| BackgroudDigestive system cancer is one of the most important causes of death in our country. The most common are esophageal cancer, gastric cancer and colorectal cancer, in2008the total incidence of the three cancers accounted for one third of the total cancer incidence. Gastric cancer had the highest prevalence in the past five years. The numbers of esophagus, stomach, and colorectal cancer cases in2005were235,000,429,000and201,000, respectively, occupying a proportion of33.5%in all cancer’s incidence; the numbers of death cases were1,910,000,320,000and102,000, occupying a proportion of34.1%in all cancer’s mortality. The mobility and mortality of colorectal cancer had increased significantly than in the past, but they had declined in gastric cancer and esophagus cancer.Most risk factors accounted for the incidence of the digestive system cancer, including bad life style, diet custom, local and systemic related diseases, drugs, genetic factors and so on. Smoking, alcohol consumption are risk factors for many cancers, compared to less than10cigarettes per day, the risk for cardiac carcinoma increased to2.386times when more than30cigarettes per day. Eating disorders, bad eating posture and heavy taste are risk factors for cardiac cancer. Regular consumption of nuts and dried vegetables, pickled foods, fried foods, hot food and moldy food can increased risk of cardiac cancer, but legumes are protective factors for cardiac cancer. High protein and high fat food are risk factors for colon cancer. Vegetables which contains lots of fiber has protective effects for colon cancer. Garlic is protective factor for gastric cancer and esophageal cancer. Gastroesophageal reflux disease is a risk factor for cardiac cancer. Helicobacter pylori infection is prone to tend gastric cancer. The history of more than10years of ulcerative colitis and colorectal polyps increase the risk of colorectal cancer. Primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma (CCA).7%-20%PSC patients will eventually develop to CCA,0.6%-1.5%PSC patients will eventually develop to CCA per year. Gallbladder adenoma history, adenomyomatosis of gallbladder, congenital bile duct anomalies, porcelain gallbladder, bacterial infection and primary sclerosing cholangitis are risk factors for gallbladder cancer. Negative life events, such as the death of loved ones, family discord, job frustration and tight relationships, etc., could easily lead to mental depression. The menopause age (51to55years), cumulative time of menstrual (>30years) and number of births (>three times) are risk factors for gallbladder in women. Nitroglycerin, calcium channel blockers, antidepressants, anticholinergics, β-adrenergic receptor agonists, aminophylline and benzodiazepines can relax lower esophageal sphincter and lead to gastroesophageal reflux disease, increase the incidence of esophageal and gastroesophageal junction adenocarcinoma. The study has shown that the patients with CYP1A1G/G genotype or GSTM1(-) genotype have an increased incidence of gastric cancer.S N P refers to a DNA sequence polymorphism due to mutation of single nucleotide in the genome level, about one variation in every1000base. Individuals with some SNPs may not show abnormalities in general environment, but under some specific conditions, individuals will show susceptibility to certain diseases, since the structure of gene influencing the functions.Angiotensin converting enzyme (ACE) which is an important part of renin-angiotensin system (RAS) plays an important role in maintaining the balance of the circulatory system. The human ACE gene is located on chromosome17q23, the polymorphism is characterized by the presence or absence of a287-bp Alu repetitive sequence, which results in three genotypes:II, DI and DD. Insertion (I) or deletion (D) polymorphism of ACE gene has functional relevance, since the carriers of D allele have higher ACE activity. Numerous studies indicated that there were association between angiotensin-converting enzyme and tumors. ACE is differentially expressed in several malignancies and influences tumor cell proliferation, tumor cell migration, angiogenesis, and metastatic behavior. Epidemiologic studies have also indicated that ACE inhibitors might decrease the risk and mortality rate of cancers. Recent years, many studies investigated the role of this polymorphism in the etiology of digestive system cancer. However, the observed associations of these studies were inconsistent. Are the different results due to random factors, or the different disease susceptibility in the same gene locus by the inherent differences in the population, or the site itself is not the causative genes but in linkage disequilibrium state with pathogenic gene, and thus due to the inconsistency of genetic model in different populations between the detection sites and pathogenic locus? Meta-analysis can be an effective solution for sample size that has lower statistical efficiency by merging data that have the same disease phenotype in the same locus. In addition, meta-analysis can find source of heterogeneity between studies that could provide guidance for future analysis of large sample. ObjectiveTo systematically evaluate the association between the polymorphism of angiotensin converting enzyme gene and digestive system cancer, so as to provide a more comprehensive and reliable theoretical and clinical basis.Methods1.According to the requisition of systematic evaluation, we formulate detailed standardization of the inclusion and exclusion criteria including type of research, genotype data available, gene frequency distributions in the control group meets Wendy-Harberger equilibrium (HWE).2.Litertature were identified by searching Pubmed, Web of Science, Medline database, Chinese Biomedical database(CBM), last search was updated on Sep1st,2013. The following search terms were used:’digestive system neoplasms or digestive cancer or biliary tract neoplasms or liver neoplasms or pancreatic neoplasms or esophageal neoplasms or stomach neoplasms or intestinal neoplasms’ and’peptidyl-dipeptidase A or angiotensin-converting enzyme or ACE’in combination with ’polymorphism, genetic or polymorphism, single nucleotide or variant or mutation’. The search was limited to English and Chinese language papers.3. For each case-control study, the HWE of genotypes in the control group was assessed by using Person’s X2test. The significance of the pooled OR was determined by the Z-test and P value less than0.05was considered as statistically significant. Heterogeneity among studies was assessed by a X2based Q-and I2-statistic. Heterogeneity was considered significant for P value less than0.10. When the P value of heterogeneity was greater than0.10, the fixed-effects model was used, otherwise, the random-effects model was used. To evaluate the ethnicity-specific, cancer type-specific effects, subgroup analyses were performed. Publication bias was assessed by using Begg’s funnel plots and Egger’s test. Sensitivity analysis was performed to assess the stability of the results by sequentially excluding each study. HWE analysis by online software (http://ihg.gsf.de/cgi-bin/hw/hwal.pl). All of the other analyses were performed using the software Revman5.2and STATA12.0.Results1. Description of general characteristics of the enrolled studies.15articles published met our inclusion criteria about the association between angiotensin converting enzyme gene polymorphism and digestive system cancer. Among the included studies, eight studies were European races, seven studies were Asian races. Most of the studies were about gastric cancer and colorectal cancer. All of the studies were genotyped by polymerase chain reaction assay (PCR).15studies were case-control study, containing a total of2390cases and9706controls. The minimum sample size of the case group was30and the maximum is582, the minimum sample size of the control group was30and the maximum is6015.2. Meta-analysis for all of the studiesA total of15case-control studies explored the association between angiotensin-converting enzyme gene polymorphism and digestive system cancer. For DD+DI vs. Ⅱ model, the test of heterogeneity showed that there was statistical heterogeneity among studies included in the Meta-analysis (P=0.0003, I2=65%), the combined OR by the meta-analysis showed that there no statistical significance (OR=0.93,95%CI=0.75-1.16, P=0.53);For DI vs. Ⅱ model, the test of heterogeneity showed that there was statistical heterogeneity among studies included in the Meta-analysis (P<0.00001,I2=81%) the combined OR by the meta-analysis showed that there no statistical significance (OR=0.82,95%CI=0.60-1.11, P=0.19);For DD vs. Ⅱ model, the test of heterogeneity showed that there was statistical heterogeneity among studies included in the Meta-analysis (P<0.00001,I2=72%), the combined OR by the meta-analysis showed that there no statistical significance (OR=0.84,95%CI=0.60-1.16, P=0.29);For DD vs. DI+Ⅱ model, the test of heterogeneity showed that there was statistical heterogeneity among studies included in the Meta-analysis (P<0.00001, I2=74%), the combined OR by the meta-analysis showed that there no statistical significance (OR=0.89,95%CI=0.67-1.17, P=0.40)3. Meta-analysis for subgroup7case-control studies explored the association between angiotensin-converting enzyme gene polymorphism and digestive system cancer(Asian subgroups). For DD+DI vs. Ⅱ model, the test of heterogeneity showed that there no statistical heterogeneity among studies included in the Meta-analysis (P=0.13, I2=40%), the combined OR by the meta-analysis showed that there no statistical significance (OR=1.03,95%CI=0.84-1.25, P=0.79);8case-control studies explored the association between angiotensin-converting enzyme gene polymorphism and digestive system cancer(European subgroups). For DD+DI vs. Ⅱ model, the test of heterogeneity showed that there was statistical heterogeneity among studies included in the Meta-analysis (P=0.0002, I2=76%), the combined OR by the meta-analysis showed that there no statistical significance (OR=0.57,95%CI=0.57-1.35, P=0.54);6case-control studies explored the association between angiotensin-converting enzyme gene polymorphism and gastric cancer subgroup. For DD+DI vs. Ⅱ model, the test of heterogeneity showed that there was statistical heterogeneity among studies included in the Meta-analysis (P=0.03, I2=61%), the combined OR by the meta-analysis showed that there no statistical significance (OR=1.17,95%CI=0.88-1.56, P=0.27);6case-control studies explored the association between angiotensin-converting enzyme gene polymorphism and colorectal cancer subgroup. For DD+DI vs. Ⅱ model, the test of heterogeneity showed that there was statistical heterogeneity among studies included in the Meta-analysis (P=0.05, I2=56%), the combined OR by the meta-analysis showed that there no statistical significance (OR=0.82,95%CI=0.58-1.15, P=0.25)ConclusionThere no significant associations between angiotensin-converting enzyme gene polymorphism and digestive system cancer for all models, including dominant model, recessive model, codominant model and four subgroups of dominant model (Asian subgroup, European subgroup, gastric cancer subgroup, colorectal cancer subgroup).In consideration of quantity, sample size, and heterogeneity of the study, we should interpret the results carefully. |
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