Associations Of Genetic Variants In Tachykinins Pathway Genes With Colorectal Cancer Risk

Backgrounds and ObjectivesColorectal cancer, including colon and rectum cancers, is one of the common malignant neoplasm in digestive tract. In2008,over1.2million new cancer cases and608,700deaths estimated to have occurred. Colorectal cancer is the third most commonly diagnosed cancer in males and the second in female. In recent years, the incidence and mortality of colorectal cancer have increased significantly with the rapid development of socio-economic.The pathogenesis of colorectal cancer has not been elucidated completely so far, however, it has been widely acceptedly that it has a multifactorial etiology involving complex interplay of environmental exposures and genetic susceptibility. Environmental exposures including high fat, low dietary fiber diet, obesity, diabetes mellitus, lacks of physical activity, ciggatte smoking, alcohol drinking and tea drinking are associated with the development of colorectal cancer. A great body of basic research showed that tachykinin and their receptors played an important role in the carcinogenesis of colorectal cancer. After binding to the NK-1receptor, SP induces mitogenesis, Neoangiogenesis, invasion and metastasis of tumor cell.We conducted a population-based case-control study to evaluate the relationship between the common variants in tachykinin pathway genes and the risk of colorectal cancer. Additionly, gene-gene interactions were also examed by GMDR.Material and MethodsThis case-control study recruited eligible new patients with histologically confirmed colorectal cancer diagnosed during1st Jan2005to31th Jul2009as cases. Simultaneously, controls those did not have a history of cancer were individually matched with cases by5-year categories, gender and residence. All the participants were ethnic Han Chinese and residents in Jiashan County. As a result,399case-control pairs were formed.After informed consent, all subjects were face-to-face interviewed with a structured questionnaire mainly including demographic characteristics, individual lifestyle (cigarette smoking, alcohol drinking, etc) and family history of cancers by trained interviewers.Selection of single nucleotide polymorphisms (SNPs) were performed by tagSNP approach.The genomic DNA was extracted from peripheral blood sample by modified salting-out procedure.Genotyping for the selected genetic polymorphisms was performed by SNPshot assay. Multiple statistical methods including logistic regression, crossover analysis, multifactor dimensionality reduction (MDR) analysis were applied to explore the major and interactive effects of the genetic polymorphims of tachykinin pathway genes with the risk of colorectal cancer.ResultsThere was no significant difference between the cases and controls in terms of socio-demographic characteristics and lifestyle habits.Among controls, all polymorphisms were conformed to Hardy-Weinberg equilibrium except for the tagSNP TACR1rs3755457(p=0.02).Significant associations were not observed for TAC1as well as TACR2gene, but for three of the tagSNPs in TACR1gene, after adjusting for potential confounders such as age, sex, cigarette smoking, alcohol drinking, tea drinking, physical activity. Compared with those carrying wild-type homozygous genotypes (CC genotype for rs3755457, TT genotype for rs12477554), individuals carrying homozygous viariants for rs3755457and rs12477554were associated with a borderline significant increased risk of colorectal cancer (adjusted OR=1.63,95%CI=0.92-2.89, p=0.096for rs3755457;adjusted OR=1.58,95%CI=0.95-2.61,p=0.076for rsl2477554). Furthermore, when the wild-type homozygous and heterozygous genotypes’were combined as reference group, homozygous viariants TT genotype for rs3755457and CC genotype for rs12477554confered an increased risk to colorectal cancer in the recessive model (adjusted OR=1.80,95%CI=1.03-3.13,p=0.039for rs3755457;adjusted OR=1.73,95%CI=1.07-2.79,p=0.024). For rs10198644, GG genotype was associated with a1.72-fold decreased risk when compared with the common CC genotype (95%CI=0.37-0.88, p=0.011).Furthermore, GG genotype was inversely correlated with colorectal cancer in the recessive model (adjusted OR=0.65,95%CI=0.44-0.94, p=0.024). The TAC1, TACRl and TACRl haplotypes were not associated with the risk of CRC.The best2-locus gene-gene interaction models of the possible SNP combinations include rsl2477554(TACRl) and rs4644560(TACR2), with a testing accuracy of55.20%(CVC=8/10, p=0.0547).Moreover, there was significant interaction between rs4644560in TACR2and rs4644560in TACRl by logistic regression model.ConclusionsThere were three TagSNPs in TACRl associated with colorectal cancer risk. rs3755457and rs12477554are associated with an increased risk of colorectal cancer, whereas rs10198644in TACRl was related to a decreased risk of colorectal cancer. There may exist gene-gene interaction between TACRl and TACRI Further studies with larger sample size are warranted to validate those findings.