| Objective:To investigate the correlation of the single nucleotide polymorphisms and haplotypes of XRCC1 and XPD related to the risk of pancreatic cancer. Methods:A hospital-based case-control design was applied in this study. In brief, a total of 111 patients diagnosed with pancreatic cancer by histopathological confirmation and imaging with long-term follow-up. Cancer-free control subjects consisted of patients from the first affiliated hospital of Xinjiang medical university at the same hospital during the same study period. All the control subjects were frequency-matched to the cases on age (±5 years), gender and nationality. The detailed information on each patient was investigated including the family history of cancer, the smoking and drinking history, demographic information and the history of digestive operation and so on. The genomic DNA was extracted from all peripheral blood samples. Based on genotype data from the international HapMap project, the tagging single nucleotide polymorphisms (tSNPs) initially were selected using haploview 4.0 software. And pairwise linkage disequilibrium values D' and r2 were calculated in the control population using the Maximation likelihood method. Haplotype frequencies were estimated using Phase 2.0 software. The locus of XRCC1 gene including rs25487 (SNP1), rs3213403 (SNP2), rs731420 (SNP3), rs3213282 (SNP4), rs12611088 (SNP5), rs1001581 (SNP6), s1799782 (SNP7) were genotyped by snapshot method and the haplotype distribution was estimated. Aimed at the factors related to pancreatic cancer, univariate and multivariate logistic regression were performed to screen the independent risk factors to pancreatic cancer and interaction between XRCC1 gene and main risk factors was studied. The same way was used in testing the locus of XPD gene including rs13181 (SNP1), rs3916874 (SNP2), rs238415 (SNP3), rs50872 (SNP4), rs50871 (SNP5), rs238406 (SNP6), while the relationship of single nucleotide polymorphisms with genetic susceptibility to pancreatic cancer were investigated. Results:Section one:Univariate and multivariate analysis were performed to examine factors affecting the incidence of pancreatic cancer by Logistic regression model. Eleven factors were included in this study. Univariate analysis showed that smoking and drinking were all significant related factors to pancreatic cancer. Multivariate analysis showed smoking (P=0.022, OR=1.946,95%CI:1.099～3.445) was independent risk factor for pancreatic cancer. Risk of pancreatic cancer was higher in male patients with more than 10 cigarettes daily than in non-smoking patients (P=0.009, OR=1.610,95%CI:1.129～2.296). Female patients with number of births of 1～2,3～4 and more than 5 did not increase the risk of pancreatic cancer (P> 0.05). Morbility of diabetes mellitus within 1 year in case group was higher than in control group (P=0.044). Section two:seven common SNPs of XRCCl genes were chosen to be tagging SNPs. All polymorphisms were in Hardy-weinberg equilibrium both in control and in case groups. The distributions of GA, AA genotypes and A allele of XRCCl SNP1 (SNP rs25487) in case patients were higher than in control subjects and P equals to 0.014,0.023. In the unconditional logistic regression analysis, after adjustment for age, gender and nationality, the SNP rs25487 was significantly associated with an increased risk of pancreatic cancer (GA versus GG:P=0.007, OR=2.510,95% CI:1.309～4.889; AA versus GG:P=0.021, OR=2.468,95% CI:1.110～5.511; GA+AA versus GG:P=0.005,OR=2.508,95% CI: 1.334～4.732). The distributions of CT, TT genotypes and T allele of SNP7 (rs1799782) in case patients were higher than in control subjects, and P equaled to 0.028,0.011 respectively. In the unconditional logistic regression analysis, after adjustment for age, gender and nationality, the SNP rs1799782 was significantly associated with an increased risk of pancreatic cancer (CT versus CC:P=0.015, OR=2.150,95% CI:1.191～3.866; CT+TT versus CC:P=0.010, OR=2.149,95% CI:1.220～3.791), the difference was statistically significant. Individuals carrying TT genotype did not increase risk of pancreatic cancer compared with the wild genotype (TT versus CC:P=0.298, OR=2.160, 95% CI:0.479～9.501).Compared with the haplotype Hapl-AACCTAG, the relationship between Hap4-AGCTTGG and the incidence of pancreatic cancer was positive (P=0.61, OR=1.19,95% CI:0.62～2.28). The haplotype analysis revealed that individuals with Hap4-AGCTTGG have a 0.19-fold excess risk of pancreatic cancer compared with individuals with the Hapl-AACCTAG haplotype, there was no statistically significant difference. Interaction between SNP1 locus and smoking over 10 cigarette per day revealed a increased risk of pancreatic cancer (GA+AA versus GG:P=0.005, adjusted OR=5.480,95% CI:1.563-19.426) as well as SNP7 locus (CT+TT versus CC:P=0.035, adjusted OR=4.012,95% CI:1.041-15.160), the difference was statistically significant. Section three:The distributions of AC, CC genotypes and C allele of XPD/ERCC2 tSNPs(SNP1 rs 13181 A35931C) in case patients were higher than in control subjects and P equals to 0.023,0.003. There were no statistically significant differences between cases and controls in genotype distribution of SNP2, SNP3, SNP4, SNP5 and SNP6 locus. In the unconditional logistic regression analysis, after adjustment for age, gender and nationality, individuals carrying AC genotype had a 1.035-fold increased risk of pancreatic cancer compared with the wild genotype (AC versus AA:P=0.030, OR=2.035, 95% CI:1.121-3.885), individuals carrying AC+CC genotype had a 1.029-fold increased risk of pancreatic cancer compared with the wild genotype (AC+CC versus AA: P=0.007, OR=2.029,95% CI:1.255-3.712), the difference was statistically significant. Those carrying CC genotype also had a increased risk (P=0.051, OR=2.251,95% CI: 1.122-5.017), there were no statistically significant differences. Interaction between SNP1 locus of XPD gene and smoking more than 10 cigarette per day revealed a increased risk of pancreatic cancer (AC+CC versus AA:P=0.033, OR=4.243,95% CI: 1.123-16.857).Conclusion:Smoking is significant independent risk factor for pancreatic cancer. Our study revealed that the polymorphisms of Arg399Gln and Arg194Trp in XRCCl and Lys751Gln in XPD might decrease the DNA repair ability and increase the susceptibility to pancreatic cancer. DNA repair gene XRCCl and XPD might be an important determinative factor for susceptibility to pancreatic cancer.
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