Adiponectin And Leptin Gene Families With Colorectal Cancer

Background:Colorectal cancer (CRC) is a serious malignant tumor threatening human health during worldwide. Along with the development of economy and the improvement of people's living conditions, China has become one of the fastest-growing countries in CRC incidence from a low incidence country. Metabolic syndrome characterized by obesity and insulin resistance caused by western life style and diet model has been identified as a risk factor for CRC, and also the reason for the fast-growing of CRC incidence in our country. Resent researches have demonstrated that adiponkines related with metabolic syndrome may be medium between obesity, insulin resistance and cancer. As important adipokines, Adiponectin and Leptin were thought to participate in regulating energy balance, cell growth, inflammatory reaction, immune response and so on, and associate with the development of obesity, insulin resistance and various tumors. Since the expression of gene was regulated and controlled by genetic factors, our study was aimed to explore the polymorphisms of Adiponenctin and Leptin gene families with the initiation and development of CRC systematically, and examine the gene-gene and gene-environment interactions in the susceptibility of CRC, which could provide evidence for CRC etiology and the screening of high-risk population and identification of patients of CRC.Method:Two-stage case-control study was sued to systematically analyze the role of polymorphisms of Adiponectin and Leptin gene families in the initiation and development of CRC. Sequenome MassARRAY method was used to detect the genotypes of TagSNPs and important functional SNPs of adiponecitn and Leptin gene families in the first case-control study in Wuhan. Logistic regression was used to detect the role of single SNP in the initiation and development of CRC. Logistic regression, Multifactor Dimensionality Reduction (MDR) and Classification and Regression Tree (CART) were used to detect the gene-gene and gene-environment interactions. Taqman OpenArrary method was used to genotype the positive SNPs identified in the first stage in the second case-control study in Beijing. Logistic regression was used to test and verify the role of single SNP, gene-gene and gene-environment interactions.Results:In the analysis of environmental factors, whatever in the first or second case-control study, smoking was identified as a risk factor for CRC, with ORs of 2.10(95%CI=1.57-2.81) and 1.87(95% CI=1.24-2.81), respectively; in the combined population, compared with non-smokers, the OR for smokers was 2.00(95%CI=1.59-2.53). Family history of cancer was also identified as a risk factor for CRC. Compared with individuals without family history of cancer, the ORs for individuals with family history of cancer were 1.51(95%CI=1.07-2.12), 2.90(95%CI=1.60-5.25) and 1.81(95%CI=1.36-2.42) in the first stage, second stage and combined study, respectively. No environmental factor studied was found to influence the development of CRC.In the study on the role of Adiponectin gene family in the initiation and development of CRC, we genotyped and analyzed 27 key SNPs in the first case-control study, during which, ADIPOQ rs1063538 and ADIPOR2 rs2108642 were found to influence the susceptibility of CRC. The carcinogenesis role of ADIPOQ rs1063538 was verified in the second case-control study. In combined population, both ADIPOQ rs1063538 and ADIPOR2 rs2108642 were significantly associated with CRC. Compared with ADIPOQ rs1083538 TT genotype, CC genotype significantly increased CRC risk, with an OR of 1.94(95%CI=1.48-2.54). The ORs for dominant and recessive model were 1.41(95%CI=1.13-1.76) and 1.79(95%CI=1.43-2.25), respectively. In comparison with ADIPOR2 rs2108642 TT genotype, GT or GG genotype significantly decreased CRC risk, with ORs of 0.65(95%CI=0.52-0.81) and 0.60 (95%CI=0.44-0.83), respectively. The OR for dominant model was 0.64(95%CI=0.52-0.78). In two-factor interaction analysis, ADIPOQ rs1063538 interacted with ADIPOR2 rs2108642, and both SNPs existed interactions with smoking status and family history of cancer. In the MDR analysis in the first case-control study, the four-factor model including ADIPOQ rs1063538, ADIPOR2 rs2108642, BMI category and smoking status was the best model. The branches in CART model included ADIPOR2 rs2108642, smoking status, ADIPOQ rs1063538, ADIPOR1 rs1539355, ADIPOR1 rs12045862 and ADIPOR2 rs1044471. The results from Logistic regression, MDR and CART indicated significant interactions among ADIPOQ rs1063538, ADIPOR2 rs2108642 and smoking status. No polymorphism in Adiponectin gene family was found to influence the development of CRC significantly.In the study on the role of Leptin gene family in the initiation and development of CRC, we genotyped and analyzed 25 key SNPs in the first case-control study, during which, none was found to influence the susceptibility of CRC after FDR adjustment. However, LEPR rs12037879 was found to significantly interact with LEPR rs6690625 and smoking status, which was also verified in the second stage. In combined analysis, compared with individuals carrying LEPR rs12037879 GG and LEPR rs6690625 TT genotypes, there was a significant increased CRC risk for individuals carrying rs12037879 AA and rs6690625 GG genotypes (OR=2.26; 95%CI=1.31-3.91). Smokers carrying LEPR rs12037879 GA or AA genotype or A allele had 1.96-fold (95% CI=1.33-2.90),2.95-fold (95% CI=1.14-7.60) and 1.67-fold (95% CI=1.39-2.01) increased CRC risk, respectively, when compared with non-smokers carrying GG genotype. In the MDR analysis in the first stage, the four-factor model including smoking status, BMI category, LEPR rs1171556 and LEPR rs1137100 was the best model. The branches in CART model included smoking status, alcohol use, LEPR rs9436740, LEPR rs12037879, LEPR rs13306519, family history of cancer, BMI category, LEPR rs6657612 and LEPR rs6690625. No polymorphism in Leptin gene family was found significantly associated with the development of CRC.Conclusion:Smoking status and family history of cancer were identified as the important environmental risk factors for the initiation of CRC. ADIPOQ rs1063538 and ADIPOR2 rs2108642 in Adiponectin gene family were found to influence the susceptibility of CRC, and the role was modified by environmental factors, such as smoking status and family history of cancer. The interactions between LEPR rs12037879 and LEPR rs6690625 in Leptin gene family or smoking status also influenced CRC susceptibility. There was no role found in adipnectin or Leptin gene family in the development Of CRC.