (15%). The CAS and T families were
more common among INHS M. tuberculosis isolates, seen at a prevalence of 17% and 8%
respectively, while, EAI family (13%) was more frequent among INHR
isolates. However,
there was no association between INH response and spoligotype characteristic among the
examined isolates. In addition, mutations of the three genes were prevalent among Beijing,
EAI and CAS spoligo families.
In summary, the present study demonstrated high rates of KatG (katG 315T ) and InhA (-
15T and -17T InhA promoter ) mutations in INH resistant M. tuberculosis isolates in
Oman, 70% of unrelated isoniazid-resistant isolates could be identified by analysis of just
two loci (katG 315T and -15T and -17T InhA promoter). The shared INHR M. tuberculosis
haplotypes, with related genetic background among Omanis and expatriates warrant
further investigation to asses if there was a transmission of resistant strains between the
two groups.
