However, up to now, association studies in NAT2 have led to conflicting results among (and even within) human populations and most association findings have been difficult to replicate. In addition, in the last decades, an increasing number of epidemiological studies have attempted to relate acetylation phenotype to a variety of complex human disorders, such as bladder cancer, atopic diseases, diabetes, Parkinson's disease and many others (see Butcher et al. The clinical consequences of the acetylation polymorphism can be severe if standard drug doses are applied, exposing patients to an increased risk of adverse drug reactions or a lack of therapeutic efficacy. These two main metabolic phenotypes occur with varying prevalence in populations of different ethnic origin. In particular, a clear bimodal distribution is observed that segregates the rapid acetylator phenotype, associated with a normal acetylation capacity, from the slow acetylator one, characterized by a reduced enzyme activity. Extensive polymorphism in NAT2 gives rise to a wide interindividual variation in N-acetylation capacity. The N-acetyltransferase 2 ( NAT2) gene plays a crucial role in the metabolism of xenobiotics, including many clinically useful drugs and exogenous chemicals present in the diet, cigarette smoke and the environment. Patterns of sequence variation at NAT2 are consistent with selective neutrality in all sub-Saharan African populations investigated, whereas the high level of population differentiation between Europeans and East Asians inferred from SNPs could suggest population-specific selective pressures acting at this locus, probably caused by differences in diet or exposure to other environmental signals. This pattern could result from region- or population-specific selective pressures acting at this locus, as further suggested in the HapMap data by extremely high values of F ST for a few SNPs positions in the NAT2 coding exon (T341C, C481T and A803G) in comparison to the empirical distribution of F ST values accross the whole 400-kb region of the NAT gene family. On the basis of the worldwide genotyping survey dataset, we found a strong genetic structure differentiating East Asians from both Europeans and sub-Saharan Africans. High diversity and no molecular signal of departure from neutrality were observed in this West African sample. The sequencing analysis of the NAT2 gene in the Mandenka sample revealed twelve polymorphic sites in the coding exon (two of which are newly identified mutations, C345T and C638T), defining 16 haplotypes. The Mandenka data were further included in a worldwide dataset composed of 41 published population samples (6,727 individuals) from four continental regions that were adequately genotyped for all common NAT2 variants so as to provide further insights into the worldwide haplotype diversity and population structure at NAT2. As it represents a likely target of population-specific selection pressures, we fully sequenced the NAT2 coding region in 97 Mandenka individuals from Senegal, and compared these sequences to extant data on other African populations.

The N-acetyltransferase 2 ( NAT2) gene plays a crucial role in the metabolism of many drugs and xenobiotics.

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