Study Of Relevant Risk Factors And Molecular Epidemiology On Polymorphism Of UTS2 Gene In Type 2 Diabetes Pedigrees

Chronic disease is already a dominant risk to human being. Diabetes isat the third rank in fatal chronic diseases following cerebral vessels andtumor. It is more critical to control and prevent diabetes in China,because the increasing rate between 1995 and 2025 will be nearly 68%,according to WHO's prediction, when the raw number of diseaseattackers is nearly to 50 million with 95% type 2 diabetes of them. One ofthe causes is dysfunctional insulin induced singnal pathway. Patients haveinsulin resistance and hyperinsulinemia but have not hyperglycemia onthe early period. The function of compensate is degenerating with thecourse developing, which results to T2DM.There is an agreement that interaction between genetic andenvironment contributes to the adjustment of insulin concentration.Heredity factor is one initial cause to Type 2 diabetes. Researches showthat the attack rate of relatives in families with patients is 4-8 times thanwhose without familial history. Sibling studies prove that T2DM hasmore powerful heredity trend. Therefore, it is naturally to find familialclustering in patients. With the development of molecular biologicaltechnology, protein variation encoded resulted from single nucleotidepolymorphism (SNPs) is probably the internal reason for T2DM.Recent researches show that the combination of Urotensin-â…¡(UTS2) andits receptor probably influeces the insulin induced singal pathway andthere is an association between UTS2 SNPs and T2DM. Therefore, ourhypothesis is to explore the association between relevant risk factorsand multiple SNPs, which has the theoretical guide in evaluation of thetrue risk on the base of assumimg pedigrees and outer controls, analysinggiven risk factors and SNPs and applying PCR-RFLP test. Besides, it ispossible to find out the relevant UTS2 genotypes in Han population insoutheast of China. Partâ… Study on relationship between insulin resistance andrelevant risk factors clustering in T2DMOne of pathophysiological defects of T2DM is insulin resistance.Heredity, age, obesity, body exercises, hypertension and hyperlipid areraleted to T2DM, which show familial clustering. The type 2 diabetespedigrees were collected to study T2DM genetic and environmental riskfactors. A questionnaire and laboratory tests were carried out to get thedetail information of the subjects. Their characteristics and the riskfactors of T2DM were analyzed based on population pedigrees. The mainresults were as follows:1. After getting rid of T1DM, MODY, mitochondria heredity positivepedigrees with immunology method, pedigree analysis and molecularbiology method, 115 eligible pedigrees had been collected, including 510persons, 219 controls had been collected in the meanwhile.2. The percentage (49.3%) is the highest in T2DM group with higher IRI(P₇₅-P₁₀₀), followed by inner control group (16.5%) and by outer control(6.4%) group. The compositive ratio among three groups has statisticalsignificance (X²=243.410, P=0.000).3. The diabetic relevant risk-factor clustering rate is different withdifferent IRI, which has statistical significance. (X_T2DM-Group²=10.105,P=0.018; X_Inner-Group²=26.501, P＜0.0005, X_Outer-Group²=24.787, P＜0.0001).4. The OR of diabetic relevant risk-factor clustering among three groupsincreased with the value of HOMA-IR growing(X_trend²=28.13, 22.53,15.30; P=0.000).5. The mean of insulin secretion in inner-group was higher than bothT2DM group and outer-group(Both P=0.000). Partâ…¡Molecular epidemiology on polymorphism of UTS2gene in type 2 diabetes pedigreesUTS2 is the most potent vasoactive hormone. It has been foundthat SNPs of this gene has association with type 2 diabetes.Constructing the haplotype, selecting tag SNPs and conducting outercases and controls are the main methods in exploring the associationbetween UTS2 variation and T2DM.102 pedigrees from the whole samples were followed during theperiod between 2002 and 2006, 439 samples with 55 IGT and 5 IFGwere enrolled totally, with 170 outer cases and 210 outer controlsassembled. Questionairs and laboratory tests were carried to eachsubject. PCR-RFLP technology and multiple logistic regression wereintroduced in calculating OR and OR95%CI with different genotypes indifferent groups. Differentiation among population with or withoutfamilial history is caculated by PPAP. The results are as follows:1. The distribution in cases and controlsAfter the adjudgement of age, gender, obesity and weight,rs228648(G-A) has positive effection to T2DM, compared with the GGgenotype, carriers with GA, AA or GA/AA genotype has higher risk of71%(adjusted OR=1.71, 95% CI=1.15-2.54), 238%(adjusted OR=3.38,95% CI=2.09-5.46) and 120% (adjusted OR=2.20, 95% CI=1.54-3.15);however, rs2890565TT variant-type was associated with significantlydecreased risk of type 2 diabetes(adjusted OR=0.47, 95% CI=0.27-0.82)carriers with rs228651GG has higher risk to T2DM of 83% (adjustedOR=1.83, 95%CI=1.03-3.24), comparing to whose with rs228651AAgenotype, there is no statistical significance of rs3753499 genotypesdistribution among cases and controls.2. Stratified analysisrs228648 AA variation increases the risk of T2DM to each stratifiedgroups, AA genotype might increase the risk of 260% (95%CI=1.66-7.81)and 231%(95%CI=1.77-6.19) in group with age＜50years and＞50 years; 246%(95%CI=1.64-7.30) to males and 230% tofemales (95%CI=1.77-6.15);3.31 times (95%CI=1.77-6.19)to abdominalobeses and 3.56 times (95%CI=1.64-7.71) to non-abdominal obeses, 4.71times (95%CI=2.31-9.59) to over-weight individuals and 2.63 times(95%CI=1.34-5.19)to normal weight individuals, while GA increases therisk to females, over 50 years old men, non abdominal obeses and normalweight individuals[95%CI are 1.73(1.05-2.85),1.87(1.09-3.22),2.46(1.23-4.90),2.17(1.19-3.94) respectively]. TT decreases the risk tomales, under 50 years old men, abdominal obeses and over weightindividuals[95%CI are 0.22(0.06-0.79),0.42(0.18-0.99),0.47(0.24-0.92),0.36(0.16-0.80) respectively] rs2289651 (A/G) variant genotypeincreased the risk to abdominal obeses and over weight individuals[OR,95%CI are 2.61(1.25-5.45),3.04(1.34-6.92) respectively]. Whereas,rs3753499AA/AG/GG has no such effect to each stratified groups.3. Haplotype of Tag SNPs analysisAnalysis on tagging SNPs (rs228651, rs2890565) shows that comparedwith the most common haplotype GC, the GT and AT were associatedwith a 41% and 45% decreased risk of Type 2 diabetes, respectively[(OR,95%CI are 0.59(0.40-0.87) and 0.55(0.35-0.86)].Carriers with CC,AG/GG and over 50 years men have higher risk of 4.49 times(95%CI=1.09-18.56).4. Analysis between inner cases and inner controlsAfter adjusting for age, gender, abdominal obesity and weight,rs228648AA genotype increases the risk to type 2 diabetes (adjustedOR=2.19, 95%CI=1.08-4.43). No significant results were observed inrs2890565 genotypes, rs228651 genotypes, rs3753499 and insulinindecies among inner cases and outer cases.5. Analysis between inner cases and outer casesAfter adjusting for age, gender, abdominal obesity and weight, the frequency of rs228648GA (40.9%) and rs2890565CT (51.0%)in innercases are higher than those in outer cases (31.0% and 24.8%)(95%CI=1.11-3.37 and 1.32-4.14). Wherears, the frequency ofrs2890565TT (1.5%) and rs3753499AG (3.3%)/GG (8.2%) in inner casesare lower than outer control (22.8%, 11.2% and 22.4%)(95%CI=0.02-0.28, 0.07-0.69 and 0.12-0.60); no significance wasobserved in genotypes distribution ofrs228651 and rs3753499.6. Analysis between inner control and outer controlThe frequency of rs228648 AA in inner control is higher than that ofouter control except rs2890565TT (95%CI=1.42-6.14 and 0.08-0.45). Nosignificant results were found in rs228651 genotypes and rs3753499genotypes.7. Measurement among pedigrees, outer cases and controlsGenetic differention coefficient is 0.221, which means the 2.21%difference among pedigrees; outer cases and controls results from groups'polymorphisms, 97.79% are caused by inner groups' polymorphism.