Study of NAT2 gene polymorphisms in an Indian population: association with plasma isoniazid concentration in a cohort of tuberculosis patients.
OBJECTIVE
Polymorphisms of the N-acetyltransferase 2 gene (NAT2) vary remarkably between populations of different ethnic origin. The NAT2 gene determines the individual's acetylator status to metabolize drugs and xenobiotics, influencing their toxicity and efficacy profiles. This study investigates the frequencies of the most commonly studied NAT2 polymorphisms in a southwestern Indian population and compares these with those reported in other Indian and world populations. The association of these polymorphisms with plasma isoniazid concentrations in a cohort of tuberculosis patients has also been investigated.


METHODS
NAT2 genotyping of 201 subjects was carried out by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis and DNA sequencing. Acetylation phenotypes were predicted from NAT2 genotypes. The association of NAT2 genotypes with plasma isoniazid concentrations was determined by measuring the plasma levels in tuberculosis patients at different time points using reverse-phase high-performance liquid chromatography (HPLC).


RESULTS
The predominant alleles found in this study population were NAT2*5B and NAT2*6A, while NAT2*5B/*6A and NAT2*6A/*6A were the most frequent genotypes; the frequency varied widely from other reported studies in the Indian population. The distribution of slow, intermediate, and fast acetylators was 55%, 32%, and 13%, respectively. We observed relatively higher plasma concentrations of isoniazid in our patients than those reported in other similar studies, and they correlated well with the NAT2 genotypes.


CONCLUSIONS
The results suggested high variation in the frequencies of NAT2 alleles and genotypes within Indian populations, which influence plasma isoniazid concentrations. Further studies of the relationship between NAT2 genotypes and adverse drug events are required to make genotyping a helpful tool for optimizing the isoniazid therapeutic response and minimizing adverse drug reactions, particularly in countries with a high burden of tuberculosis.
Singh
Neera
N
Molecular Endocrinology Laboratory, National Institute for Research in Reproductive Health, Indian Council of Medical Research, Parel, Mumbai, India.
Dubey
Sudhisha
S
Chinnaraj
Saravanan
S
Golani
Anil
A
Maitra
Anurupa
A
D000107:Acetylation; D000328:Adult; D054458:Amplified Fragment Length Polymorphism Analysis; D000995:Antitubercular Agents / Q000097:blood* / Q000493:pharmacokinetics; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D007194:India; D007538:Isoniazid / Q000097:blood* / Q000493:pharmacokinetics; D008297:Male; D010641:Phenotype; D016133:Polymerase Chain Reaction; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000188:drug therapy / Q000235:genetics*
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid