Association Between Genetic Polymorphism Of Ugt1a7 And Susceptibility Of Bladder Cancer

Background and ObjectiveBladder cancer is common malignant tumors of urinary system.In the word, bladder cancer is the second common cancer after prostate cancer in Urology malignant tumors,but in China,the bladder cancer is the first common cancer. Bladder cancer is considered as a multifactofial disease where the surrounding environment factors interact with the individual genetic factors resulting in risk modulation.In the environmental factors,smoking has a closed relationship with the bladder cancer,and is an independent risk factor for bladder cancer.As we all know, processed tobacco contains many carcinogens and pre-carcinogens,in which polycyclic aromatic hydrocarbons and aromatic amines are the most important carcinogens.But not all smokers have got bladder cancer,suggesting that there may be differences in individual genetic susceptibility.Studies have shown that carcinogen-metabolizing enzymes gene polymorphisms are important foundation to decide the individual genetic susceptibility.Uridine diphosphate glucuronosyltransferase (UGT) are important phaseⅡmetabolic enzymes in the human body,it can catalyze a large class of exogenous toxins,such as -OH,-SH,-COOH,-NH2 groups.The UGT gene polymorphisms may affect its metabolic activity.In vitro cell experiments,the UGT1A7 enzymes which are encoded by the variant genes can decrease the metabolism activity to 3-,7-,9- hydroxy Benzopyrene,which are strong carcinogens in cigarettes.Thus,we guess that the UGT1A7 polymorphisms may be associated with the bladder cancer.Some reports have showed that UGT1A7 gene polymorphisms were associated with the susceptibility of gastrointestinal cancer,hepatocellular carcinoma,throat cancer,lung cancer,but there are no reports about the association with the susceptibility of bladder cancer.Therefore,the purpose of this study is to explore the association between the UGT1A7 gene polymorphisms and bladder cancer susceptibility.Materials and MethodsSubjectsThe study design was approved by the Committee on Human Research of Zhengzhou University.The study population consisted of a series of bladder cancer patients and non-cancer controls admitted to the department of urology,the first affiliated hospital of Zhengzhou University and the department of urology from January of 2006 to august of 2008.The study subjects gave informed consent prior to participation in the study.Patients who were diagnosed as incident bladder cancer cases with histopathological confirmation,and from whom a peripheral blood sample was drawn and selected as cases.Controls who were individuals with no present or previous history of bladder cancer or other tumors were simultaneously recruited in the same hospitals.The two groups were collected from Han ethnic population in Henan province.The rate distribution of age,gender in two groups is balanced,and they were comparable with each other.Epidemiological investigationInformation on demographic characteristics,education,marital status,family history of bladder cancer in the first and second relatives,occupational exposure history,life style including tobacco smoking,were collected by trained interviewers using a structured questionnaire.GenotypingGenotyping of UGT1A7 variants was conducted by the semi-nested polymerase chian reaction(SN-PCR) and allele-specific polymerase chian reaction(AS-PCR). PCR products were detected by agarose gel electrophoresis.Alleles and genotypes were defined by fragments in agarose gel.Statistical analysisStatistical analysis was conducted using the package SPSS 14.0 for Windows. Chi-square was used to compare the distribution of genotypes and single alles in cases and controls.The association between smoking factors and bladder cancer was studied by unconditional logistic regressive analysis.An odds(OR) and 95% confidence interveral(95%CI) were also caculated,P-value＜0.05.Results1 The Detection of UGT1A7 genetic equilibriumThe distribution of the UGT1A7 allele frequencies among control subjects was in Hardy-Weinberg equilibrium.2 Association between UGT1A7 genotypes or alleles and susceptibility of bladder cancerThe frequency of variant homozygous genotype in cases(20.7%) was higher than that in controls(12.2%),and the difference was statistically significant[P＜0.05, OR=2.16(1.18- 3.96)].The frequencies of ~* 1,~* 2,~* 3,~* 4 allele in cases were 52.9%,18.5%,27.9%, 0.7%respectively,while the frequencies of ~* 1,~* 2,~* 3,~* 4 allele in controls were 60.7%,18.0%,20.5%,0.8%.The frequency of the variant allele ~*3 in cases was higher that in controls(27.9%and 20.5%,respectively),and the difference was statistically significant[P=0.009,OR=1.56(95%CI:1.12-2.18)].3 Smoking factor and bladder cancerCompared with the nonsmokers,smokers have a higher risk to bladder cancer, which is 2.20 times as high as nonsmokers.(OR =2.20,95%CI:1.47-3.28).4 Interaction of UGT1A7 genotypes and smoking fator to susceptibility of bladder cancerThe smokers with variant homozygous genotypes or variant heterozygous genotypes showed increased risk of bladder cancer compared with those with wild genotype[2.16(95%CI:1.07-4.36) and 2.64(95%CI:1.02-6.80),respectively].The nosmokers with variant homozygous genotypes or variant heterozygous genotypes have no significant difference with wild genotypes(P＞0.05).It Indicates that the gene polymorphisms and smoking behavior have interaction in the occurrence of bladder cancer process.5 UGT1A7 genotypes and phymatology character of bladder cancerFor the UGT1A7 genotypes,there was no association between the UGT1A7 polymorphisms and pathological grade and clinical stage of bladder cancer.Conclusions1.The genetic polymorphisms of UGT1A7 are associated with the susceptibility of bladder cancer,it can increase the bladder cancer risk.2.The UGT1A7 gene polymorphisms and smoking behavior have interaction in the occurrence of bladder cancer process,the variant genotypes can increase the bladder cancer risk of smokers.3.There is no association between the UGT1A7 polymorphisms and pathological grade and clinical stage of bladder cancer.