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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

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

  • Mónica Acuña1
  • Sergio Flores Carrasco2
  1. 1Nucleo Interdisciplinario de Biologia y Genetica, Instituto de Ciencias Biomedicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia, Santiago 8380000, Chile
  2. 2Centro de Investigacion en Medicina de Altura, Vicerrectoria de Investigacion e Innovacion, Universidad Arturo Prat, Santiago 8320000, Chile
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{acuna2026native,
  title = {{Native American Ancestry Is Associated with NAT2 Haplotype and Inferred Metabolizer Phenotype Variation in Latin American Populations}},
  author = {Mónica Acuña and Sergio Flores Carrasco},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = nov,
  doi = {10.3390/ijms27219884},
  url = {https://www.mdpi.com/1422-0067/27/21/9884},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Native American Ancestry Is Associated with NAT2 Haplotype and Inferred Metabolizer Phenotype Variation in Latin American Populations
AU  - Mónica Acuña
AU  - Sergio Flores Carrasco
PY  - 2026
DA  - 2026/11/04
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219884
UR  - https://www.mdpi.com/1422-0067/27/21/9884
AB  - 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.
SN  - 1422-0067
ER  -