| Objective:(1)Incident of cardiovascular disease in Xinjiang region different in multiply ethnic groups, in order to identification of cholesterol absorption key genetic variations associated with disease research; for the prevention and treatment of disease and clinical risk groups provide help for the best treatment plan.(2) To further study the function and mechanism of NPC1L1 variations in cholesterol uptake in the Uygur Han and Kazakhs of Xinjiang.(3) To explore the associations of genetic polymorphisms of Histone-lysine N-methyltransferase(MLL5) and coronary coronary artery disease in the Han of Xinjiang.Methods:(1) A case-control study collected 349 samples according with the plasma low density lipoprotein cholesterol(LDL-C) level, these samples were divided into high LDL-C group, low LDL-C group; two groups of nationality, gender, age matched; Using human genome-wide exons sequencing methods to analysis 32 cholesterol related genes, 659 exons pieces and analysis of the relationship with the serum lipid.(2) A case-control study selected 600 patients with high level LDL-C, and low level LDL-C were designed to use human genome-wide exons sequencing methods to analysis the function and mechanism of NPC1L1 variations in cholesterol uptake in the Uygur Han and Kazakhs of Xinjiang.(3) A case-control study including 565 cases with coronary heart disease confirmed by coronary angiography and 694 gender-, age-, and ethnic-matched controls was designed to analyze the relationship between MLL5 SNPs(rs12671368 and rs2192932 and CAD. Genotyping was undertaken using the PCR and enzyme-digested product genotyping assay.Results:(1) Sequenced 32 genes were differentially expressed associated with the serum lipid LDL-C in mutli ethnic groups. First using human genome-wide exons sequencing analysis cholesterol key genes in Xinjiang Uygur, Kazak and Han ethnic groups. There were 6 genes differentially expressed among Uygur patients compare with the other groups in cholesterol key genes; there 1 gene differentially in Han and in Kazak group compare with the other remaining groups.(2) Here, we uncovered 3 nonsynonymous(NS) variations and 64 synonymous variations in NPC1L1 gene from subsets of Chinese Han, Uygur, and Kazakh people with high or low LDL-C. Significantly, the 3 identified NS variations encoding R174 H, V177 I, and V1284 L substitution are found restricted to the Uygur and Kazakh groups, and they are associated with the aberrant plasma LDL-C level. We further investigated the cholesterol-regulated recycling of NPC1L1 NS variants, and their glycosylation and stability. There was no significant difference from the wild-type NPC1L1. In vivo assay performed in mouse liver using adenovirus-mediated expression demonstrated that all the 3 NPC1L1 NS variants did not lower the uptake of biliary cholesterol compared with the wild-type NPC1L1.(3) For total, the distribution of SNP1(rs12671368), SNP2(rs2192932) genotypes showed a significant difference between CAD and control participants. For total the distribution of SNP1(rs12671368), SNP2(rs2192932) alleles, the dominant model and the recessive model showed a significant difference between CAD and control participants. For total the significant difference distribution of SNP1, SNP2 in dominant model and recessive model was retained after adjustment for covariates for dominant model; for recessive model have satistic significant.Conclusion:(1) This study of coronary artery disease in the Uygur, Kazakh, and Han population of Xinjiang by genome-wide exons sequencing expression profiles showed that cholesterol genes varitions expression differentially among the three groups, especially high in Uygur and Kazak groups.(2) These data revealed that the R174 H, V177 I, and V1284 L NPC1L1 variations identified from high or low LDL-C individuals may not impair the NPC1L1 function in cholesterol absorption directly.(3) The GG genotype of rs12671368 and the AA genotype of rs2192932 in MLL5 gene could be protective genetic markers of CAD. |
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