Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity

Abstract

N-acetyltransferase 2 (NAT2), an important enzyme in clinical pharmacology, metabolizes antibiotics such as isoniazid and sulfamethoxazole, and catalyzes the transformation of aromatic and heterocyclic amines from the environment and diet into carcinogenic intermediates. Polymorphisms in NAT2 account for variability in the acetylator phenotype and the pharmacokinetics of metabolized drugs. Native Americans, settled in rural areas and large cities of Latin America, are under-represented in pharmacogenetics studies; therefore, we sequenced the coding region of NAT2 in 456 chromosomes from 13 populations from the Americas, and two from Siberia, detecting nine substitutions and 11 haplotypes. Variants *4 (37%), *5B (23%) and *7B (24%) showed high frequencies. Average frequencies of fast, intermediate and slow acetylators across Native Americans were 18, 56 and 25%, respectively. NAT2 intra-population genetic diversity for Native Americans is higher than East Asians and similar to the rest of the world, and NAT2 variants are homogeneously distributed across native populations of the continent.

Sequence analysis of theN-acetyltransferase 2 gene (NAT2) among Jordanian volunteers

“…Humans can be divided, according to acetylation phenotype, into slow, intermediate, and fast acetylators [3]. Slow acetylators have a higher plasma drug concentration than rapid acetylators, which may be associated with drug toxicity [4].…”

A Homogenizing Process of Selection Has Maintained an “Ultra-Slow” Acetylation <em>NAT2</em> Variant in Humans

“…NAT2 acetylation has attracted much research interest in evolutionary biology and several population genetic studies have attempted to clarify the role that slow acetylation could have played in the adaptation of our species (Fuselli et al, 2007;Luca et al, 2008;Magalon et al, 2008;Mortensen et al, 2011;Patin et al, 2006;Sabbagh and Darlu, 2006;Sabbagh et al, 2011). The high prevalence of slow acetylators in humans (well above 50% worldwide) is thought to be a consequence of the shift in modes of subsistence and lifestyle in the last 10,000 years, which triggered significant changes in diet and human exposure to xenobiotic compounds.…”

Arylamine N-acetyltransferase 2 genotypes in a Mexican population

“…In general, single nucleotide substitutions in NAT2 result in low activity, decreased expression or enzyme instability (Hein et al, 1994), and as a consequence, variation in N-acetylation activity (Parkin et al, 1997;Gardiner and Begg, 2006). These differences in activity have resulted in the classification of individuals as rapid or slow acetylators (bimodal distribution) and the proportion of slow and rapid acetylators differs between ethnic populations (Lin et al, 1994;Gross et al, 1999;Fuselli et al, 2007;Garcia-Martin, 2008). Both rapid and slow phenotypes and genotypes have been associated with either an increased or a decreased risk of several types of cancer (Cascorbi et al, 1996;Costa et al, 2002;Ladero et al, 2002;Garcia-Closas et al, 2005;Agundez, 2008).…”