A Molecular Epidemiological Study On The Association Between Functional Polymorphisms Of IGFBP3 And The Susceptibility To Gastric Cancer

Insulin-like growth factors(IGFs)play a crucial role in regulating cell proliferation,differentiation and apoptosis.More than 90 percent of the circulating IGF-â… is bound to insulin-like growth factor binding protein-3 (IGFBP3),which regulates the biologic activity of IGF-â… .It was reported that IGFBP3 be related to individual's cancer susceptibility dependent or independent of IGF-â… .Epidemiological studies revealed that IGFBP3 may have a protective effect by preventing the formation of gastric pre-malignancy.Recent studies also stated that circulating concentrations of IGFBP3 were linked to its genetic variances(A-202C and Gly32Ala). In the present study,we hypothesized that the above two functional polymorphisms(A-202C and Gly32Ala)in IGFBP3 were associated with gastric cancer susceptibility.【Objective】To study the distribution of two polymorphisms of IGFBP3(A-202C and Gly32Ala)in gastric cancer cases and cancer-free controls and to investigate the association between variant genotypes of IGFBP3 and individual's susceptibility to gastric cancer.【Methods】A case-control study was conducted in Jiangsu Province of China,with histologically confirmed gastric cancer cases who were newly diagnosed while controls were selected from cancer-free individuals matched with cases by sex and age.Face-to-face interviews were conducted by the trained interviewers using a structured questionnaire and blood samples were collected with informed consent. Polymerase Chain Reaction(PCR)and Restriction Fragment Length Polymorphism(RFLP)methods were used to measure polymorphisms of IGFBP3(A-202C and Gly32Ala);enzyme-linked immunosorbent assay (ELISA)was used to detect IgG antibodies to Helicobacter pylori(H. pylori)infection.Chi-squal test and logistic regression model were used to measure the associations between IGFBP3 variants and gastric cancer risk.【Results】Totally,576 gastric cancer cases and 647 cancer-free controls were involved in the final analyses.No significant difference was found in the distribution of smoking status and alcohol consumption between cases and controls.H.pylori infection status was significantly elevated in controls(61.6%)than that in cases(52.7%)(P = 0.010).The frequency of genotype AA,AC and CC for IGFBP3 A202C were 61.3%,33.3%and 5.4%in cases and 64.8%,30.8%and 4.5%in controls respectively.No significant difference in the distribution of IGFBP3 A202C genotypes was found between cases and controls(P= 0.424).The genotype frequencies of Gly/Gly,Gly/Ala and Ala/Ala for IGFBP3 Gly32Ala were 42.9%,49.0%and 8.2%in the case patients and 58.7%,36.6%and 4.6%in the control participants,and the difference was statistically significant(P＜0.001).After adjusted by potential confounders,compared to Gly/Gly genotype,individuals carrying Gly/Ala heterozygote and Ala/Ala variant homozygote had an increased risk for gastric cancer with adjusted OR at 1.84(95%CI = 1.45-2.33)and 2.39(95%CI = 1.47-3.90)respectively.Subjects carrying the combined variant genotypes of 32Gly/Ala and 32Ala/Ala were associated with a significantly 3.24-fold increased risk for gastric cancer(adjusted OR = 3.24,95%CI = 2.34-4.49)while they also carry the wild-type -202AA genotype,but inversely with a 21% decreased risk(adjusted OR = 0.79;95%CI = 0.69-0.90),when they simultaneously carry the variant -202AC or -202CC genotypes.A remarkable locus-locus interaction was observed between IGFBP3 Gly32Ala and A-202C loci on gastric cancer risk(P_int＜0.001).The IGFBP3(Gly32Ala)was LD with(A-202C)(r²= 0.349,D' = 0.748).Haplotype analysis showed that compared to the most frequent genotype(Gly/A),the haplotype(Gly/C)was associated with the decrease risk of gastric cancer,but not statistical significant(OR = 0.69, 95%CI = 0.45-1.04).Haplotypes Ala/A and Ala/C would significantly decrease the risk of gastric cancer(OR = 0.38,95%CI = 0.29-0.50;OR = 0.79,95%CI = 0.64-0.98,respectively).【Conclusion】Functional variant of IGFBP3(Gly32Ala)was important marker for gastric cancer susceptibility and further studies are warranted to characterize the functional relevance of the locus-locus interaction of this gene. 【Objects】Insulin-like growth factor binding protein 3(IGFBP3)plays an important role in carcinogenesis.This study aims to explore the association among circulating levels of IGFBP3,functional polymorphisms and cancer susceptibility by using a meta-analysis.【Method】A literature search was performed using PubMed and CNKI databases.Fixed effect model and random effect models were used to calculate the combined odds ratios(ORs)and 95%confidence intervals (95%CIs)according to the level of heterogeneity.Egger's test was used to detect the potential publication bias.【Results】Eighty-one published studies were available for this meta-analysis,including 60 studies on the association between phenotype (circulating levels of IGFBP3)and cancer risk with 13,719 cases and 25,763 controls and 18 studies on the association between genotypes (SNPs,single nucleotide polymorphisms)and cancer risk with 23,435 cases and 31,039 controls.Five studies were eligible for genotype-phenotype correlation study.It was shown that higher levels of IGFBP3 were non-significantly associated with cancer risks in the random model[odd ratios(OR)= 1.02, 95%confidence interval(95%CI)= 0.91-1.15].However,it could predict pre-menopausal breast cancer risk(OR = 1.41,95%CI = 1.03-1.94).In addition,higher IGFBP3 concentrations significantly decreased advanced prostate cancer risk(Stage "C or D")(OR = 0.47,95%CI = 0.27-0.79). 0.27-0.79).Two confirmed functional polymorphisms of IGFBP3 were non-significantly associated with cancer risk[Dominant model,OR = 1.03,95%CI = 0.97-1.10)and 1.15(95%CI = 0.82-1.43);Recessive model,OR = 1.02(95%CI = 0.97-1.06)and 1.12(95%CI = 0.85-1.49), respectively].Remarkably,for IGFBP3 A-202C,variant homozygote -202CC was associated with increased risk of prostate cancer[CC vs AA: OR=1.18,(95%CI = 0.99-1.41)].We found that the circulating levels of IGFBP3 could be influenced by its promoter polymorphism(A-202C).Compared to the variant homozygote -202CC,the wild homozygote -202AA was associated with the higher circulating levels of IGFBP3(AA vs CC:Weight Mean Difference(WMD)= 545.97ng/ml,95%CI = 412.38-679.56,P＜0.001).【Conclusion】Circulating levels of IGFBP3 could be predicted by the functional polymorphism A-202C.Higher circulating levels of IGFBP3 were associated with increased pre-menopausal breast cancer risk whereas decreased early stage prostate cancer risk.