| Objective: The aim of this study was to investigate the ASCVD risk factors among Chinese Tajiks,which living in the Pamir plateau of Kashgar,Xinjiang;To analyze the10-year and lifetime risk of CVD in Tajiks,and establish a risk prediction model for hyperlipidemia and metabolic syndrome among Tajiks.To study the molecular mechanisms and functions of the new mutation in LDLR gene,which affects low-density lipoprotein cholesterol(LDL-C)levels of the Tajiks.Methods: 1)From March to August2021,a cross-sectional study was conducted in Kashgar Tajik Autonomous County of Xinjiang to collect the data of laboratory tests,physical examinations,and questionnaires on the risk factors of ASCVD in Tajiks over 18 years old.Descriptive analysis,subgroup analysis and stratified analysis were conducted to analyze the influencing factors of dyslipidemia in Tajiks.To analyze the prevalence and influencing factors of metabolic syndrome(MS)in Tajiks.Also analyzed the association between uric acid with dyslipidemia and metabolic syndrome in Tajiks.2)The Chinese ASVCD risk prediction model was used to conduct descriptive analysis,subgroup analysis and stratified analysis of 10-year and lifetime CVD risk data among Tajiks;Logistic regression model was used to establish the risk prediction model for dyslipidemia and metabolic syndrome in Tajiks.3)1307 Tajik subjects aged 18-30 years old were selected to participate in the study,and their LDLR cholesterol was sorted into three groups(50 people in each group)of very high,intermediate,and very low using extreme phenotyping strategy,and 150 subjects were used to detect the new non-synonymous mutation of LDLR gene in the Tajiks using whole-exome sequencing;At the cellular level,using different molecular biology research methods including western blot and ubiquitination detection to investigate the molecular mechanisms of LDLR protein expression,stability,degradation and other characteristics and effects.Confocal microscopy was used to study the localization of the new mutant LDLR protein and the uptake function of LDL.Results: 1)The age-standardized total prevalence of hyperlipidemia was 38.75%,hypertension 24.45%,elevated blood glucose3.60%,smoking 8.00% and overweight 22.33% of Tajik subjects.Among Tajik male subjects,the percentage of 1 CVD risk factor was 36.70%,the percentage of 2 CVD risk factors was 22.20%,the percentage of 3 and upper CVD risk factors was 10.30%;The percentage of 1 CVD risk factor was 27.70%,2 CVD risk factors was 14.00%,and 3 or upper CVD risk factors was 6.40% in female.The influencing factors of hyperlipidemia in Tajik subjects were region(urban/rural),sex,waist circumference,hypertension(Y/N),high BMI,educational level,and occupation(All P values <0.05).Using 4 diagnostics(CDS,NCEP-ATP-III,IDF and JIS),the age-standardized prevalence of MS among Tajik subjects was 12.80%,16.92%,17.98% and 17.41%,respectively,the consistency of multiple diagnostics was effective.The common influencing factors of the 4 diagnostics for MS were age,BMI and waist circumference(All P values <0.001),high BMI had the greatest influence on MS of the Tajik subjects under all diagnostics.The optimal threshold of uric acid(UA)for predicting hyperlipidemia and metabolic syndrome was 361.5μmol/L and 412.5μmol/L in Tajik male subjects respectively.The optimal threshold of UA to predict hyperlipidemia was 287.5μmol/L and metabolic syndrome was 301.5μmol/L in female respectively.When UA exceeded 450μmol/L in male and 400μmol/L in female,the risk of hyperlipidemia and metabolic syndrome was significantly increased.2)The10-year risk of CVD among Tajik subjects from low to high age groups(18-24,25-34,35-44,45-54,55-64,and ≥65 years old)were 0.22%,0.50%,1.92%,5.26%,10.64%,17.58%(P<0.001)respectively.The lifetime risk of CVD for Tajik subjects from low to high age groups(18-24 years,25-34 years,35-44 years,45-54 years,55-60 years)(P<0.001)were 16.17%,14.05%,21.47%,26.19% and 29.93% respectively.The prediction model of hyperlipidemia in Tajik subjects is Logit P=-5.373-0.357×(region)+0.008×(age)-0.907×(sex)+0.119×(FBG)+0.02×(waist circumference)+0.138×(BMI)+0.007×(diastolic blood pressure)+0.131×(education level)+0.081×(occupation);The area under ROC curve(AUC)of the model was 0.749(95%CI: 0.735-0.763,P<0.001).The metabolic syndrome prediction model of Tajik subjects is Logit P=-22.319-0.291×(sex)+2.858×(hyperlipidemic)+0.101×(waist circumference)+0.133×(BMI)+0.499×(FBG)+0.033×(systolic blood pressure)+0.214×(marriage).The area under ROC curve(AUC)of the model was 0.955(95%CI: 0.949-0.962,P<0.001).3)The results of the mechanism study at the cellular levels showed that compared with wild-type LDLR,LDLR D131 N mutant was more stable,the LDLR D131 N express and uptake LDL capacity was not increased.D131 N mutant protein was more deposited in the endoplasmic reticulum,but not transported to Golgi apparatus.The expression of LDLR D131 N mutant protein was higher than that in the wild type in both intracellular and extracellular,and the degradation of LDLR protein by PCSK9 was reduced in the acidic environment of cells.The D131 N mutant was not degraded by the proteasome and lysosome pathways,and the reduced ubiquitination of the mutant results in reduced protein degradation.Conclusion: 1)The prevalence of dyslipidemia,hypertension,hyperglycemia,overweight,smoking and metabolic syndrome in Tajiks were lower than the national level.When uric acid exceeded450μmol/L in male and 400μmol/L in female,the risk of dyslipidemia and metabolic syndrome increased significantly.2)The risk prediction model of dyslipidemia and metabolic syndrome in Tajiks established in this study has high sensitivity and specificity,good fitting and reliable prediction effect.3)The LDLR gene new mutation D131 N in Tajiks has increased protein stability,and more deposited in the endoplasmic reticulum but not transported to the Golgi circulation.The protein of new mutation D131 N may be degraded through the ubiquitination pathway. |
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