ABSTRACT
Recently, rs11892031[A] has been identified in a genome-wide association study (GWAS) to confer increased risk of urinary bladder cancer (UBC). To confirm this association and additionally study a possible relevance of exposure to urinary bladder carcinogens, we investigated the IfADo UBC study group, consisting of eight case-control series from different regions including 1,805 cases and 2,141 controls. This analysis was supplemented by a meta-analysis of all published data, including 13,395 cases and 54,876 controls. Rs11892031 A/A was significantly associated with UBC risk in the IfADo case-control series adjusted to cigarette smoking, gender, age and ethnicity (OR = 1.18; 95% CI = 1.02-1.37; P = 0.026). In the meta-analysis, a convincing association with UBC risk was obtained (OR = 1.19; 95% Cl = 1.12-1.26; P < 0.0001). Interestingly, the highest odds ratios were obtained for individual case-control series with a high degree of occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines: cases with suspected occupational UBC (OR = 1.41) and cases from the highly industrialized Ruhr area (OR = 1.98) compared with Ruhr area controls (all combined OR = 1.46). Odds ratios were lower for study groups with no or a lower degree of occupational exposure to bladder carcinogens, such as the Hungary (OR = 1.02) or the ongoing West German case-control series (OR = 1.06). However, the possible association of rs11892031[A] with exposure to bladder carcinogens still should be interpreted with caution, because in contrast to the differences between the individual study groups, interview-based data on occupational exposure were not significantly associated with rs11892031. In conclusion, the association of rs11892031[A] with UBC risk could be confirmed in independent study groups.
Subject(s)
Carcinogens, Environmental/toxicity , Chromosomes, Human, Pair 2/genetics , Genetic Loci , Glucuronosyltransferase/genetics , Polymorphism, Single Nucleotide , Urinary Bladder Neoplasms/chemically induced , Urinary Bladder Neoplasms/genetics , Animals , Carcinogens, Environmental/administration & dosage , Carcinogens, Environmental/pharmacokinetics , Genetic Association Studies , Genetic Predisposition to Disease , Glucuronosyltransferase/metabolism , Humans , Inactivation, Metabolic , Introns , Isoenzymes/genetics , Isoenzymes/metabolism , Multigene Family , Occupational Exposure , Risk , Smoking/adverse effects , Toxicogenetics/methods , Urinary Bladder Neoplasms/metabolismABSTRACT
Genotyping N-acetyltransferase 2 (NAT2) is of high relevance for individualized dosing of antituberculosis drugs and bladder cancer epidemiology. In this study we compared a recently published tagging single nucleotide polymorphism (SNP) (rs1495741) to the conventional 7-SNP genotype (G191A, C282T, T341C, C481T, G590A, A803G and G857A haplotype pairs) and systematically analysed if novel SNP combinations outperform the latter. For this purpose, we studied 3177 individuals by PCR and phenotyped 344 individuals by the caffeine test. Although the tagSNP and the 7-SNP genotype showed a high degree of correlation (R=0.933, P<0.0001) the 7-SNP genotype nevertheless outperformed the tagging SNP with respect to specificity (1.0 vs. 0.9444, P=0.0065). Considering all possible SNP combinations in a receiver operating characteristic analysis we identified a 2-SNP genotype (C282T, T341C) that outperformed the tagging SNP and was equivalent to the 7-SNP genotype. The 2-SNP genotype predicted the correct phenotype with a sensitivity of 0.8643 and a specificity of 1.0. In addition, it predicted the 7-SNP genotype with sensitivity and specificity of 0.9993 and 0.9880, respectively. The prediction of the NAT2 genotype by the 2-SNP genotype performed similar in populations of Caucasian, Venezuelan and Pakistani background. A 2-SNP genotype predicts NAT2 phenotypes with similar sensitivity and specificity as the conventional 7-SNP genotype. This procedure represents a facilitation in individualized dosing of NAT2 substrates without losing sensitivity or specificity.
Subject(s)
Arylamine N-Acetyltransferase/genetics , Caffeine/pharmacology , Acetylation , Case-Control Studies , Ethnicity/genetics , Female , Genotype , Genotyping Techniques/methods , Haplotypes , Humans , Linkage Disequilibrium , Male , Phenotype , Polymorphism, Single Nucleotide/genetics , Sensitivity and SpecificityABSTRACT
Single nucleotide polymorphism (SNP) rs710521[A], located near TP63 on chromosome 3q28, was identified to be significantly associated with increased bladder cancer risk. To investigate the association of rs710521[A] and bladder cancer by new data and by meta-analysis including all published data, rs710521 was studied in 1,425 bladder cancer cases and 1,740 controls that had not been included in previous studies. Blood samples were collected from 1995 to 2010 in Germany (n = 948/1,258), Hungary (n = 262/65), Venezuela (n = 112/190) and Pakistan (n = 103/227) supplemented by a meta-analysis of 5,695 cases and 40,187 controls. Detection of a A/G substitution (rs710521) on chromosome 3q28, position 191128627 was done via fast real-time polymerase chain reaction (rt-PCR). Rs710521[A] is associated with increased risk in the unadjusted analysis (OR = 1.21; 95% Cl = 1.04-1.40; P = 0.011) and in the recessive model adjusted for age, gender, smoking habits and ethnicity (OR = 1.23; 95% Cl = 1.05-1.44; P = 0.010). No difference between individuals occupationally exposed versus not occupationally exposed to urinary bladder carcinogens was observed concerning the relevance of rs710521[A]. Similarly, rs710521[A] did not confer different susceptibility in smokers and non-smokers. Performing a meta-analysis of 5,695 cases and 40,187 controls including all published studies on rs710521, a convincing association with bladder cancer risk was obtained (OR = 1.18; 95% Cl = 1.12-1.25; P < 0.0001). However, the odds ratio is relatively small.
