| Genetic susceptibility of tumors has been becoming hotspot for many years. The tumorigenic process was commonly determined by the interaction between susceptive tumor genes and environmental factors. In our previous study, we found that many malignant tumor tissues had high expression of peptidylarginine deiminase 4(PADI4). PADI4, as a post-translational enzyme, could convert arginine residue to citrulline residue at the presence of Ca ion. The molecular structure of substrate proteins was changed following citrullination, which leads to alternation of activity. Recent studies of others suggest that PADI4 repressed expression of p53-regulated genes via citrullination of histones at gene promoters. Therefore, PADI4 played a very important role in tumorigenesis. Considering the relation of PADI4 and the process of tumorigenosis, we suggest that genetic polymorphism of PADI4 may produce significant effect on the expression, structure or functions of PADI4. Until now, there were no study on PADI4 polymorphism and tumors. In the study of our group, we genoptyped 74 SNPs of PADI4 using DNA microassay. We had found that several SNPs were significantly correlated with colorectal cancer, esophageal cancer, and breast cancer. In this study, we genotyped four tagSNPs, rs1886302, rs2477131, rs1635561 and rs1635567 with large samples to investigate the potential correlation between PADI4 gene and colorectal cancer, esophageal cancer and breast cancer.OBJECTIVE: The present study investigated the susceptibility of PADI4 to tumors including colorectal cancer, esophageal cancer and breast cancer. METHODS: A case-control study was applied in this study. We analyzed 515 patients with colorectal cancer (female 179, mean age 55.93±12.04), 707 patients with esophageal cancer (female 224, mean age 52.29±11.79) and 191 patients with breast cancer (all female, mean age 47.80±10.43). 549 health (female 192, mean age 46.44±12.96) was applied as controls for colorectal cancer and esophageal cancer, and 329 female health control (mean age 44.89±13.47) for breast cancer. coding SNP, regulating SNP on gene's 3'and 5' regulating region and SNPs on the boundary of exons and introns (within 1000bp of upstream or downstream) were initially selected in database of the international HapMap project for DNA chips. Genomic DNA was extracted from peripheral blood leukocytes of each subject with Omega E-Z 96 Blood DNA Kit. Based on our DNA chip results, we continued to genotype 4 tagSNP, rs1886302, rs2477131, rs1635561 and rs1635567 to confirm the association to the tumors. All the data of SNP were analyzed by the association analysis based on alleles and genotypes. OR and 95% confidence intervals (CIs) were computed by the unconditional logistic regression to estimate the relative risk for the single locus genotypes by SPSS11.5 software. Haplotype frequencies were assessed for difference in haplotype distributions between cases and controls by Haploview 4.0 and SPSS11.5 software.RESULTS: 1) Epidemiologic data analysis: there were no significant difference of age distribution and sex proportion between colorectal cancer, esophageal cancer and breast cancer group and theirs control group. 2) H-W analysis: Goodness—of—fit Chi—square test was used to calculate the genetic equilibrium of cases and control. rs1635567 was not consistent with Hardy-Weinberg Law in colorectal cancer, esophageal cancer and breast cancer group and theirs control group (P<0.05). The other three SNPs were in Hardy-Weinberg equilibrium in case group and control group (P>0.05). 3) SNP Allele analysis: The difference was significant between the allele frequency distribution of rs1886302 in colorectal cancer patients and health controls (P=0.036). However, the result was not consistent in esophageal cancer and corresponding health control (P>0.05). And the allele frequency distribution of rs2477131 and rs1635561 in colorectal cancer, esophageal cancer breast cancer group and theirs corresponding control group has no significant difference (P>0.05). 4) SNP genotype analysis: The genotypes distributions of rs1886302 was statistically different in dominant mode between colorectal cancer patients and health controls (p=0.040, OR=0.754). AA genotype may take protective effect on the susceptibility of colorectal cancer. Genotypes distributions of rs2477131 and rs1635561 were not statistically different between colorectal cancer, esophageal cancer breast cancer group and theirs control group in three hereditary mode (P>0.05). 5) Haplotype analysis: rs1886302 was in close linkage with rs2477131, and made up three haplotypes, AA, GA and GG. There is no any positive halotype with colorectal cancer or esophageal cancer. 6) Genotype and sex association analysis: Among these three SNPs, genotype frequency of rs1886302 was significantly different between male and female in cohort of colorectal cancer patients (P<0.05). Genotype frequency of rs2477131 and rs1635561's did not show sex difference in cohort of patients with colorectal cancer and patients with esophageal cancer.CONCLUSION: Based on the above description, we found that rs2477131 and rs1635561 were not correlated with colorectal cancer esophageal cancer and breast cancer. On the other hand, rs1886302 was susceptibility to colorectal cancer. A allele or AA genotype of the SNP also take protective effect on colorectal cancer, and its genotype frequencies were significantly different between male and female in colorectal cancer patients. Thus, we suggest that genetic variation of PADI4 can influence the tumorigenic process of colorectal cancer.
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