| BackgroundMetabolic syndrome(MS)is a clustering of some cardioavascular risk factros, including obesity,hypertension,hyperglycemia and dyslipidemia.With the development of society and changes of life style,the prevalence of MS is increased.The pathogenesis of MS is very complex,and it is now considered that MS is caused by genetic and environmental factors.Recently,the role of gene in the pathogenesis of MS attracts more and more attention.TRB3,the mammalian homologue of Drosophila tribbles,has become a 'popular' gene in many medical labs.Studies have found that TRB3 participated in the regulation of glucose and fat metabolism and the differentiation of fat cells.Therefore TRB3 has become a candidate gene contributing to insulin resistance(IR).Recent studies have revealed that TRB3 has a functional polymorphism named 'Q84R' in Caucasian population of Italy,which can inhibit Akt phosphorylation in HepG2 ceils and is also associated with IR and cardiovascular diseases.This is the first study that demonstrated TRB3 relates to human diseases.Based on these results,we bring forward some problems as follows:Is TRB3 a candidate gene for MS? Since the single nucleotide polymorphisms (SNPs)vary widely in different populations and different regions,does TRB3 have SNPs in Chinese Han population residing in Shandong Province? And is TRB3 associated with each component of MS? Nowadays,there are few studies referring to these questions.Therefore, we carried out the present study and tried to find satisfying answers to all the above problems.Objectives1.Genotyping the TRB3 gene polymorphisms by direct sequencing methods in Chinese Han population residing in Shandong Province.2.To investigate the genotypic and allelic distributions of TRB3 in Chinese Han population residing in Shandong Province and determine the association of the TRB3 gene polymorphisms with MS.3.To explore the relationship between the TRB3 gene polymorphisms and individual component of MS.Subjects and methodsIn our study,we recruited 217 consecutive subjects with MS(118 females,52.7±9.0 yr of age)and 200 age- and sex-matched normal subjects(110 females,51.3±9.7 yr of age) without cardiovascular diseases or diabetes mellitus.96 consecutive subjects with simple obesity(51 females,52.4±10.7 yr of age)were also included.All subjects completed a questionnaire on present condition,family and medical histories of cardiovascular risk factors and complications.Height,weight,body mass index(BMI),waist circumference, hip circumference and blood pressure(BP)were measured.Furthermore,fasting blood sample was collected from each subjects after 12-14 hours fast to determine the fasting blood glucose(FBG),insulin,triglycerides(TG),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C)and uric acid(UA).DNA was obtained from blood samples using Phenol/chloroform method and saved at -80℃until the assay.The gene polymorphisms of TRB3 including +251A/G in exon 2 and +333T/C in exon 3 were detected using direct sequencing and restriction fragment length polymorphism-polymerase chain reaction(RFLP-PCR)methods.The relationship between the gene polymorphisms of TRB3 and MS,as well as the relationship between the gene polymorphisms of TRB3 and individual component of MS were determinded.Results(1)Clinical characteristics of the control group and MS group:There were no significant differences in age and gender between MS group and control group.Compared with controls,BMI,waist circumference,waist-to-hip ratio,systolic blood pressure(SBP), diastolic blood pressure(DBP),TG,TC,LDL-C,FBG,fasting insulin(FINS), HOMA-insulin resistance(HOMA-IR),UA,percentage of smoking and drinking were significantly higher in the patients with MS(all P＜0.001),whereas HDL-C was significantly lower in MS group(P＜0.001).(2)Clinical characteristics of the non-abdominal obesity group and abdominal obesity group:To elucidate the relationship between the gene polymorphisms of TRB3 and obesity, we use 100 age and sex matched subjects served as controls.Compared with control group, BMI,waist circumference,waist-to-hip ratio,SBP,DBP,TG,TC,LDL-C,FBG,FINS and HOMA-IR were significantly higher in abdominal obesity group(P＜0.05～0.01),whereas other clinical characteristics had no significant differences.(3)The results of PCR sequencing:We randomly selected 50 DNA samples including 25 from MS group and 25 from controls to detect the sequence of exon 2 and exon 3 by direct sequencing method.Then +251A/G missense in exon 2 and +333T/C synonymous in exon3 were identified.These two SNPs were consistent with the single nucleotide polymorphisms (dbSNP)labeled rs2295490 and rs6051637 in the National Center for Biotechnology Information(NCBI)database.(4)Comparison of clinical characteristics among genotypes of+251A/G:①Comparison of clinical characteristics among genotypes of +251A/G in MS group and controls:In MS group,compared with those with AA genotypes,waist-to-hip ratio,TC,TG and LDL-C in patients with GG genotypes were significantly higher(P＜0.05～0.01), whereas HDL-C was significantly lower(P＜0.01);When compared to those with AG genotypes,waist-to-hip ratio in patients with GG genotypes was significantly higher (P＜0.05),whereas HDL-C was obviously lower(P＜0.05);Other clinical characteristics showed no significant differences among genotypes.Meanwhile,in controls,significant differences of clinical characteristics were not observed among genotypes(all P＞0.05).②Comparison of clinical characteristics among genotypes of +251A/G in abdominal obesity group and non-abdominal obesity group:Compared with carriers of GG genotypes in the non-abdominal obesity group,BMI,waist circumference,waist-to-hip ratio and TG were significantly higher(P＜0.05～0.01),whereas HDL-C was significantly lower in the abdominal obesity group(P＜0.05).Other clinical characteristics showed no significant differences between two groups(all P＞0.05).In abdominal obesity group,compared with carriers of AA genotypes,waist-to-hip ratio and TG were significantly higher (P＜0.05～0.01),whereas HDL-C was significantly lower(P＜0.01)in GG genotype carders.(5)Comparison of SNPs genotypic and allelic distribution frequencies between MS group and controls:The distribution of genotypic frequencies of +251A/G polymorphism showed significant difference between MS group and controls(Control group:AA 70.5%,AG 24.5%,GG 5.0%vs.MS group:AA 57.6%,AG 36.4%,GG 6.0%;χ2=7.705,P=0.021). Compared with controls,A allelic frequency was significantly lower(82.8%vs.75.8%, P＜0.05)while G allelic frequency was higher(17.2%vs.24.2%,P＜0.05)in MS group. However,the distributions of +333T/C genotypic and allelic frequencies did not differ significantly between MS group and controls(all P＞0.05).(6)Haplotype analyses of SNPs:The analyses ofhaplotype and linkage disequilibrium were performed by SHEsis Software,demonstrating that there was obvious linkage disequilibrium between +251A/G and +333T/C(D'=0.740,r2=0.032)polymorphisms.In our study,four haplotypes were formed by the two SNPs,including AC,AT,GC and GT. GT haplotype was not considered because its frequency was less than 3%.The other three haplotypes were analyzed,showing that compared with controls,the frequency of AC haplotype was significantly lower(58.2%vs.67.1%,P=0.012,OR 0.682,95%CI 0.504-0.923)and GC haplotype was significantly higher(22.6%vs.15.8%,P=0.018,OR 1.563,95%CI:1.075-2.272)in MS group,which indicated that MS is associated with TRB3 +251G allele but not +333 T or C allele.(7)Comparison of SNPs genotypic and allelic distribution frequencies in MS group:①According to the cutoff point of TG in MS,the patients with MS were divided into two subgroups,the high TG group(HTG,TG≥1.7mmol/L)and the normal TG group(NTG, TG＜1.7mmol/L).The genotypic distribution frequencies of +251A/G polymorphism showed significant differences between NTG and HTG(NTG:AA 71.0%,AG 22.4%,GG 6.6%vs.HTG:AA 50.4%,AG 43.9%,GG 5.7%;χ2=10.071,P=0.007).Moreover, Compared with NTG,A allelic frequency was significantly lower(82.2%vs.72.3%,P＜0.05) and G allelic frequency was higher(17.8%vs.27.7%,P＜0.05)in HTG.②According to the diagnostic criteria of hypertension drawn by WHO/ISH,the patients with MS were divided into two subgroups,the hypertensive group and normotensive group. The distributions of +251A/G genotypic and allelic frequencies showed no significant differences between the two subgroups(Genotypic frequency:χ2=4.780,P=0.092;Allelic frequency:χ2=2.480,P=0.115).③According to the cutoff point of FBG in MS,the patients with MS were divided into two subgroups,the abnormal FBG group(FBG≥5.6 mmol/L)and the normal FBG group (FBG＜5.6 mmol/L).The distributions of +251A/G genotypic and allelic frequencies showed no significant differences between the two subgroups(Genotypic frequency:χ2=0.695,P=0.707;Allelicfrequency:χ2=0.624,P=0.429).④According to the cutoff point of HOMA-IR established in ADA guideline,the patients with MS were divided into two subgroups,the IR group(HOMA-IR≥2.69)and non-IR group(HOMA-IR＜2.69).The genotypic distribution frequencies of +251A/G polymorphism showed significant difference between the two subgroups(non-IR group: AA 71.2%,AG 23.7%,GG 5.1%vs.IR group:AA 52.5%,AG 41.2%,GG 6.3%;χ2=6.283, P=0.043).Moreover,compared with non-IR group,A allelic frequency was obviously lower(83.1%vs.73.1%,P＜0.05)and the rare G allele was significantly more frequent (16.9%vs.26.9%,P＜0.05)in IR group.(8)Comparison of +251A/G genotypic and allelic distribution frequencies between the abdominal obesity group and controls:The genotypic distribution frequencies of +251A/G showed significant difference between controls and abdominal obesity group(controls:AA 70.0%,AG 25.0%,GG 5.0%vs.abdominal obesity group:AA 53.1%,AG 40.6%,GG 6.3%;χ2=6.058,P=0.048).Moreover,Compared with controls,A allelic frequency was significantly lower(82.5%vs.73.4%,P＜0.05)and G allelic frequency was higher(17.5% vs.26.6%,P＜0.05)in abdominal obesity group.(9)The relationship between SNPs and MS:①Stepwise multivariate logistic regression analysis was performed to determine the predictive variables of MS among age,sex,smoking,drinking and the alleles of +251A/G, which showed that smoking and G allele were the independent predictors,indicating that +251A/G polymorphism is the risk factor of MS.Carriers with G allele are 2.35 times as high at risk for MS as those with A allele(OR:2.349,95%CI:1.156-4.775,P=0.018).②Association of +251A/G polymorphism with abdominal obesity:Stepwise multivariate logistic regression analysis showed that sex,TG and G allele were the independent risks, indicating G allele increases the risk for abdominal obesity(OR:2.351,95%CI: 1.210-4.568,P=0.012).③The effect of +251A/G polymorphism on dyslipidemia:Stepwise multivariate logistic regression model for determining the predictive variables of dyslipidemia(TG≥1.7mmol/L) among age,sex,smoking,drinking,BP,BMI,waist circumference,waist-to-hip ratio,FBG, FINS,HOMA-IR and the alleles of +251A/G,showed that waist-to-hip ratio,SBP,FBG, insulin and G allele were the independent predictors,indicating G allele increases the risk of dyslipidemia(OR:2.314,95%CI:1.494-3.585,P=0.000).④Association of +251A/G polymorphism with hypertension:Stepwise multivariate logistic regression analysis was used to determine the risk factors in age,sex,smoking, drinking,BP,TG,FBG,FINS and the alleles of +251A/G,for hypertension,which showed that the alleles of +251A/G were not the independent predictors.Moreover,univariate logistic regression analysis also showed the +251 G allele was not the significant predictor of hypertension.⑤The effect of +251A/G polymorphism on hyperglycemia:Stepwise multivariate logistic regression model was conducted for screening the predictive variables of hyperglycemia among age,sex,smoking,drinking,BMI,waist circumference,waist-to-hip ratio,BP and the alleles of+251A/G,which showed that the alleles of+251A/G were not the independent predictors.Moreover,univariate logistic regression analysis also showed the +251A/G alleles were not the significant predictors of hyperglycemia.⑥Association of +251A/G polymorphism with insulin resistance:Stepwise multivariate logistic regression analysis was used to decide the risk factors in age,sex,smoking, drinking,BP,TG,FBG,FINS and the alleles of +251A/G for insulin resistance,which showed that sex,waist circumference and waist-to-hip ratio were the independent predictors,except for the TRB3 +251A/G polymorphism.However,univariate logistic regression analysis showed G allele was the significant predictor of IR(OR:1.697,95%CI: 1.076-2.677,P=0.023).Conclusions1.The gene of TRB3 polymorphisms including +251A/G in exon 2 and +333T/C in exon 3 could be identified in Chinese Han population residing in Shandong Province. 2.Significant differences of +251A/G genotypes and allelic distribution frequencies were observed between MS groups and controls,which indicates that +251A/G polymorphisms are associated with the susceptibility to MS.However,the distributions of +333T/C genotypic and allelic frequencies did not differ significantly between MS groups and controls.3.TRB3 +251 G allele was an independent predictor of MS.4.Compared with controls,the frequency of GC haplotype,one of the four haplotypes formed by +251A/G and +333T/C polymorphisms of TRB3,was significantly higher in MS group.Therefore,the existence of +333T/C polymorphisms increases the risk of G allele for MS.5.TRB3 +251 G allele,a risk factor of IR as well,was the independent predictor of obesity and dyslipidemia.However,no associations of TRB3 +251 G allele with hyperglycemia and hypertension were identified. BackgroundThe metabolic syndrome has received increased attention in the past few years.It consists of multiple,interrelated risk factors of metabolic origin that appear to directly promote the development of atherosclerotic cardiovascular disease(ASCVD).At present, however,it is not clear whether the metabolic syndrome has a single cause.As is true with many medical conditions,genetics and the environment both play important roles in the development of the metabolic syndrome.Environmental issues such as low activity level, sedentary lifestyle,and progressive weight gain also contribute significantly to the risk of developing the metabolic syndrome.However,genetic factors influence each individual component of the syndrome,and the syndrome itself.Many genes interact with the environment to produce the metabolic syndrome.The newly identified TRB3 gone has been reported by most,although not all,studies to affect insulin action by binding to and inhibiting Akt phosphorylation and to play a role in insulin resistance.Insulin resistance is a major hallmark in the development of the metabolic syndrome.It has been demonstrated that the prevalent TRB3 missense Q84R polymorphism is associated with the metabolic syndrome.However whether the polymorphism will increase the risk for atherosclerosis remains unknown.Therefore,the present study aims to elucidate the changes of the carotid arterial structure and functions with the metabolic syndrome,the association of the TRB polymorphism with the changes of carotid arterial structure,the association of the TRB polyrnorphism with the changes of carotid arterial functions,the association of TRB polymorphism with carotid atherosclerosis and the underlying mechanisms. Objectives1.To elucidate the changes of the carotid arterial structure and functions with the metabolic syndrome.2.To detect the association of the TRB polymorphism with the changes of carotid arterial structure.3.To detect the association of the TRB polymorphism with the changes of carotid arterial functions.4.To investigate the association of TRB polymorphism with carotid atherosclerosis and the underlying mechanisms.Subjects and methodsThe studied population were the same as described previously.Those who underwent the ultracardiographic examination were enrolled.The cohort consists of the control group (90 men and 110 women,aged 51.3±9.7 years),the MS group(86 men and 114 women, aged 52.2±9.3 years),the obese group(45 men and 51 women,aged 52.4±10.7 years)and the selected control group(47 men and 53 women,aged 52.2±9.2 years)B-mode ultrasonography of the carotid arteries was performed and Ultrasound images were acquired using a 5～10MHz linear array transducer and a commercially available ultrasound machine(Vivid 7 dimension;General Electric Medical Systems,Horten, Norway).Genotyping of the TRB3 polymorphism was carried out by PCR-RFLP method. Theχ2 was used to test for associations between categorical variables and for Hardy-Weinberg equilibrium.To model the effect of the polymorphism on bivariate variables,multivariate logistic regression analysis was performed,and odds ratios(95%CI) are shown.Results(1)Comparison of clinical and biochemical characteristics of the subjectsCompared with the controls,the MS group showed significantly higher BMI,waist circumference,waist-to-hip ratio,cholesterol,triglyceride and LDL-c but lower HDL-c (P＜0.001,respectively).(2)Comparison of carotid ultrasonic parameters The mean IMT,maximum IMT,Ds,Dd,plaque index of the MS group were significantly higher than those of the control group(P＜0.001,respectively).Furthermore the MS group showed significantly decreases in Vs,Vd,Vm,RI and AC(P＜0.001, respectively),with significantly increases in PI,Ep,Ep* andβ(P＜0.001,respectively).(3)Comparison of carotid ultrasonic parameters according to the genotypesSubjects with the SNP251 GG genotype had significantly higher mean and maximum IMT,higher plaque index(P＜0.01,respectively)but lower mean velocity and arterial compliance than those with the AA genotype(P＜0.05,respectively).Furthermore,mean and maximum IMT and plaque index of the GG genotypes were still significantly higher when compared with those of the AG genotypes(P＜0.01,respectively).(4)Effects of the TRB3 +251A/G polymorphisms on the IMT of MS patients①Distributions of +251A/G genotype and allele between the normal and thickened IMT groupsThere were significantly different frequency distributions of +251A/G genotype and allele between the normal and thickened IMT groups(Among the normal IMT group: AA65.1%,AG 33.3%,GG 1.6%vs.among the thickened IMT group:AA45.4%,AG41.6 %,GG13.0%,χ2=14.224,P=0.001).Also the frequency of TRB3 +251A was significantly lower in the thickened IMT group than that in the normal IMT group(81.7%vs.66.2%,χ2=12.345,P=0.000),whilst TRB3 +251G allele was significantly increased(18.3%vs. 33.8%,χ2=12.345,P=0.000),suggesting the association of the TRB3 +251G with the thickened IMT.②Screening risk factors for the thickened IMT by multivariate logistic regression analysisStepwise multiple variable logistic regression analysis was conducted to determine the risk factors in age,sex,smoking,waist circumference,waist-to-hip ratio,BP,lipids,FBG, FINS and HOMA-IR for the thickened IMT,which showed +251G allele was an independent risk,indicating +251G allele increases the risk for the thickened IMT(OR: 2.208,95%CI:1.036-4.709,P=0.04).③Multivariate linear regression model for IMTMultivariate linear regression model for IMTmeanis as follows:IMTmean=0.099×(+251A/G)+0.234×SBP-0.138xHDL+0.217×WC+0.277×age.The SNPs(P=0.026),SBP (P=0.000),HDL(P=0.004),waist circumference(P=0.000)and age(P=0.000)were enrolled,among which the SNPs,SBP,waist circumference and age were risk factors. Multivariate linear regression model for IMTmaxis as follows:IMTmax=0.278×age +0.179×(+251A/G)+0.120×SBP+0.115×WHR.The SNPs(P=0.000),SBP(P=0.038), waist-to-hip ratio(P=0.039)and age(P=0.000)contributed to IMTmax,among which none was protective.(5)Effects of the TRB3 +251A/G polymorphism on the IMT plaque index of MS patients①Distributions of +251A/G genotype and allele among different IMT plaque index groupsThere were significantly different frequency distributions of +251A/G genotype and allele among different IMT plaque index groups.Also the lower IMT plaque index group shared more +251A allele than the higher IMT plaque index group,suggesting the association of the TRB3 +251G with the increased IMT plaque index.②Screening risk factors for increased IMT plaque index by multivariate logistic regression analysisStepwise multiple variable logistic regression analysis was conducted to decide the risk factors in age,sex,smoking,waist circumference,waist-to-hip ratio,BP,lipids,FBG, FINS and HOMA-IR for the increased IMT plaque index,which showed +251G allele was an independent risk,indicating +251G allele increases the risk for the elevated IMT plaque index(OR:2.275,95%CI:1.119-4.623,P=0.023).(6)Effects of the TRB3 +251A/G polymorphism on the carotid arterial compliance of MS patientsMultivariate linear regression model for carotid arterial compliance is as follows:AC= -0.691×SBP-0.155×TC+0.218×DBP+0.163×HDL -0.099×Age -0.111×Sex.The SBP (P=0.000),DBP(P=0.005),TC(P=0.000),HDL(P=0.000),age(P=0.029)and sex (P=0.012)except for the +251A/G polymorphism were enrolled,suggesting that the +251A/G polymorphism had no association with carotid arterial compliance.(7)Association of obesity with carotid atherosclerosis①Comparison of carotid ultrasonic parameters between the obese group and the control groupCompared with the controls,the pressure-strain elastic modulus(Ep)increased significantly in the obese group(P＜0.05).②Correlation of waist circumference with carotid ultrasonic parameters Waist circumference significantly correlated positively with mean IMT,maximum IMT,plaque index,Ds and Dd(P＜0.01,respectively),which denoted the structure of the carotid artery.Meanwhile waist circumference had a significantly inverse correlation with Vs,Vd,Vm and RI(P＜0.05～0.001,respectively),and a significantly positive correlation with AC,PI,Ep,Ep* andβ(P＜0.001,respectively).③Partial correlation of waist circumference with carotid ultrasonic parametersWaist circumference significantly correlated positively with mean IMT,Ds and Dd, which denoted the structure of the carotid artery,even after age,sex,smoking,SBP,DBP, lipids,blood glucose,insulin and HOMA-IR were controlled for partial correlation analysis. That is,obesity is an independent risk factor for carotid atherosclerosis,especially the structure of carotid artery.(8)Association of triglycerides with carotid atherosclerosis①Comparison of carotid ultrasonic parameters between the normal triglycerides group and the elevated triglycerides group among the MS patientsCompared with the normal triglycerides group,the mean IMT,pressure-strain elastic modulus(Ep)and normalized Ep(Ep*)increased significantly in the elevated triglycerides group(P＜0.05)among the MS patients.②Correlation of triglycerides with carotid ultrasonic parametersTriglycerides significantly correlated positively with mean IMT,maximum IMT, plaque index,Ds and Dd(P＜0.01,respectively),which denoted the structure of the carotid artery.Meanwhile triglycerides had a significantly inverse correlation with Vs,Vd,Vm,RI and AC(P＜0.05～0.001,respectively),and a significantly positive correlation with PI,Ep, Ep* andβ(P＜0.001,respectively).③Partial correlation of triglycerides with carotid ultrasonic parametersTriglycerides significantly correlated negatively with RI(r=-0.157,P=0.012),which denoted the function of the carotid artery,even after age,sex,smoking,waist circumference, BMI,SBP,DBP,TC,HDL,LDL,blood glucose,insulin and HOMA-IR were controlled for partial correlation analysis.That is,triglyceride is an independent risk factor for carotid atherosclerosis,especially the function of carotid artery.(9)Association of insulin resistance with carotid atherosclerosis①Correlation of insulin resistance with carotid ultrasonic parameters Insulin resistance significantly correlated positively with mean IMT,maximum IMT, plaque index,Ds and Dd(P＜0.05,respectively),which denoted the structure of the carotid artery.Meanwhile insulin resistance had a significantly inverse correlation with Vs,Vd, Vm,RI and AC(P＜0.05～0.001,respectively),and a significantly positive correlation with PI,Ep,Ep* andβ(P＜0.001,respectively).②Partial correlation of insulin resistance with carotid ultrasonic parametersInsulin resistance significantly correlated positively with plaque index,which denoted the structure of the carotid artery,even after age,sex,smoking,waist circumference, waist-to-hip ratio,BMI,SBP,DBP,lipids,blood glucose and insulin were controlled for partial correlation analysis.That is,insulin resistance is an independent risk factor for carotid atherosclerosis,especially the structure of carotid artery.Conclusions1.Significant alterations to carotid arteries of the MS patients include thickened IMT, increased plaque index,distended vessel diameter,reduced elasticity and augmented stiffness.2.Carriers of the TRB3 +251G allele are susceptible to carotid atherosclerosis.Furthermore, the MS patients with TRB3 +251G allele are more predisposed to thickened IMT and increased plaque index.3.The MS patients carrying TRB3 +251G allele incline to carotid structural alterations and the possibly consequent functional alterations.Functional alterations are consequent upon structural alterations.4.Without regard to the genotypes,obesity and insulin resistance are independent risk factors for damaging carotid structure of MS patients,whereas elevated triglyceride is an independent risk factor for the impaired functions of carotid artery.When coexisting with other risk factors,all of them can impart significant effect on both structures and functions of carotid artery,suggesting the synergistic effect.5.The TRB3 +251G allele increases the risk of carotid atherosclerosis associated with the presence of obesity,insulin resistance and elevated triglycerides which promote atherosclerosis by impairing the structure and function of carotid artery.6.Obesity,insulin resistance and elevated triglyceride share the same predisposing gene is why the MS patients with TRB3 +251G allele are prone to atherosclerosis.That the three independent risk factors interact with each other causes outweighing risk predicted by assuming additivity of effects,which will be synergized by the traditional risk factors to accelerate atherosclerosis. BackgroundThe metabolic syndrome(MS),a cluster of atherogenic risk factors including abdominal obesity,insulin resistance,hypertension,dyslipidemia,is a strong herald for cardiovascular morbidity and mortality.Previous studies showed that cardiac function is impaired in patients with diabetes or hypertension although their blood pressure and glucose were well controlled.The main features of cardiac dysfunction are left ventricular hypertrophy,diastolic dysfunction in individuals with metabolic syndrome.However,the left atrial function in patients with MS is unclear.Recently,studies revealed that metabolic syndrome is associated with cardiac interstitial fibrosis,which has been associated with cardiac remodeling and produced a wide range of alterations in cardiac structure and function.Insulin resistance,obesity, disturbance of adipocyte may contribute to the pathogenesis of metabolic syndrome. Studies revealed that TRB3 is emerging as an important player in insulin resistance,fat metabolism and differentiation of adipocyte.TRB3,as a regulative protein,can influence the activations of MAPKs,CDC25/String and Akt.We found TRB3 gene +251A/G polymorphism was associated with risk of metabolic syndrome,dyslipidemia,obesity and insulin resistance in the first part of our thesis.Altogether,these data support the hypothesis that TRB3 gene +251A/G may be implicated in pathogenesis of myocardial fibrosis and the changes of cardiac structure and function.Objective The purpose of the present study was 1 To evaluate the characteristics of the structures and functions of LA and LV in the patients with MS by using strain and strain rate imaging and to investigate possible mechanisms for the pathogenesis of structural and functional alterations.2 To investigate the association of TRB3 gene +251A/G polymorphism with the alterations of cardiac functions in MS patients.Subjects and MethodsWe recruited 200 consecutive subjects with metabolic syndrome,(114 females, 52.2±9.3 yr of age),with cardiovascular risk factors(obesity,hypertension,glucose tolerance/diabetes mellitus and dyslipidemia),but without a previous history or clinical evidence of heart failure or overt coronary artery disease.To assess the influence of metabolic syndrome components on cardiac functions,MS patients were further divided into two subgroups according to diagnostic criteria of WHO/ISH for hypertension.The hypertensive MS group consisted of 135 patients while the normotensive MS group consisted of 65 patients.200 age- and sex-matched normal subjects(110 females,51.3±9.7 yr of age)without cardiovascular disease,hypertension or diabetes mellitus served as controls.The details of clinical and biological parameters were obtained.Of total 400 participants who had an echocardiographic examination,333 had adequate measurements enabling a valid estimate of strain and strain rate imaging of left atrium and tissue velocity imaging.Study enrollment consisted of 177 patients with metabolic syndrome(102 females, 53.7±8.5 yr of age)and 156 control subjects(99 females,52.7±8.7 yr of age).The patients were further divided into Ve/Va＞1 group and Ve/Va＜1 group based on the ratio of early diastolic mitral annular velocity(Ve)and late diastolic mitral annular velocity(Va)because left ventricular dysfunction influence left atrial function.The Ve/Va≥1 group consisted of 76 patients(44 females,52.6±9.5 yr of age)while the Ve/Va＜1 group consisted of 101 patients(58 females,54.1±7.7 yr of age).Echocardiograms were obtained with a commercially available ultrasound machine (Vivid 7;GE Vingemed Ultrasound,Horten,Norway)with a 1- to 3- MHZ phased array transducer.Participants were examined in the left lateral decubitus position and images were acquired at passive end expiration to minimise global cardiac movement from standard parasternal long axis and apical planes by the same expert operator.The M-mode echocardiographic study of the left ventricle was performed under 2D control. Pulsed-Doppler echocardiography was performed in 4- chamber apical view with the sample volume situated between the mitral leaflet tips.Tissue Doppler imaging mode was employed to measure the velocity of mitral valve to assessing the segmental radial myocardial motion.Gray-scale and color tissue Doppler images from apical four-,threeand two-chamber views were recorded,with frame rates＞100 frames/s by keeping the angle of insonation as small as possible(ideally＜30°)and the depth of field low enough just to include the left ventricle only.Images were stored on a magneto-optical and compact disks and were analyzed offline.Genomic DNA was obtained from peripheral blood leukocytes using standard phenol-chloroform extraction methods.TRB3 gene +251A/G and +333T/C polymorphisms were detected by direct sequencing and polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)methods in Han population residing in Shandong province.The associations of TRB3 gene +251A/G polymorphism with the alterations of cardiac functions were investigated.Results1.(1)Mean S and SSR,which was considered to be indicators of LA reservoir function, were significantly lower in patients with MS than control subjects.Mean ESR,which was considered to be an indicator of LA pump function,was also significantly lower in patients with MS than control subjects(P＜0.001).However,mean ASR,which was considered to be an indicator of LA booster function,was similar in two groups.2.The early diastolic mitral annular velocity(Ve)and the ratio of early diastolic mitral annular velocity and late diastolic mitral annular velocity(Va)were significantly lower in patients with metabolic syndrome than those in control subjects(P all＜0.001). However,there was no significant difference in late diastolic mitral annular velocity between the two groups.
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