Finally, to understand which compounds are contributing to the NAT2-SF signal, we examined 11 compounds assayed from skin biopsies (n = 198): the fast acetylator genotype was associated with lower levels of the AGEs hydroimidazolones of glyoxal (p = 0.017).
Altogether, 35 NAT2 alleles forming two acetylator phenotypes (distributed almost in equal proportion in India) were found; while the alleles determining slow acetylators were highly differentiated, the fast acetylator alleles were less in number but highly frequent.
The MTHFR codon 222 variant allele was associated with high CTGs in smokers, the MTR codon 919 variant allele with high CTAs in older smokers and the NAT2fast acetylator genotype with high CTGs in older subjects.
The joint effects in the highest risk category (NAT2 slow acetylator, NAT1 fast acetylator, and current or ever cigarette smoking) as compared with the reference category (NAT2fast acetylator, NAT1 slow acetylator, and never smoking) were associated with an odds ratio of 2.73 (95% CI: 1.70, 4.31).
A combined significant effect was also observed in the Italian study for the NAT2fast acetylator and EPHX1 low-activity genotypes, while this combination was protective in the Finnish study.
In combination with NAT2fast acetylator status, however, the SULT1A1*1/*1 genotype might increase breast cancer risk in women exposed to tobacco smoke.
Highest DNA adduct levels were observed in slow acetylators for both NAT1 and NAT2 also lacking the GSTM1 gene (2.03 +/- 0.17), and lowest in GSTM1(+) subjects with the fast acetylator genotype for both NAT1 and NAT2 (0.91 +/- 0.45, P = 0.01).
Increased MNC frequencies were also associated with ageing at 0.5 microg/ml BrdU, with the GSTM1-positive genotype at both 1 (P=0.028) and 0.5 (P=0.056) microg/ml BrdU in all subjects, and with the NAT2fast acetylator genotype in smokers at 0.5 microg/ml BrdU (P=0.043).
We found neither an increased adenoma prevalence in subjects homozygous or heterozygous for the NAT1*10 fast acetylator allele (odds ratio 1.04; 95% confidence interval 0.79-1.36), nor a gene-gene interaction between NA1 and NAT2 (P(interaction) = 0.59).
The individuals with combined GSTM1 and NAT2 defects had about a 4-fold risk of developing malignant mesothelioma compared to those with the GSTM1 gene and NAT2fast acetylator genotype (OR = 3.6; 95% CI = 1.3-9.6).
Highest DNA adduct levels were observed in slow acetylators for both NAT1 and NAT2 also lacking the GSTM1 gene (2.03 +/- 0.17), and lowest in GSTM1(+) subjects with the fast acetylator genotype for both NAT1 and NAT2 (0.91 +/- 0.45, P = 0.01).
Increased MNC frequencies were also associated with ageing at 0.5 microg/ml BrdU, with the GSTM1-positive genotype at both 1 (P=0.028) and 0.5 (P=0.056) microg/ml BrdU in all subjects, and with the NAT2 fast acetylator genotype in smokers at 0.5 microg/ml BrdU (P=0.043).
The individuals with combined GSTM1 and NAT2 defects had about a 4-fold risk of developing malignant mesothelioma compared to those with the GSTM1 gene and NAT2 fast acetylator genotype (OR = 3.6; 95% CI = 1.3-9.6).
We identified 'less credible' associations (higher heterogeneity, lower statistical power, BFDP > 0.02) with a further four variants of four independent genes: MTHFR c.677C>T p.A222V (rs1801133), TP53 c.215C>G rs1042522;rs1131691014;rs878854066" genes_norm="7157">p.R72P (rs1042522), NQO1 c.559C>T p.P187S (rs1800566), and NAT1 alleles imputed as fast acetylator genotypes.
Highest DNA adduct levels were observed in slow acetylators for both NAT1 and NAT2 also lacking the GSTM1 gene (2.03 +/- 0.17), and lowest in GSTM1(+) subjects with the fast acetylator genotype for both NAT1 and NAT2 (0.91 +/- 0.45, P = 0.01).