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• W2157777608 abstract "Dear Sir, We thank Hein et al. (1) for their interest in our paper (2) on the relationship between aromatic DNA adducts and single-nucleotide polymorphisms (SNP) in metabolic genes. We determined three SNPs in the Exon 2 of N-acetyltransferase 2 (NAT2): þ487C.T (rs1799929; L161L), 580G.A (rs1799930; R197Q) and 313G.A (rs1799931; G286E). Then, we used these three SNPs to assign the alleles NAT2 5A, NAT2 6A and NAT2 7A/B, and we imputed an acetylator phenotype according to alleles NAT2 5A and NAT2 7A/B. In our study, the adduct levels decreased with the (imputed) acetylation activity, i.e. slower acetylators having lower concentration of adducts. Hein et al. (1) mainly question the way we assigned phenotypes deduced from the SNPs in NAT2, as well as the terms we used to refer to them. We would like to comment some of the issues they pointed, which actually will allow us to clarify the results reported in our paper. We measured DNA adducts by 32P-Postlabeling, a technique that mainly detects bulky adducts formed by polycyclic aromatic hydrocarbons. This was actually the main aim of our study and polymorphic enzymes potentially involved in pathways of activation or detoxification of polycyclic aromatic hydrocarbons, such as CYP1A1, EPHX1, GSTM1 and GSTT1, were our primary interest. Thus, it was rather unexpected that the lower level of adducts among subjects carrying the allele A in 7A/B of NAT2 was the only significant association found in the genotype analysis, as shown in table II of the study of Agudo et al. (2). We acknowledge that phenotype assignments based solely on determinations of three SNPs can lead to phenotype misclassifications (3,4). However, it is a common practice in many epidemiological studies, even after many additional SNPs in NAT2 have been identified. Furthermore, this is a pragmatical option since NAT2 polymorphisms were analyzed by the LC NAT2 Mutation Detection kit (Roche Molecular Biochemicals, Mannheim, Germany), as previously reported (5). Apart from the three SNPs already mentioned, the kit also includes the polymorphism Ex2þ197G.A (rs1801279, R64Q); all but one subjects were homozygous for the wild genotype GG, so no further details for this SNP were given in the paper. On the other hand, we used the synonymous polymorphisms L161L as a marker of Ex2þ347T.C (rs1801280, I114T). There is strong linkage disequilibrium between these two SNPs, with D# 5 1 and r2 5 0.91 (6); thus most subjects with allele T of L161L have the allele C (Thr114) of I114T. The core of criticisms by Hein et al. (1) focus on the way how we imputed acetylator phenotypes from genotypes, as well as the way we refer to them. First of all, they noticed that our definition of phenotypes was different in the text and in the footnote of table IVof Agudo et al. (2). This is due to a mistake in the text [(2), page 970], where we stated that ‘moderately slow activity was assigned to subjects with allele T for 5A keeping the wild-type CC for 7A/B’, whereas the wild-type of 7A/B is GG; the definition in the footnote is the correct one. We termed the phenotypes of acetylation activity as ‘normal’, ‘moderately slow’ and ‘very slow’; Hein et al. (1) claim that this implies that slow acetylators would be considered as ‘abnormal’, whereas they are 50% in some populations. We used these terms to be consistent with definition of other phenotypes in the same work (oxidation, hydrolysis), but we agree that they are neither correct nor appropriate for acetylation, and it is better classifying subjects as rapid or slow acetylators or even distinguishing intermediate acetylators when appropriate phenotyping methods are available. We used a work by Zang et al. (7) to deduce acetylator phenotypes, but we incorrectly attributed to G286E ( 7A/B) the slowest activity. Although this polymorphism had the lowest N-acetylation kinetics to some substrates and the lowest thermostability, SNPs associated to alleles 5A and 6A showed both slower Nand O-acetylation activity. Actually there seems to be an agreement to accept that I114T polymorphism causes the largest reduction in NAT2 catalytic activity owing to enhanced protein degradation (7–9). Although it was not directly determined in our study, we may use L161L as a marker I114T owing to the strong linkage disequilibrium between them. Finally, it may be somehow contradictory using only two SNPs ( 5A and 7A/B) to deduce the phenotypes, whereas the haplotype analysis of NAT2 is based upon the three alleles. Haplotype analysis was carried out by means of an expectation-maximization algorithm that accounts for the uncertainty in the estimation of haplotypes from individuals with multiple heterozygous when phase is unknown (10). However, the estimates from this method tend to be inaccurate for very rare haplotypes, so that some of the results shown in table III of Agudo et al. (2) must be taken with caution. Keeping in mind the issues discussed above, we carried out some reanalysis in order to provide a better interpretation of our results regarding NAT2 polymorphisms and aromatic adduct levels. First of all, it must be considered that in our study 5A and 6Awere in strong linkage disequilibrium (D# 5 0.98) and thus, it is difficult to address separate effects from each other. Within subjects with the homozygous wild-type for 5A the adduct levels were almost the same for different genotypes of 6A, and the same was observed among subjects with at least one allele T for 5A. On the contrary, a lower adduct level was found for subjects with at least one allele T for 5A, independently of the 6A genotype. Thus, it seems reasonable to address the effect of NAT2 using only two SNPs, namely 5A and 7A/B. We used the dominant model for 5A since it seems to fit the data reasonably well [(2), table I]; moreover, this helps to avoid very small numbers. The combined effect on adduct levels of different genotypes for 5A and 7A/B is shown in Table I. As compared with subjects with the homozygous wild-type for both alleles (CC and GG, respectively), those with allele T for 5A and wild-type 7A/B, as well those with one allele A for 7A/B and wild-type 5A had lower level of aromatic adducts. In both cases, the test had small P-values, although they did not reach statistical significance. A small group of subjects with both variants (allele T 5A and A in 7A/B) showed a significantly decreased concentration of aromatic adducts. These effects are consistent with the haplotype analysis including only these two SNPs (results not shown). One potential interpretation of our results is that, in spite of significant differences, they may be due to chance. An alternative explanation is that aromatic adduct formation is somehow influenced by the activity of NAT2. This enzyme is mainly involved in either the N-acetylation or O-acetylation of several aromatic amines and hydrazines, including potential carcinogens and drugs (3,7). Both ySee the original publication (2) for the complete list of contributors." @default.
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• W2157777608 date "2009-11-23" @default.
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• W2157777608 title "Relationship between N-acetyltransferase 2 single-nucleotide polymorphisms and aromatic DNA adducts" @default.
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• W2157777608 doi "https://doi.org/10.1093/carcin/bgp291" @default.
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