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

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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“…Actually, it has been reported that C282T and C481T SNPs are synonymous changes and seem to exert no effect on NAT2 acetylation capacity or protein stability (Zang et al, 2007;Selinski et al, 2013;Boukouvala, 2016). It has been shown that G191A, C345T, and A803G SNPs are missense mutations that cause amino acid changes in a mature protein (Walraven et al, 2008;Toure et al, 2012;Boukouvala, 2016). Polymorphisms C345T and A803G seem to have no functional effect on NAT2 enzyme, in contrast to the G191A SNP which has been associated with reduced catalytic activity (Toure et al, 2012;Selinski et al, 2013;Boukouvala, 2016).…”

“…It has been shown that G191A, C345T, and A803G SNPs are missense mutations that cause amino acid changes in a mature protein (Walraven et al, 2008;Toure et al, 2012;Boukouvala, 2016). Polymorphisms C345T and A803G seem to have no functional effect on NAT2 enzyme, in contrast to the G191A SNP which has been associated with reduced catalytic activity (Toure et al, 2012;Selinski et al, 2013;Boukouvala, 2016). NAT2 G191A SNP variant presents equal allelic and genotypic distributions between the controls and pa- Table 3.…”

“…Thirty-six allelic variants of NAT2 gene have been reported, and each allele is classified as fast or slow depending on the combination of different single nucleotide polymorphisms (SNPs) present in its coding region (Khedhiri et al, 2010;Di Pietro et al, 2012). NAT2 *4 allele is defined as the wild-type allele and has been associated with the fast acetylation phenotype (Hein et al, 2000a;Walker et al, 2009;Toure et al, 2012). Individuals homozygous for rapid NAT2 acetylator alleles are classified as rapid acetylators, those homozygous for slow NAT2 acetylator alleles as slow acetylators, and those possessing one rapid and one slow NAT2 acetylator alleles as intermediate acetylators (Hein, 2006).…”

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“…A total of nine SNPs were genotyped: rs2256871 in CYP2C9*9 and rs7900194 in CYP2C9*8 ; rs1057126 and rs15561 in NAT1 ; rs1041983, rs1801280, rs1799929, rs1799930 and rs1208 in NAT2 . …”

“…Quantitative PCR with TaqMan probes was used for CYP2C9 genotyping and Big Dye sequencing PCR for NAT1 and NAT2. For NAT1, the technique used is that described by Hsieh et al [35]; and for NAT2 as described by Touré et al [34].…”