Association of genetic variants with anti-tuberculosis drug induced hepatotoxicity: A high resolution melting analysis

•CYP2E1 and NAT2 gene plays an important role in determining the hepatotoxicity.•We used HRM analysis in tuberculosis patients of Western Indian population.•We report 18 novel SNPs, 3 in 5′-UTR, 14 in exonic and 1 in intronic region. Tuberculosis (TB) treatment remains a challenge owing to the high...

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Published in:Infection, genetics and evolution genetics and evolution, 2014-04, Vol.23, p.42-48
Main Authors: Singh, Meenakshi, Gupta, Vinod H., Amarapurkar, Deepak N., Joshi, Jyotsna M., Baijal, Rajiv, Ramegowda, Praveenkumar H., Amarapurkar, Anjali D., Wangikar, Pramod P.
Format: Article
Language:English
Subjects:
Antitubercular Agents - adverse effects
Antitubercular Agents - metabolism
Chemical and Drug Induced Liver Injury - genetics
Cohort Studies
Drug induced hepatotoxicity
Genetic Association Studies - methods
High resolution melting
Humans
Mutation screening
Polymorphism, Single Nucleotide
Sequence Analysis, DNA
Tuberculosis
Tuberculosis - complications
Tuberculosis - drug therapy
Tuberculosis - pathology
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Summary:•CYP2E1 and NAT2 gene plays an important role in determining the hepatotoxicity.•We used HRM analysis in tuberculosis patients of Western Indian population.•We report 18 novel SNPs, 3 in 5′-UTR, 14 in exonic and 1 in intronic region. Tuberculosis (TB) treatment remains a challenge owing to the high incidence of drug induced hepatotoxicity (DIH). Apart from environmental factors, single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs), nuclear receptors (NRs) and transporter proteins (TPs) contribute to DIH. In the present study, we report known and novel SNPs in a total of seven genes of DMEs, NRs and TPs with high resolution melting (HRM) technique. DNA samples of 185 TB patients of Western Indian population, of which 50 showed DIH, were analyzed. Grouping of the temperature-shifted difference plots obtained from the DNA melt curves enables identification of known and novel SNPs. Representative samples of each group were sequenced. We report 18 novel SNPs, of which 3 are in 5′-UTR, 14 in exonic and 1 in intronic region. Of the SNPs in exons, 7 non-synonymous, 3 synonymous and 4 deletion mutations were observed. Among the known SNPs, CYP2E1 wild-type, NAT2∗5 mutant and NAT2∗6 heterozygous genotypes were associated with DIH (p
ISSN:1567-1348
1567-7257
DOI:10.1016/j.meegid.2014.01.027