Improvements in Algorithms for Phenotype Inference: The NAT2 Example
Numerous studies have analyzed the impact of N-acetyltransferase 2 (NAT2) polymorphisms on drug efficacy, side effects as well as cancer risk. Here, we present the state of the art of deriving haplotypes from polymorphisms and discuss the available software. PHASE v2.1 is currently
considered a gold standard for NAT2 haplotype assignment. In vitro studies have shown that some slow acetylation genotypes confer reduced protein stability. This has been observed particularly for G191A, T341C and G590A. Substantial ethnic variations of the acetylation status have been described.
Probably, upcoming agriculture and the resulting change in diet caused a selection pressure for slow acetylation. In recent years much research has been done to reduce the complexity of NAT2 genotyping. Deriving the haplotype from seven SNPs is still considered a gold standard. However, meanwhile
several studies have shown that a two-SNP combination, C282T and T341C, results in a similarly good distinction in Caucasians. However, attempts to further reduce complexity to only one 'tagging SNP' (rs1495741) may lead to wrong predictions where phenotypically slow acetylators
were genotyped as intermediate or rapid. Numerous studies have shown that slow NAT2 haplotypes are associated with increased urinary bladder cancer risk and increased risk of anti-tuberculosis drug-induced hepatotoxicity. A drawback of the current practice of solely discriminating slow, intermediate
and rapid genotypes for phenotype inference is limited resolution of differences between slow acetylators. Future developments to differentiate between slow and ultra-slow genotypes may further improve individualized drug dosing and epidemiological studies of cancer risk.
Keywords: Anti-tuberculosis drug-induced hepatoxicity; NAT2 activity; bladder cancer; ethnic differences; haplotype phasing; haplotype reconstruction; individualized medicine; ultra-slow acetylators
Document Type: Research Article
Publication date: 01 February 2014
- Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts. - Editorial Board
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