Dissertation > Medicine, health > Basic Medical > Pathology > Pathophysiology

On high-density lipoprotein and triglycerides in molecular genetics

Author YangZuo
Tutor WangQing;Xin
School Huazhong University of Science and Technology
Course Biochemistry and Molecular Biology
Keywords Linkage analysis Single nucleotide polymorphism (SNP) High-density lipoprotein cholesterol (HDL-C) Triglycerides Coronary artery disease (CAD) Myocardial infarction (MI) Genome-wide scan Quantitative trait loci LIPC gene Correlation Analysis
CLC R363
Type PhD thesis
Year 2010
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Is working on a variety of human genes that cause disease research, trying to find the genes that cause various diseases to study the molecular mechanisms of pathogenesis, so as to achieve disease prevention and control. So far, most of the genes that cause the disease have been reported, even in the field of cardiovascular disease, there are more than 30 kinds of genes that cause the disease was discovered by molecular cloning. However, the risk of many diseases of human life are often complex diseases, such as diabetes, coronary heart disease, and, usually associated with complex diseases, there are many number of physiological and biochemical parameters. Such diseases or indicators are not normally regulated by a single gene, but by multiple genes are regulated. Therefore, this multi-gene regulation of complex diseases and related indicators of each other, usually the following two ways: 1, by the nuclear family consisting of the crowd; 2, distributed crowd. Two kinds of people, each with advantages: the composition of the core letters home crowd, more emphasis on the genetic background, but the sampling difficult; distributing sample population was relatively simple, usually easy to obtain a large sample size. Complex polygenic disease genetics of modern molecular medicine is also made up of two main methods: 1, linkage analysis; 2, association analysis. Linkage analysis of microsatellite markers usually used with a variety of alleles, but the density is small; relatively speaking, association analysis using single nucleotide polymorphism markers (SNP), a SNP allele with only two genes, but SNP density, able to carry out SNP genotyping techniques much. This paper studies the two main factors of coronary heart disease - HDL-C and triglycerides quantitative trait loci, used in the above two groups and two analysis methods, discovered by far the most significant affecting HDL-C levels of new loci, is conducive to the future impact on HDL-C levels of polymorphism and gene discovery, in the hope of coronary heart disease prevention and treatment, play a positive effect. In the first part, we study first a 388 premature coronary trios (total 714 individuals) conducted a linkage analysis, genome-wide linkage analysis to find two of the same HDL-c was significantly associated with quantitative trait loci (QTL): 7p22 and 15q25, maximum multipoint LOD score of 3.76 and 6.69, respectively. After that we used microsatellite markers and single nucleotide polymorphism marker loci on the above two were fine mapping, the results show, 7p22 locus maximum multipoint LOD score dropped to 3.09, less than remarkable standard and is therefore not a with HDL-C was significantly associated with QTL; 15q25 locus finely positioned, split into two linked QTLs - 15q22 (LOD value 2.73) and 15q25 (LOD value 5.63). Which, 15q22QTL under the LIPC gene, gene promoter SNP rs1800588 calculated through QTDT been demonstrated in our population with HDL-C levels were significantly associated (P = 0.0067), showed 15q22 QTL may be caused by the rs1800588. 15q25 locus is to be found so far the most significant impact on HDL-C levels of QTL, the discovery of this locus, but also for the future regulatory mechanism for HDL-C study provides new clues. The second part of the article, three newly reported associated with HDL-C and triglyceride SNPs and six associated SNPs (rs1323432, rs2338104, rs4846914, rs16996148, rs17321515, rs17145738, rs1748195, rs12130333), urgently in other populations was able to verify. In this study, 1231 patients with myocardial infarction and 560 normal controls, the above eight SNPs were genotyped for the results, the use of General linear model was used for statistical calculations to 1231 period in our MI patients and 560 healthy subjects validate these SNPs. The results showed that three in the analysis of genome-wide association with HDL-C was significantly associated SNPs: rs1323432, rs2338104 and rs4846914, both groups of patients with myocardial infarction in 1231, or 560 in the normal population, but also the crowd or in combination, were associated with HDL-C level is not relevant; 6 in genome-wide association analysis with HDL-C was significantly associated SNPs: rs4846914, rs16996148, rs17321515, rs17145738, rs1748195, rs12130333 also showed similar results in our 1231 MI patient groups , 560 normal control group and the merger of groups, and triglyceride levels were not related. After that, we carried out these eight SNPs associated with myocardial infarction analysis showed that, rs12130333 may be related with myocardial infarction (P = 0.007, OR = 0.773), but still not up to standards significantly.

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