Evaluating NAT2PRED for inferring the individual acetylation status from unphased genotype data

Audrey Sabbagh,Michel Vidaud,Pierre Darlu

doi:10.1186/1471-2350-10-148

Abstract

BackgroundGenetically determined differences in N-acetylation capacity have proved to be important determinants of both the effectiveness of therapeutic response and the development of adverse drug reactions and toxicity during drug treatment. NAT2PRED is a web-server that allows a fast determination of NAT2 acetylation phenotype from genotype data without taking the extra step of reconstructing haplotypes for each individual (publicly available at http://nat2pred.rit.albany.edu). However, the classification accuracy of NAT2PRED needs to be assessed before its application can be advocated at a large scale.MethodsThe ability of NAT2PRED to classify individuals according to their acetylation status (slow, intermediate and rapid acetylators) was evaluated in a worldwide dataset composed of 56 population samples (8,489 individuals) from four continental regions.ResultsNAT2PRED correctly identified slow acetylators with a sensitivity above 99% for all populations outside sub-Saharan Africa. Nevertheless, NAT2PRED showed a poor ability to distinguish between intermediate and rapid acetylators, with a classification error rate reaching up to 10% in the non-African samples.ConclusionNAT2PRED is an excellent tool to infer the individual acetylation status from NAT2 genotype data when the main interest is to distinguish slow acetylators from the others. This should facilitate the determination of the individual acetylation status in routine clinical practice and lead to better monitoring of risks associated with cancer and adverse drug reactions.

Highlights

Determined differences in N-acetylation capacity have proved to be important determinants of both the effectiveness of therapeutic response and the development of adverse drug reactions and toxicity during drug treatment
We included those non-African samples that were genotyped for all Single nucleotide polymorphisms (SNPs) except SNP 191G>A as this is rare in non-African populations
Our results show that NAT2PRED is an excellent tool to infer the individual acetylation status from NAT2 genotype data when the main interest is to distinguish slow acetylators from the others

Summary

Introduction

Determined differences in N-acetylation capacity have proved to be important determinants of both the effectiveness of therapeutic response and the development of adverse drug reactions and toxicity during drug treatment. NAT2PRED is a web-server that allows a fast determination of NAT2 acetylation phenotype from genotype data without taking the extra step of reconstructing haplotypes for each individual (publicly available at http:// nat2pred.rit.albany.edu). Determined differences in Nacetylation capacity have proved to be important determinants of both the effectiveness of therapeutic response and the development of adverse drug reactions and toxicity during drug treatment [1,2]. Thanks to the well-established genotype-phenotype correlation at this locus, the individual acetylation status can be reliably predicted from the haplotype combination at NAT2, according to the acknowledged classification of NAT2 haplotypes into either low-activity or fully functional alleles (see the consensus NAT2 gene nomenclature website: http://www.louisville.edu/medschool/pharma cology/NAT.html). Many studies did not distinguish between rapid and intermediate acetylators, categorizing both types of subjects as rapid acetylators

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