Native American Ancestry Is Associated with NAT2 Haplotype and Inferred Metabolizer Phenotype Variation in Latin American Populations

The N-acetyltransferase 2 (NAT2) gene contributes to drug metabolism, yet its pharmacogenetic variation in admixed populations remains incompletely characterized. We evaluated associations of estimated Native American genetic ancestry with NAT2 haplotypes defined by seven single-nucleotide polymorphisms (SNPs) and inferred metabolizer phenotypes in four Admixed American (AMR) populations from the 1000 Genomes Project (n = 347). The complete Phase 3 dataset (n = 2504) provided comparative context. Haplotype distributions differed among AMR populations (χ2 = 78.61; Monte Carlo p = 1.0 × 10−5). After adjustment for sampling population, each 10-percentage-point increase in Native American ancestry was associated with lower odds of an inferred poor metabolizer phenotype (odds ratio [OR] = 0.78; 95% confidence interval [CI], 0.66–0.93; p = 0.006). NAT2*4.001-compatible and NAT2*7.002-compatible haplotypes were more frequent with higher Native American ancestry. The inferred poor metabolizer proportion was 57.5% in the lowest and 26.4% in the highest ancestry quartile. Excluding four individuals with indeterminate expanded coding-variant assignments yielded a similar association (n = 343; OR = 0.80; 95% CI, 0.67–0.95; p = 0.0097). These observational associations support further genotype-based investigation but do not establish causality or replace individual NAT2 genotyping.