RESUMO
The association between DNA repair gene polymorphisms and bladder cancer has been widely studied. However, few studies have examined the correlation between urothelial carcinoma (UC) and arsenic or its metabolites. The aim of this study was to examine the association between polymorphisms of the DNA repair genes, XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln, with urinary arsenic profiles and UC. To this end, we conducted a hospital-based case-control study with 324 UC patients and 647 age- and gender-matched non-cancer controls. Genomic DNA was used to examine the genotype of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln by PCR-restriction fragment length polymorphism analysis (PCR-RFLP). Urinary arsenic profiles were measured by high performance liquid chromatography (HPLC) linked with hydride generator and atomic absorption spectrometry. The XRCC1 399 Gln/Gln and 194 Arg/Trp and Trp/Trp genotypes were significantly related to UC, and the odds ratio (OR) and 95% confidence interval (95%CI) were 1.68 (1.03-2.75) and 0.66 (0.48-0.90), respectively. Participants with higher total urinary arsenic levels, a higher percentage of inorganic arsenic (InAs%) and a lower percentage of dimethylarsinic acid (DMA%) had a higher OR of UC. Participants carrying XRCC1 risk diplotypes G-C/G-C, A-C/A-C, and A-T/G-T, and who had higher total arsenic levels, higher InAs%, or lower DMA% compared to those with other XRCC1 diplotypes had a higher OR of UC. Our results suggest that the XRCC1 399 Gln/Gln and 194 Arg/Arg DNA repair genes play an important role in poor arsenic methylation capacity, thereby increasing the risk of UC in non-obvious arsenic exposure areas.
Assuntos
Arsênio/metabolismo , Proteínas de Ligação a DNA/genética , Venenos/metabolismo , Neoplasias Urológicas/genética , Neoplasias Urológicas/metabolismo , Idoso , Arsênio/urina , Ácido Cacodílico/metabolismo , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Intervalos de Confiança , DNA/genética , Reparo do DNA/efeitos dos fármacos , Exposição Ambiental , Feminino , Genótipo , Humanos , Masculino , Metilação , Pessoa de Meia-Idade , Razão de Chances , Venenos/urina , Polimorfismo Genético , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Fatores Socioeconômicos , Espectrofotometria Atômica , Inquéritos e Questionários , Proteína 1 Complementadora Cruzada de Reparo de Raio-X , Proteína Grupo D do Xeroderma Pigmentoso/metabolismoRESUMO
The aim of this study was to examine the associations between the combined effects of urinary 8-Hydroxydeoxyguanine (8-OHdG) level and polymorphisms of XRCC1 Arg194Trp and XRCC1 Arg399Gln on the risk of urothelial carcinoma (UC). We conducted a hospital-based case-control study that included 168 cases of UC and 336 age- and gender-matched healthy controls. We used polymerase chain reaction and restriction fragment length polymorphism analyses to examine the genotypes of XRCC1 Arg194Trp and XRCC1 Arg399Gln. We used a competitive in vitro enzyme-linked immunosorbent assay to determine urinary 8-OHdG levels. The XRCC1 399 Gln/Gln genotype and the XRCC1 194 Arg/Arg genotype were positively correlated to UC (OR [95%CI] = 2.27 [1.20-4.27] and 1.59 [1.06-2.36], respectively). Urinary 8-OHdG levels were associated with UC in a dose-dependent manner. Participants with the XRCC1 (Arg399Gln) Gln/Gln genotype or the G-C/A-C haplotype of XRCC1 and a high urinary 8-OHdG level had a significantly higher risk of UC than those with the Arg/Arg + Arg/Gln genotype or the G-T haplotype and a low urinary 8-OHdG level. This is the first study to investigate the combined effect of urinary 8-OHdG level and XRCC1 polymorphisms on UC risk. The findings are especially meaningful for participants with XRCC1 399Gln or XRCC1 Arg194 genotypes and a high urinary 8-OHdG level, since these variables are associated with an increased risk of UC.