Case-Only Study And Meta Analysis On The Relationship Between The XRCC1 Gene Polymorphismand The Risk Of Hepatocellular Carcinoma

Hepatocellular Carcinoma (hereafter referred to as HCC) is one of the most common malignant tumors in the world. Ranking 3rd place on the world's rumor list by morality rate, it has great threat on peoples'health and life.With an HCC incidence rate of 30.3 out of every 100,000 people, China makes one of the countries with high HCC occurrence. Its mortality rate in Guangxi, an HCC high-risk area, is 27.31 out of every 100,000 people, ranking HCC top on the province's rumor list by mortality rate. HCC has short clinical course as well as high morality rate, and there is not yet any effective therapy to extend HCC patients'lives. Therefore, primary and secondary HCC prevention has become an urgent and important public health issue.Pathogeny of HCC is very complicated, as it results from the interactions of genetic and environmental factors and varies by race, region and individual. Previous studies have shown that HCC was mainly caused by infection of virus hepatitis, aflatoxin contamination in food, algal toxin contamination in drinking water, improper living habits such as smoking and drinking, etc. However, even in the HCC high-risk group, only a small part get infected. Genetic polymorphism leads to different susceptibilities of environmental pathogenic factors, and susceptibility genes only have limited pathogenic effect during disease occurrence. Only by combining genetic and specific environmental factors can we explain the mechanism of HCC. After entering human body from the environment, carcinogen develops into ultimate carcinogen by biotransformation under the function of various enzymes, and hence brings out chronic toxic effects on its main target organ; while DNA repair enzyme plays an important role in prevention of genetic mutation. Studies reveal certain relationship between gene polymorphism of many DNA repair enzymes and susceptibility of HCC, Such as X-ray repair cross-complementing (XRCC1), Xeroderma pigmentosum group D(XPD), human 8-oxoguanine glycosylase 1(hOGG1),etc. In the recent years, gene polymorphism of DNA repair enzymes and impacts of gene-environment interactions on HCC occurrence have attracted broad attention, but there hasn't been any final conclusion due to inconsistent research results.This study is based on XRCC1 gene, which participates in base excision repair (BER) of DNA repair pathways, to explore on impacts of interactions between XRCC1 and certain environmental risk factors on HCC occurrence risk with case-only study method, and to discuss the correlation between XRCC1 gene polymorphism and HCC occurrence by conducting synthesis analysis and quantitative combination on documentary study results relevant to XRCC1 gene polymorphism and HCC occurrence with meta analysis method. Part 1 Case-only Study on Interactions between XRCC1 Gene and Specific Environmental Factors during HCC OccurrenceObjective To explore the impacts of interactions between environmental exposure factors and genetic polymorphism in XRCC1 on risk of HCC.Methods The research was designed by a case-only study based on hospitals. Studied cases are the 500 new HCC cases in The First Affiliated Hospital of Guangxi Medical University and The First Affiliated Hospital of Guangxi Traditional Chinese Medical University during June 2007 to December 2010, who agreed to attend the survey, received relevant clinical diagnosis but never accepted chemotherapy and radiation.This study adopts epidemiological questionnaire. Professional surveyors surveyed on various aspects of the research objects, including their basic condition, previous history, personal history, family history, smoking history, drinking history, etc. and collected their physical examination and laboratory examination results. Surveyors collected 4ml peripheral blood of each study subject to conduct the examinations on 5 indexes for HBV diagnosis and Anti-HCV by enzyme-linked immunosorbent assay (ELISA); extracted entire genomic DNA with phenol-chloroform extracting method to detect single nucleotide polymorphism of XRCC1 gene with TaqMan MGB Real-time quantitative polymerase chain reaction (RT-PCR); conducted statistical analysis on the data with the statistical software called"SPSS13.0 for Windows", using binary logistic regression model to analyze gene-environment and gene-gene interactions and indicating relative risk with odds ratio (OR) and its 95% confidence interval (CI).Results (1)General conditions of study subjects: The two groups are divided by wild-type and mutant-type of XRCC1 gene, so differences in their age, gender, nationality and vocation have no statistical significance(P>0.05). (2)Gene-environment interactions: XRCC1-280 and Anti-Hbe have positive multiplicative interaction on HCC occurrence(after adjusting, P=0.047, OR=1.809,95%CI=1.007~3.249);XRCC1-194 and drinking alcohol, multipli- cative interaction on HCC occurrence(after adjusting ,P=0.041,OR=1.496, 95%CI=1.016~2.204); XRCC1-194 and HBsAb have negative multiplicative interaction on HCC occurrence(after adjusting, P=0.045,OR=0.0576, 95%CI= 0.336~0.987). Multiplicative interactions are not found between mutant alleles and smoking, chronic HBV infection, raw-fish eating history, family history,HBeAg, HBcAb, Anti-HCV, AFP, etc. (3) gene-gene interaction: XRCC1 mutant allele had interaction on HCC. When carrying at least one XRCC1-194 (CT / TT) mutant allele and at least one XRCC1-280 (GA / AA) Mutant allele ,it would have 2.595-fold increased risk of HCC (ORadj = 3.595). When carrying at least one XRCC1-194 (CT / TT) mutant allele and at least one XRCC1-399 (GA / AA) mutant allele, it would have 1.790-fold increased risk of HCC (ORadj = 2.790). When carrying at least one XRCC1-280 (GA / AA) mutant allele and at least one XRCC1-399 (GA / AA) mutant allele ,it would have 1.310-fold increased risk of HCC (ORadj = 2.310).Conclusions (1) Carrying XRCC1-194 mutant allele and drinking may have an interaction related with HCC; carrying XRCC1-194 the mutant allele and HbsAb would have an interaction related with HCC.(2) Carrying XRCC1-280 mutant allele and HbeAb may have an interaction related with HCC(3) While carrying XRCC1-194, XRCC1-280 and XRCC1-399 mutant alleles of any two may have multiplied interaction related HCC. Part 2 Meta-Analysis on Relationship between XRCC1 Gene Polymorphisms and Susceptibility to Hepatocellular CarcinomaObjective To explore the XRCC1 gene polymorphism and susceptibility to hepatocellular carcinoma.Methods To obtain case-control study information about XRCC1 gene poly- morphisms and hepatocellular carcinoma occurrence risk by searching English databases such as PubMed, Medline and Embase with terms including"hepatocellular carcinoma"(or"HCC"),"XRCC1"(or"X-ray repair cross- comple-menting group 1""genetic polymorphism"(or"SNP"), etc. , and searching Chinese databases such as CNKI, VIP, Wanfang Data and CBM with terms including"ganai","ganxibaoai","ganzhongliu","duotaixing","X xian xiufujiaochahubujiyin 1"in chinese;As for Meta-Analysis, to calculate combined OR value and its 95% CI by conducting combinatorial statistics and heteroge- neity test on the data collected with software Review Manager5.0 and Stata10.0.Results After literature searching and screening, the following information is ultimately selected: for the XRCC1-399, a total of eight articles of independent study, involving 1604 HCC cases and 2185 controls; for the XRCC1-280, three articles, involving 700 cases and 678 controls; and for the XRCC1-194, three articles, involving 663 cases and 761 controls. Meta-Analysis was conducted on the three genotype data by grouping in four genetic models. The pooled OR for XRCC1-399,XRCC1-280 and XRCC1-194 were 0.99(95%CI:0.75~1.31),0.98 (95%CI:0.74~ 1.28) and 0.98 (95%CI:0.79~1.22) in the dominance model.Conclusions XRCC1-199, XRCC1-280 and XRCC1-399 polymorphism may be unrelated to the risk of hepatocellular carcinoma occurrence.