| BackgroundCholecystolithiasis is a common digestive system and is an important public health problem worldwide.In recent years,with the improvement of people's living standards,diet and life behavior changes,the incidence of cholecystolithiasis(especially cholesterol gallstone)in our population is increasing.The occurrence and development of cholesterol gallstone is closely related to heredity,environmental factors and levels of hormones(estrogen,leptin,etc.).Persistent organochlorine pollutants in the environment,such as organochlorine pesticides(OCPs)DDTs and HCHs,interfere with the normal process of estrogen metabolism and function.In addition,studies have shown that OCPs can also affect the expression of leptin in adipocytes,whereas the G>A mutation in the 2548 locus of the leptin gene promoter region can change the gene transcription rate from the transcriptional level and also affect the secretion of leptin in adipocytes.Coupled with a large number of population and animal studies have shown that cholesterol gallstone is closely related to the level of leptin in the body,then any can interfere with the level of body leptin secretion of genetic or environmental factors may affect the risk of cholesterol gallstone and may be an opportunity for us to understand the pathogenesis of cholesterol gallstone disease.Therefore,based on the above reasons,this study used 1:2 matched case-control study method,from the perspective of environmental and genetic factors,and combined with the questionnaire survey information to explore whether the interaction of gene-OCPs were associated with cholesterol gallstone.ObjectivesTo evaluate the relationship between SNP of G2548A gene and related factors and the risk of gallstone cholesterol;To compare the exposure levels of 8 OCPs DDTs and HCHs homologues and to assess the risk of gallstone cholesterol;Comprehensive study of interactions between leptin gene G2548A polymorphism and 8 OCPs DDTs and HCHs homologues exposure effect on cholesterol gallstone occurrence,in order to strengthen the understanding of the pathogenesis of gallstone,provide data support and theoretical basis for the prediction and prevention of cholesterol gallstone.Methods1.According to the inclusion of exclusion criteria,selected from March 2015 to February 2016 in Xiamen City,the second hospital surgical and physical examination section of 600 patients.Cases and controls were matched by gender and age for 1:2.Using the questionnaire to collect the survey of the general situation,lifestyle and eating habits.All subjects were fasting venous blood for gene polymorphism,serum leptin level.All cases were qualitative components of the stones after cholecystectomy.The multivariate conditional logistic regression model was used to investigate the effect of G2548A polymorphism of leptin gene and the related factors on the risk of cholesterol gallstone.2.Based on the first chapter,the levels of trace OCPs and their derivatives were measured by gas chromatography(GC-ECD)and related pre-treatment.Multivariate conditional logistic regression was used to assess the effect of OCPs exposure on the risk of gallstone cholesterol.3.On the basis of the first two chapters,multi factor dimensionality reduction method(MDR)combined with logistic regression model was used to study the relationship between the interaction of the OCPs exposure and polymorphism of G2548A gene with the susceptibility of cholesterol gallstone.Results1.(1)Single factor conditional Logistic regression showed that BMI;SBP;DBP;serum leptin level,drinking habits,smoking,exercise habits and eating greasy intake frequency in the two groups had significant differences(P<0.1),family history of gallstones between the two groups almost had statistical significance(P=0.105).(2)The leptin gene G2548A locus Genotype GG(52),mutant heterozygous GA(192)and mutant homozygous AA(356)were obtained by genotyping by HRM genotyping.The level of serum leptin in different genotype carriers was different,and the level of leptin in AA genotype carriers was higher than that in GA/GG genotype carriers(H=6.83,P<0.05).(3)Multivariate regression model showed that high SBP(OR=1.927,95%CI:1.140?3.255),high serum leptin levels(OR=5.012,95%CI:3.248?7.734),smoking(OR=1.717,95%CI:1.006-2.928),family history of gallstone(OR=2.984,95%CI:1.329-6.700)and leptin gene G2548A locus AA genotype(OR=2.292,95%CI:1.012-5.193)are susceptible to gallstone occurrence factors,and insist on physical exercise and drink(OR=0.591,95%CI:0.395-0.882)tea habit(OR=0.552,95%CI:0.336-0.907)are protective factor for occurrence of cholesterol gallstone.2.(1)Eight kinds of HCHs and DDTs homologues were detected in both groups.The difference of ?-HCH,?-HCH and p,p'-DDT between the two groups was statistically significant(P<0.05).(2)The Sperarman correlation analysis was performed both serum DDTs and HCHs of two groups.In serum,?-HCH shows positive correlation with?-HCH,?-HCH and ?-HCH.?-HCH shows positive correlation with?-HCH and ?-HCH.?-HCH shows positive correlation with ?-HCH;??-DDT shows negative correlation with o?-DDT and ??-DDE.o?-DDT shows negative correlation with o?-DDE.(3)Multivariate conditional logistic regression model results show that serum ?-HCH(OR=1.260 95%C1:1.119-1.418),?-HCH(OR=1.096,95%CI:1.001-1.201)and ??-DDT(OR=2.651,95%C1:,1.702-4.129)high exposure may increase the risk of cholesterol gallstone.3.(1)Multiple linear regression analysis showed that serum ?-HCH and ?-HCH exposure were associated with serum leptin levels,and with the increase of the concentration of these two levels,serum leptin level showed an increasing trend(P<0.1).(2)Using MDR assessment of gene-environment interactions,the results showed that leptin gene G2548A genotype AA-?-HCH-p,p '-DDT-o'-DDT-P,P,p '-p'-DDE-o,p-DDE optimal six factor interaction model of "high risk" group was 8.554 times the risk of cholesterol gallstone in the above-mentioned combination group of "low risk",the difference between two groups was statistically significant(P<0.001).(3)The logistic regression model was further used to assess the risk of gene-environment interactions on gallstones.The results showed that the risk of carrying AA genotype and serum high p,p'-DDE exposure was 2.645 times for patients with low exposure of p'-DDE and carrying GA/GG genotype.There was a statistically significant reciprocal interaction based on the multiplication model(P<0.01);The risk of exposure to AA genotype was higher than that of the control group(P<0.01).The risk of exposure to AA genotype was higher than that of GA/GG genotype(95%CI:2.451?8.453).There was a significant negative correlation between the two groups(P<0.01),and there was a statistically significant negative interaction based on the multiplication model(P<0.01);Carrying AA genotype and high serum DDT exposure in patients with cholesterol gallstone risk is 4.552 times the low serum DDT expose and carrying GA/GG genotype,and here was a statistically significant negative interaction(P<0.01)based on the multiplicative model.Conclusions1.Leptin gene promoter region 2548 G>A polymorphism may affect the expression of leptin gene and the level of circulating leptin from transcriptional level,promote the occurrence of cholesterol gallstone,so that AA genotype carriers are susceptible to cholesterol gallstone disease.2.Eight kinds of HCHs and DDTs homologues were detected in the serum of the case group and the control group,and the detection level was much higher than that of the developed countries,which indicated that there was still a high level of organochlorine pesticide residues in the Xiamen area.3.High levels of serum p,p'-DDT,?-HCH,and 8-HCH exposure may be important independent risk factors for cholesterol stones.4.Carrying the leptin gene G2548A locus AA homozygous mutation of high levels of OCPs exposure is high risk population of cholesterol gallstones,there is interaction between the multiplicative model can magnify the risk,should be paid more attention in cholesterol gallstone prevention programs. |
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