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A Molecular Epidemiological Study on the Association between Functional Polymorphisms of IGFBP3 and the Susceptibility to Gastric Cancer

Author: ChenWenSen
Tutor: ShenHongBing
School: Nanjing Medical University
Course: Epidemiology and Biostatistics,
Keywords: Gastric Cancer Case-control study Risk Factors Molecular Epidemiology Genetic predisposition IGFBP3 Gene polymorphism Meta-analysis
CLC: R735.2
Type: Master's thesis
Year: 2008
Downloads: 120
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Abstract

The first part IGFBP3 functional polymorphism and susceptibility to gastric cancer molecular epidemiology of insulin-like growth factor 1 (IGF-I) in cell proliferation, differentiation and apoptosis plays an important role in the occurrence of tumor. Circulation of more than 90% of the IGF-I and insulin-like growth factor binding protein 3 (IGFBP3) combines its bioavailability by IGFBP3 regulation. IGFBP3 protein of IGF-I by regulating the function or effect of affecting the individual independent cancer risk. Epidemiological studies have shown, IGFBP3 expression levels and prognosis of gastric carcinoma. Studies have shown that, IGFBP3 expression levels under its polymorphism (A-202C and Gly32Ala) adjustment. Therefore speculate IGFBP3 functional polymorphisms may influence gastric carcinogenesis. [Objective] IGFBP3 functional polymorphism (A-202C and Gly32Ala) and susceptibility to gastric cancer, and to explore the potential of gene-environment interactions in gastric carcinogenesis in rats. [Methods] A case - control study design and molecular epidemiological research methods. Case was diagnosed by pathology of patients with new-onset cancer, residing in the same period were selected from local residents without a history of malignancy, with cases by sex and age frequency matched. By PCR-restriction fragment length polymorphism (PCR-RFLP) method for detection of two-locus genotype; using enzyme-linked immunosorbent assay (ELISA) detection of H.pylori antibodies in plasma. Single factor χ ^{2 test and multivariate conditional Logistic regression analysis of environmental, genetic and their interaction in gastric carcinogenesis in rats. Application χ ^{2 test and multivariate conditional Logistic regression model analysis of environmental, genetic and their interaction in gastric carcinogenesis in rats. [Results] Totally 576 cases and 647 cases of patients were included in the analysis found no history of smoking and alcohol consumption and gastric cancer risk related to the control group H.pylori antibody positive rate 61.6%, significantly higher than the case group 52.7% (P = 0.010). IGFBP3 A-202C three genotypes AA, AC and CC in the case group was 61.3 percent, respectively, the frequency distribution, 33.3% and 5.4% in the control group, the distribution of frequencies were 64.8%, 30.8% and 4.5%. Three genotypes in the case group and control group had no significant difference in the distribution (P = 0.424). IGFBP3 Gly32Ala three genotypes Gly / Gly, Gly / Ala and Ala / Ala in case group and the distribution of frequencies were 42.9%, 49.0% and 8.2% in the control group, the distribution of frequencies were 58.7%, 36.6% and 4.6 %. The genotype distribution in both groups were significantly different (P <0.001). After adjustment for potential confounders, with wild homozygous Gly / Gly genotypes, carrying mutant heterozygous Gly / Ala and mutant homozygous Ala / Ala individuals suffering from gastric cancer risk was significantly increased, OR were 1.84 (95 % CI = 1.45-2.33), 2.39 (95% CI = 1.47-3.90). Dominance model study found that those who carry the mutant allele 32Ala will increase the risk of gastric cancer is 90% (OR = 1.90,95% CI = 1.51-2.39). Joint two-point analysis shows that carry the mutant allele 32Ala (Gly / Ala or Ala / Ala) and carrying the wild-type-202AA individuals increased 2.24 times the prevalence of gastric cancer risk (adjusted OR = 3.24,95% CI = 2.34 -4.49). However, the two polymorphic loci are present mutations in individual [(AC CC) and (Gly / Ala Ala / Ala)] the risk of gastric cancer was reduced 21% (adjusted OR = 0.79,95% CI = 0.69-0.90) . Two points there was a significant interaction between (P _int <0.001). The study found that IGFBP3 over two polymorphic sites (Gly32Ala and A-202C) linkage disequilibrium (r ^{2 = 0.349, D '= 0.748). Haplotype analysis showed that the most common Gly / A haplotype as the reference group, carrying Gly / c haplotype individuals reduced risk of gastric cancer, but the difference was not statistically significant (OR = 0.69,95% CI = 0.45-1.04), while carrying Ala / A and Ala / C haplotype risk of stomach cancer was significantly reduced, OR was 0.38 (95% CI = 0.29-0.50) and 0.79 (95% CI = 0.64-0.98) . [Conclusion] IGFBP3 gene polymorphism (Gly32A1a) and gastric cancer genetic susceptibility, and the locus and promoter region polymorphisms A-202C there is a significant interaction. The second part of the insulin-like growth factor binding protein 3 (IGFBP3) and tumor association studies [Objective] Meta-analysis of the literature review in the form of circulating levels of IGFBP3 gene polymorphism and the relationship between malignancy and thus comprehensively evaluate IGFBP3 in tumorigenesis development role. 【Methods】 Chinese journals hand searched PubMed and network databases (CNKI), met the inclusion criteria screening literature. According heterogeneity test results, select a fixed effects model and random effects model combined OR (odds ratio, odds ratio) and its 95% confidence interval (95% confidence interval, 95% CI). And publication bias using the Egger method to estimate. [Results] The total of 81 articles met the inclusion criteria, 60 articles were circulating IGFBP3 levels and cancer association study, a total of 13,719 cases of patients in the control 25,763 cases; 18 literature involving IGFBP3 functional polymorphisms associated with cancer research , totaling 23,435 cases of patients in the control 31,039 cases; 5 literature genotype - phenotype analysis. Random effects model showed that high concentrations of circulation IGFBP3 and cancer risk was no statistically significant association (combined OR = 1.02,95% CI = 0.91-1.15). Subgroup analysis showed that high concentrations of IGFBP3 increase the risk of premenopausal breast cancer (combined OR = 1.41,95% CI = 1.03-1.94), but can be significantly reduced with advanced prostate cancer (Stage \risk (OR = 0.47,95% CI = 0.27-0.79). Merge all tumor types and found no IGFBP3 A-202C, Gly32Ala gene polymorphism and risk of significant association between the presence of [dominant model analysis, the combined OR was 1.03 (95% CI = 0.97-1.10) and 1.15 (95% CI = 0.82-1.43); recessive model analysis, the combined OR was 1.02 (95% CI = 0.97-1.06) and 1.12 (95% CI = 0.85-1.49)]. According to different tumor types subgroup analysis, and IGFBP3-202AA genotype compared carry-202CC genotype may increase the risk of prostate cancer, the combined OR = 1.18 (95% CI = 0.99-1.41). For five involving genotype - phenotype research literature merger analysis, IGFBP3 A202C polymorphism and its circulating levels statistically significant correlation exists between: homozygous type AA individuals, circulating IGFBP3 levels were significantly higher carrying mutations homozygous CC individuals (weighted concentration difference = 545.97 ng / ml, 95% CI = 412.38-679.56), P <0.001). [Conclusion] IGFBP3 promoter polymorphism (A-202C) affect the expression level of the cycle, high levels of circulating IGFBP3 increased risk of premenopausal breast cancer, but it can significantly reduce the risk of advanced prostate cancer incidence.}}}

A Molecular Epidemiological Study on the Association between Functional Polymorphisms of IGFBP3 and the Susceptibility to Gastric Cancer

Abstract

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