| Objective:(1) To identify the association of cholesterol metabolism key genetic variants with cardiovascular disease, aim to develope and provide the best treatment strategy for different ethnic groups in Xinjiang.(2) To further study the molecular mechanism of Numb variants in cholesterol absorption.(3) To explore the relationship between Numb genetic polymorphisms and coronary coronary artery disease, lipid levels among Uighurã€Han Chinese population in Xinjiang. Methods:(1) 349 gender, age, and ethnic-matched samples were recruited and divided in to high low density lipoprotein-cho lesterol(LDL-C) group, and low LDL-C group according to plasma LDL-C level. 32 cholesterol metabolism relative genes were analyzed by using human genome-wide exons sequencing methods and further investigate the relationship between genetic variants and plasma lipid levels.(2) New variants of Numb gene were identified by using human genome-wide exons sequencing method among 671 patients with high LDL-C level, and low LDL-C level and were designed to study the molecular mechanism of Numb variants in cholesterol absorption.(3) A case-control study including 890 coronary heart disease(CAD) patients and 786 gender, age, and ethnic-matched controls and were designed to analyze the association of three SNPs(rs2108552, rs12435797 and rs1019075) and two variants(A587T and Q533K) of the Numb gene with CAD and lipid levels. Genotyping was undertaken using the Taqman genotyping assay. Results:(1) There were six cholesterol metabolism relative genes differentially expressed in Uighur groups and there was one gene differentially expressed in Han and Kazak group. Additionally, we have found that there were three cholesterol absorption relative genes(NPC1L1, Numb, and SOAT2) and their variants were associated with lipid levels.(2) We have found two nonsynonymous(NS) variations and eight synonymous variations of Numb gene in Han,and Uighur population with high or low LDL-C. The two identified NS variants encoding A587T and Q533 K substitution were associated with the low level of plasma LDL-C level.(3) We further investigated Numb NS variants with their response to the cholesterol level, stability, and affinity to the clathrin/AP2. There was no significant difference between two variants and the wild-type Numb when analyzing their response to the cholesterol level, and stability. A587 T and Q533 K of Numb gene attenuated affinity to clathrin/AP2 when compared to the wild-type Numb.(4) For total and male Han Chinese population, the dominant model of SNP2(rs2108552) showed a significant difference between CAD and control subjects and the significance remaied after multivariate adjustment(OR:1.876, 95%CI:1.482~1.979, P=0.004; OR:1.498, 95%CI:1.305~1.815,P=0.006). The frequency of the haplotype(T-C-T) was significantly higher in the CAD patients than in the controls(P=0.002 and P=0.004), and the frequency of the haplotype(G-G-T) was significantly lower in the CAD patients than in the control subjects(P=0.007 and P=0.013).(6) There were significant differences between rs12435797,rs1019075 genotype and TC level, rs2108552 genotype and TC, LDL-C level before and after adjusting gender, age, ethnicity, obesity and smoking(all P<0.05). There were also significant differences between A587 T,Q533K and TC,LDL-C, HDL-C before and after adjusting gender, age, ethnicity, obesity and smoking(all P=0.000).Conclusion:(1)This study showed that cholesterol genes variations expression were significantly different among three groups, especially high in Uighur and Kazak groups.(2) A587 T and Q533 K Numb variants were identified from high or low LDL-C individuals and may impair the Numb function in cholesterol absorption.(3) The CC genotype of rs2108552 and haplotype T-C-T is a possible risk marker for CAD and G-G-T haplotype is a possible protective marker for CAD in Han male population.(4) Numb genetic variants were associated with low level of LDL-C or TC and high level of HDL-C levels. |
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