Haplotype tagging efficiency and tagSNP sets portability in worldwide populations in NAT2 gene

Genetic polymorphism in the NAT2 gene is responsible for pronounced interindividual differences in the acetylation activity of the N-acetyltransferase 2 (NAT2) enzyme, which plays a crucial role in the metabolism of many clinically useful drugs and exogenous chemicals. Up to now, most association studies that have attempted to relate the acetylation phenotype in NAT2 to a variety of complex human disorders have led to contradictory results in different populations. Some of these inconsistencies may result from a poor knowledge of linkage patterns at NAT2 and their geographic variation. Using data from an extensive survey of the literature, we investigated the worldwide haplotype diversity and linkage disequilibrium structure of NAT2. For 28 population samples (including 3,994 individuals) from four continental regions (Africa, Europe, Asia, America), we evaluated haplotype tagging efficiency at NAT2 and defined population-specific sets of haplotype tagging SNPs (htSNPs) to be used for future association studies. Tagging common haplotypes yielded 2- to 3-fold savings in European and East Asian samples, while no gains from tagging were observed in samples of African ancestry, which displayed high haplotype diversity at NAT2. htSNPs sets appeared to be portable among populations from a same continent, provided that the continent-specific htSNPs sets were selected with a stringent criterion. A “cosmopolitan” htSNPs set suitable for all human populations could not be identified for the NAT2 gene, but a single four-htSNP set proved to perform successfully in all the non-African populations investigated.