N-Acetyltransferase-2 (NAT2) phenotype is influenced by genotype-environment interaction in Ethiopians
Open accessAbstract
BACKGROUND AND OBJECTIVES: N-acetyltransferase 2 (NAT2) metabolize several drugs including isoniazid. We investigated the effect of genotype, geographical difference, and smoking habit on NAT2 phenotype in Ethiopians. METHODS: Genotyping for NAT2 191G > A, 341 T > C, 590G > A, and 857G > A was performed in 163 unrelated healthy Ethiopians (85 living in Ethiopia and 78 living in Sweden). The NAT2 phenotype was determined using caffeine as a probe and log AFMU/(AFMU + 1X + 1 U) urinary metabolic ratio (MR) as an index. RESULTS: The frequencies of NAT2*4, *5, *6, *7, and *14 haplotypes were 14.1, 48.5, 30.1, 5.5, and 1.8%, respectively. The frequencies of rapid (NAT2*4/*4), intermediate (heterozygous *4), and slow (no *4 allele) acetylator genotypes were 1.8, 24.6, and 73.6%, respectively. The distribution NAT2 MR was bimodal with 70% being phenotypically slow acetylators. NAT2 genotype (p < 0.0001) and country of residence (p = 0.004) independently predicted NAT2 phenotype. Controlling for the effect of genotype, ethnic Ethiopians living in Ethiopia had significantly higher NAT2 MR than those living in Sweden (p = 0.006). NAT2 genotype-phenotype concordance rate was 75%. Distinct country-of-residence-based genotype-phenotype discordance was observed. The proportion of phenotypically determined rapid acetylators was significantly higher and slow acetylators was lower in Ethiopians living in Ethiopia (39% rapid, 61% slow) than in Sweden (20% rapid, 80% slow). Sex and smoking had no significant effect on NAT2 MR. CONCLUSIONS: We report a high prevalence of NAT 2 slow acetylators in Ethiopians and a conditional NAT2 genotype-phenotype discordance implicating a partial phenotype conversion and metabolic adaptation. Gene-environment interactions regulate NAT2 phenotype.
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In Ethiopians, genotypically determined NAT2 slow acetylators displayed a rapid acetylator phenotype in vivo using caffeine as a probe.
“Recent literature has shown a genotype-phenotype discordance in the slow acetylator group for NAT2, in which genotypically determined NAT2 slow acetylators living in Ethiopia displayed a rapid acetylator phenotype, as measured in vivo with caffeine as a probe substrate.8”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [8]
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- Authors
- Aklillu, E., Carrillo, J. A., Makonnen, E., Bertilsson, L., & Djordjevic, N.
- Affiliations
- Karolinska University Hospital (SE)
- Universidad de Extremadura (ES)
- Addis Ababa University (ET)
- Corresponding author
- Aklillu, Eleni
- Venue
- European Journal of Clinical Pharmacology
- Published
- 2018-03-27
- Volume
- 74
- Issue
- 7
- Pages
- 903-911
- ISSN
- 0031-6970 (ISSN-L)
- 1432-1041
- PMC
- PMC5999125
- OpenAlex
- W2795337108
- Cited by
- 28
- References
- 51
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 6 · 2022: 1 · 2021: 4 · 2020: 6 · 2019: 5 · 2018: 1
- FWCI
- 4.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Journal of Clinical Pharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Vetenskapsrådet (VR 2015-03295)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- N-acetyltransferase 2, genotype-phenotype discordance, gene-environment interaction, slow acetylators, isoniazid metabolism, haplotype frequencies, smoking, Ethiopians, metabolic adaptation, drug metabolism
- MeSH terms
- Adult, Arylamine N-Acetyltransferase, Caffeine, Ethiopia, Female, Genotype, Humans, Male, Phenotype, Sweden, Uracil, Uric Acid, Xanthines, Polymorphism, Single Nucleotide, Black People, Gene-Environment Interaction
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