Allergy Asthma Immunol Res.  2012 May;4(3):132-136. 10.4168/aair.2012.4.3.132.

Genetic Variations in TXNRD1 as Potential Predictors of Drug-Induced Liver Injury

• Kwon JW
• Shin ES
• Lee JE
• Kim SH
• Kim SH
• Jee YK
• Kim YK
• Park HS
• Min KU
• Park HW
• The Adverse Drug Reaction Research Group in Korea

• KMID: 2167064
• DOI: http://doi.org/10.4168/aair.2012.4.3.132

Abstract

PURPOSE
Drug-induced liver injury (DILI) is the most common adverse drug reaction; however, it is not easily predicted. We hypothesize that DILI has a common genetic basis. Based on the findings of previous animal studies on toxic hepatitis, we selected the thioredoxin reductase 1 gene (TXNRD1) as a candidate marker of DILI for this genetic association study.
METHODS
Records from 118 patients with DILI were extracted from the database of the Adverse Drug Reaction Research Group in South Korea. Causative drugs included antituberculosis drugs (n=68, 57.6%), antibiotics (n=22, 18.6%), antiepileptic drugs (n=7, 5.9%), non-steroidal anti-inflammatory drugs (n=5, 4.2%), and others (n=16, 13.7%). Seven single nucleotide polymorphisms (SNPs) in TXNRD1 (rs10735393, rs4964287, rs4595619, rs10861201, rs11111997, rs4246270, and rs4246271) were scored in 118 DILI patients and in 120 drug-matched controls without liver injury.
RESULTS
No differences were found between the frequencies of any of the 7 SNPs in the cases and controls; however, a significant association was found between a TTA haplotype composed of rs10735393, rs4964287, and rs4595619 and DILI using an allele model (odds ratio, 1.79; 95% confidence interval, 1.18-2.73; P=0.008; Bonferroni corrected P=0.024).
CONCLUSIONS
These results suggest that genetic variations in TXNRD1 favor the development of DILI, although a larger confirmative study is needed.

Keyword

Drug-induced liver injury; genetic association study; genetic polymorphism; single nucleotide polymorphisms; thioredoxin reductase 1

MeSH Terms

Alleles
Animals
Anti-Bacterial Agents
Anticonvulsants
Drug Toxicity
Drug-Induced Liver Injury
Genetic Association Studies
Genetic Variation
Haplotypes
Humans
Liver
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Republic of Korea
Thioredoxin Reductase 1
Anti-Bacterial Agents
Anticonvulsants
Thioredoxin Reductase 1

Figure

• 

  Figure Gene map of thioredoxin reductase 1 (TXNRD1) and inferred haplotype blocks. (A) Schematic gene map and single nucleotide polymorphisms (SNPs) in TXNRD1 on chromosome 12q23-q24.1. Black blocks represent coding exons and white blocks represent 5' and 3'UTR. (B) Inferred haplotype blocks with LD coefficients (|D'| and r2) among SNPs. (C) Distributions of major haplotypes in block 1.

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