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Study of NAT2 genetic polymorphism in West African subjects: example of an healthy non-smoker Senegalese population

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Abstract

The NAT2 genetic polymorphism determines the individual acetylator status and, consequently, the capacity to metabolize, or not, drugs and xenobiotics which are substrates of NAT2. As the nature and frequency of the NAT2 polymorphisms vary remarkably between populations of different ethnic origins, genotyping strategies used to predict the acetylation phenotype need to be adapted for each particular population regarding their genetic backgrounds at this locus. As few data on the genetic polymorphism of NAT2 are available in the Senegalese population, we performed an extensive identification of NAT2 variants in 105 healthy non-smoker Senegalese subjects by direct PCR sequencing of the coding region. Eleven previously described SNPs were identified in this Senegalese population. Upon allele analysis, the four most frequent alleles were of the NAT2*5- (35.7 %), NAT2*6- (21.0 %), NAT2*12- (16.7 %) and NAT2*14- (10.0 %) type, the remaining alleles, including the wild-type NAT2*4, having each a frequency lower than 10 %. According to the observed genotypes, 51 and 50 subjects were predicted to be of the rapid (48.6 %) and slow (47.6 %) acetylator phenotype, respectively, while four individuals (3.8 %) were considered of unknown phenotype as they carry at least one allele with a yet unknown functional effect. These baseline data would be of particular interest to set up an efficient genotyping strategy to predict the acetylation status of Senegalese patients with tuberculosis and, thus, to optimize their isoniazid treatment.

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References

  1. Blum M, Grant DM, McBride W, Heim M, Meyer UA (1990) Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol 9:193–203

    Article  PubMed  CAS  Google Scholar 

  2. Evans DAP (1989) N-acetyltransferase. Pharmacol Ther 42:157–234

    Article  PubMed  CAS  Google Scholar 

  3. Hein DW (2002) Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis. Mutat Res 506–507:65–77

    PubMed  Google Scholar 

  4. Upton A, Johnson N, Sandy J, Sim E (2001) Arylamine N-acetyltransferases -of mice, men and microorganisms. Trends Pharmacol Sci 22:140–146

    Article  PubMed  CAS  Google Scholar 

  5. Vatsis KP, Weber WW, Bell DA, Dupret JM, Evans DAP, Grant DM, Hein DW, Lin HJ, Meyer UA, Relling MV, Sim E, Suzuki T, Yamazoe Y (1995) Nomenclature for N-acetyltransferases. Pharmacogenetics 5:1–17

    Article  PubMed  CAS  Google Scholar 

  6. Meyer UA, Zanger UM, Grant D, Blum M (1990) Genetic polymorphisms of drug metabolism. In: Testa B (ed) Advances of drug research. Academic London 19: 197–241

  7. The consensus gene nomenclature of human NAT2 alleles [http://www.louisville.edu/medschool/pharmacology/NAT2.html]. Accessed 15 June 2012

  8. Hein DW, Doll MA, Rustan TD, Ferguson RJ (1995) Metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides by 16 recombinant human NAT2 allozymes: effects of 7 specific NAT2 nucleic acid substitutions. Cancer Res 55:3531–3536

    PubMed  CAS  Google Scholar 

  9. Lin HJ, Han CY, Lin BK, Hardy S (1994) Ethnic distribution of slow acetylator mutations in the polymorphic N acetyltransferase (NAT2) gene. Pharmacogenetics 4:125–134

    Article  PubMed  CAS  Google Scholar 

  10. Lin HJ, Ya Han C, Lin BK, Hardy S (1993) Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, Blacks, Hispanics, and Whites: application to metabolic epidemiology. Am J Hum Genet 52:827–834

    PubMed  CAS  Google Scholar 

  11. Zang Y, Doll MA, Zhao S, States JC, Hein DW (2007) Functional characterization of single-nucleotide polymorphisms and haplotypes of human N-acetyltransferase 2. Carcinogenesis 28(8):1665–1671

    Article  PubMed  CAS  Google Scholar 

  12. Deguchi T, Mashimo M, Suzuki T (1990) Correlation between acetylator phenotypes and genotypes of polymorphic arylamine N-acetyltransferase in human liver. J Biol Chem 265:12757–12760

    PubMed  CAS  Google Scholar 

  13. Fretland AJ, Leff MA, Doll MA, Hein DW (2001) Functional characterization of human N-acetyltransferase 2 (NAT2) single nucleotide polymorphisms. Pharmacogenetics 11:207–215

    Article  PubMed  CAS  Google Scholar 

  14. Lee WEJD, Zhao B, Seow-Choen F (1998) Relationship between polymorphism of N-acetyltransferase gene and susceptibility to colorectal carcinoma in a Chinese population. Pharmacogenetics 8:513–517

    Article  PubMed  CAS  Google Scholar 

  15. Zang Y, Zhao S, Doll MA, States JC, Hein DW (2004) The T341C (Ile114Thr) polymorphism of N-acetyltransferase 2 yields slow acetylator phenotype by enhanced protein degradation. Pharmacogenetics 14(11):717–723

    Article  PubMed  CAS  Google Scholar 

  16. Patin E, Harmant C, Kidd K, Kidd J, Froment AS, Mehdi Q, Sica L, Heyer E, Quintana-Murci L (2006) Sub-Saharan African coding sequence variation and haplotype diversity at the NAT2 gene. Hum Mutat 27(7):720

    Article  PubMed  Google Scholar 

  17. Teixeira RLF, Miranda AB, Pacheco AG, Lopes MQP, Fonseca-Costa J, Rabahi MF, Melo HM, Kritski AL, Mello FCQ, Suffys PN, Santos AR (2007) Genetic profile of the arylamine N-acetyltransferase 2 coding gene among individuals from two different regions of Brazil. Mutat Res 624:31–40

    Article  PubMed  CAS  Google Scholar 

  18. Meisel P (2002) Arylamine N-acetyltransferases and drug response. Pharmacogenomics 3:349–366

    Article  PubMed  CAS  Google Scholar 

  19. Butcher NJ, Boukouvala S, Sim E, Minchin RF (2002) Pharmacogenetics of the arylamine N-acetyltransferases. Pharmacogenomics J 2:30–42

    Article  PubMed  CAS  Google Scholar 

  20. Sabbagh A, Langaney A, Darlu P, Gérard N, Krishnamoorthy R, Poloni ES (2008) Worldwide distribution of NAT2 diversity: implications for NAT2 evolutionary history. BMC Genet 9:21

    Article  PubMed  Google Scholar 

  21. Rodriguez S, Gaunt TR, Day INM (2009) Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 169:505–514

    Article  PubMed  Google Scholar 

  22. Sabbagh A, Darlu P, Langaney A, Poloni ES (2007) Haplotype tagging efficiency and tagSNP sets portability in worldwide populations in NAT2 gene. Bull Mém Soc d’Anthrop de Paris 19(3–4):233–241

    Google Scholar 

  23. Sekine A, Saito S, Iida A, Mitsunobu Y, Higuchi S, Harigae S, Nakamura Y (2001) Identification of single-nucleotide polymorphisms (SNPs) of human N-acetyltransferase genes NAT1, NAT2, AANAT, ARD1, and L1CAM in the Japanese population. J Hum Genet 46(6):314–319

    Article  PubMed  CAS  Google Scholar 

  24. Teixeira RLF, Silva Junior FP, Silveira AR, Cabello PH, Mendonca-Lima L, Rabahi MF, Kritski AL, Mello FCQ, Suffys PN, Miranda AB, Santos AR (2010) Sequence analysis of NAT2 gene in Brazilians: identification of undescribed single nucleotide polymorphisms and molecular modeling of the N acetyltransferase 2 protein structure. Mutat Res 683:43–49

    Article  PubMed  CAS  Google Scholar 

  25. Hamdy SI, Hiratsuka M, Narahara K, Endo N, El-Enany M, Moursi N, Ahmed MSE, Mizugaki M (2003) Genotype and allele frequencies of TPMT NAT2 GST SULT1A1 And MDR-1 in the Egyptian population. Br J Clin Pharmacol 55:560–569

    Article  PubMed  CAS  Google Scholar 

  26. Bell DA, Taylor JA, Butler MA, Stephens EA, Wiest J, Brubaker LH, Kadlubar FF, Lucier GW (1993) Genotype/phenotype discordance for human arylamine N-acetyltransferase (NAT2) reveals a new slow acetylator allele common in African-Americans. Carcinogenesis 14:1689–1692

    Article  PubMed  CAS  Google Scholar 

  27. Cavaco I, Reis R, Gil JP, Ribeiro V (2003) CYP3A4*1B and NAT2*14 alleles in a native African population. Clin Chem Lab Med 41:606–609

    PubMed  CAS  Google Scholar 

  28. Dandara C, Masimirembwaa CM, Magimbab A, Kaayab S, Sayib J, Sommersb DK, Snymanc JR, Haslera JA (2003) Arylamine N acetyltransferase (NAT2) genotypes in Africans: the identification of a new allele with nucleotide changes 481C>T and 590G>A. Pharmacogenetics 13:55–58

    Article  PubMed  CAS  Google Scholar 

  29. Deloménie C, Sica L, Grant DM, Krishnamoorthy R, Dupret JM (1996) Genotyping of the polymorphic N-acetyltransferase (NAT2*) gene locus in two native African populations. Pharmacogenetics 6:177–185

    Article  PubMed  Google Scholar 

  30. Agúndez JA, Golka K, Martínez C, Selinski S, Blaszkewicz M, García-Martín E (2008) Unraveling ambiguous NAT2 genotyping data. Clin Chem 54:1390–1394

    Article  PubMed  Google Scholar 

  31. Anitha A, Banerjee M (2003) Arylamine N-acetyltransferase 2 polymorphism in the ethnic populations of South India. Int J Mol Med 11:125–131

    PubMed  CAS  Google Scholar 

  32. Magalon H, Patin E, Austerlitz F, Hegay T, Aldashev A, Quintana-Murci L, Heyer E (2008) Population genetic diversity of the NAT2 gene supports a role of acetylation in human adaptation to farming in Central Asia. Eur J Hum Genet 16:243–251

    Article  PubMed  CAS  Google Scholar 

  33. Ebisawa T, Deguchi T (1991) Structure and restriction fragment length polymorphism of genes for human liver arylamine N-acetyltransferases. Biochem Biophys Res Commun 177:1252–1257

    Article  PubMed  CAS  Google Scholar 

  34. Ebeshi BU, Bolajil OO, Masimirembwa CM (2011) Arylamine N-acetyltransferase 2 (NAT2) single nucleotide polymorphisms’ frequencies in Nigerian populations. Afr J Pharm Pharmacol Res 1:1–6

    Google Scholar 

  35. Sabbagh A, Darlu P, Crouau-Roy B, Poloni ES (2011) Arylamine N-acetyltransferase 2 (NAT2) genetic diversity and traditional subsistence: a worldwide population survey. PLoS ONE 6(4):e18507. doi:10.1371

    Article  PubMed  CAS  Google Scholar 

  36. Suarez-Kurtz G, Vargens DD, Sortica VA, Hutz MH (2012) Accuracy of NAT2 SNP genotyping panels to infer acetylator phenotypes in African, Asian, Amerindian and admixed populations. Pharmacogenetics 13:851–854

    CAS  Google Scholar 

  37. Hein DW, Doll MA (2012) Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediaire and slow acetylator phenotypes. Pharmacogenetics 13:31–34

    CAS  Google Scholar 

Download references

Acknowledgments

We would like to acknowledge Mr. Christophe Hallaert and Ms Isabelle Szuster (Laboratory of Pharmacogenetics, University Hospital Center of Lille, France) for their help and technical assistance.

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Authors and Affiliations

  1. Service de Toxicologie-Hydrologie, Faculté de Médecine, Pharmacie et Odontostomatologie, Université Cheikh Anta DIOP, BP 5246, Dakar, Senegal

    A. Touré, C. Diop, M. Cabral, M. Fall & A. Diouf

  2. EA4483, Faculté de Médecine, UDSL, Université Lille Nord-de-France, Lille, France

    A. Touré, M. Lhermitte, F. Broly & D. Allorge

  3. Service de Toxicologie-Génopathies, Centre de Biologie-Pathologie, CHRU de Lille, Lille, France

    M. Lhermitte, F. Broly & D. Allorge

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  1. A. Touré
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  2. C. Diop
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  3. M. Cabral
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Correspondence to A. Touré.

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Touré, A., Diop, C., Cabral, M. et al. Study of NAT2 genetic polymorphism in West African subjects: example of an healthy non-smoker Senegalese population. Mol Biol Rep 39, 10489–10496 (2012). https://doi.org/10.1007/s11033-012-1931-2

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  • DOI: https://doi.org/10.1007/s11033-012-1931-2

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