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

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Title Association of genetic variants with anti-tuberculosis drug induced hepatotoxicity: A high resolution melting analysis
 
Creator SINGH, M
GUPTA, VH
AMARAPURKAR, DN
JOSHI, JM
BAIJAL, R
RAMEGOWDA, PH
AMARAPURKAR, AD
WANGIKAR, PP
 
Subject Tuberculosis
Drug induced hepatotoxicity
High resolution melting
Mutation screening
SINGLE NUCLEOTIDE POLYMORPHISMS
CYTOCHROME-P450 2E1 GENOTYPE
N-ACETYLTRANSFERASE
INDUCED HEPATITIS
DNA
SLC22A3
COHORT
MODEL
RISK
NAT2
 
Description Background: 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. Methods: 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. Results: 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 < 0.05). Among the novel SNPs, group 2 of SLCO1B1 showed a significant association (p < 0.05). Conclusions: While several SNPs showed borderline p values between 0.05 and 0.15, the confidence in association can be improved further by using larger data sets. (C) 2014 Elsevier B.V. All rights reserved.
 
Publisher ELSEVIER SCIENCE BV
 
Date 2014-12-28T14:30:50Z
2014-12-28T14:30:50Z
2014
 
Type Article
 
Identifier INFECTION GENETICS AND EVOLUTION, 2342-48
1567-1348
1567-7257
http://dx.doi.org/10.1016/j.meegid.2014.01.027
http://dspace.library.iitb.ac.in/jspui/handle/100/16758
 
Language English