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. 2018 Jul;74(7):903-911.
doi: 10.1007/s00228-018-2448-y. Epub 2018 Mar 27.

N-Acetyltransferase-2 (NAT2) phenotype is influenced by genotype-environment interaction in Ethiopians

Eleni Aklillu  1 , Juan Antonio Carrillo  2 , Eyasu Makonnen  3 , Leif Bertilsson  4 , Natasa Djordjevic  5
Affiliations

N-Acetyltransferase-2 (NAT2) phenotype is influenced by genotype-environment interaction in Ethiopians

Eleni Aklillu et al. Eur J Clin Pharmacol. 2018 Jul.

Abstract

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.

Keywords: Environment; Gene-environment interactions; Genotype; Isoniazid; NAT2 Ethiopians; Phenotype.

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Conflict of interest statement

Conflict of interest

The authors declare that they have conflict no interest.

Figures

Fig. 1
Fig. 1
The frequency distributions of the log AFMU/(AFMU + 1X + 1 U) ratio in all ethnic Ethiopians and stratified by country of residence. The arrows indicate the anti-mode at 0.1
Fig. 2
Fig. 2
Comparison of mean log AFMU/(AFMU + 1X + 1 U) ratio between Ethiopians living in Ethiopia versus Ethiopians living in Sweden using independent t test
Fig. 3
Fig. 3
Comparison of mean NAT2 urinary metabolic ratios between Ethiopians living in Ethiopia and Ethiopian living in Sweden stratified by NAT2 genotype-inferred acetylators group as intermediate and slow group. Vertical bars denote 95% confidence interval of the mean
See this image and copyright information in PMC

References

    1. Sim E, Abuhammad A, Ryan A. Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery. Br J Pharmacol. 2014;171(11):2705–2725. doi: 10.1111/bph.12598. - DOI - PMC - PubMed
    1. Sabbagh A, Langaney A, Darlu P, Gerard N, Krishnamoorthy R, Poloni ES. Worldwide distribution of NAT2 diversity: implications for NAT2 evolutionary history. BMC Genet. 2008;9:21. doi: 10.1186/1471-2156-9-21. - DOI - PMC - PubMed
    1. Djordjevic N, Carrillo JA, Roh HK, Karlsson S, Ueda N, Bertilsson L, Aklillu E. Comparison of N-acetyltransferase-2 enzyme genotype-phenotype and xanthine oxidase enzyme activity between Swedes and Koreans. J Clin Pharmacol. 2012;52(10):1527–1534. doi: 10.1177/0091270011420261. - DOI - PubMed
    1. Hein DW, Doll MA. Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediate and slow acetylator phenotypes. Pharmacogenomics. 2012;13(1):31–41. doi: 10.2217/pgs.11.122. - DOI - PMC - PubMed
    1. Suarez-Kurtz G, Vargens DD, Sortica VA, Hutz MH. Accuracy of NAT2 SNP genotyping panels to infer acetylator phenotypes in African, Asian, Amerindian and admixed populations. Pharmacogenomics. 2012;13(8):851–854. doi: 10.2217/pgs.12.48. - DOI - PubMed

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