本文選題：冠心病 + 脂蛋白(a)　； 參考：《吉林大學(xué)》2015年博士論文

【摘要】：第一部分SLC22A3-LPAL2-LPA基因簇單核苷酸多態(tài)性與冠心病發(fā)病風(fēng)險(xiǎn)及血脂水平的關(guān)系 目的： 探索SLC22A3-LPAL2-LPA基因簇上的rs9346816、rs2221750、rs3127596、rs9364559、rs1367211、 rs6415085、rs9347438及rs9355296位點(diǎn)與中國(guó)東北部漢族人群冠心病發(fā)病風(fēng)險(xiǎn)及血脂水平的關(guān)系。 方法： 本研究采用病例對(duì)照研究方法。病例組和對(duì)照組分別為551例和544例。研究人群均為中國(guó)東北部漢族人群，且個(gè)體間無血緣關(guān)系。病例組人群篩選自2009年~2012年在吉林大學(xué)第一醫(yī)院二部心血管內(nèi)科確診并進(jìn)行住院治療的冠心病患者。選擇同期在吉林大學(xué)第一醫(yī)院體檢中心健康體檢的正常人群為對(duì)照組。采用Sequenom MassArray系統(tǒng)對(duì)位于SLC22A3-LPAL2-LPA基因簇上的rs9346816、rs2221750、rs3127596、rs9364559、rs1367211、 rs6415085、rs9347438及rs9355296位點(diǎn)進(jìn)行基因分型，同時(shí)收集研究對(duì)象的流行病學(xué)資料。采用SPSS16.0統(tǒng)計(jì)軟件對(duì)一般資料、等位基因及基因型與冠心病關(guān)系、SNPs和冠心病危險(xiǎn)因素的關(guān)聯(lián)分析及不同基因型人群間血脂水平的關(guān)系；采用SHEsis軟件分析單倍型與冠心病的關(guān)系；采用Haploview軟件進(jìn)行連鎖不平衡分析。采用多元線性回歸分析校正混雜因素對(duì)結(jié)果的影響。 結(jié)果： 1.病例組中吸煙人數(shù)高于對(duì)照組，并且病例組中患有高血壓病、糖尿病患者人數(shù)均多于對(duì)照組，病例組患者血清總膽固醇、低密度脂蛋白膽固醇、高密度脂蛋白膽固醇、脂蛋白(a)水平高于對(duì)照組，并且以上差異均具有統(tǒng)計(jì)學(xué)意義（P0.05）。 2.校正混雜因素后，，SLC22A3-LPAL2-LPA基因簇上rs9364559位點(diǎn)基因型與等位基因在病例組和對(duì)照組人群中的分布仍存在顯著性差異（X2=7.126, P=0.028；X2=4.436,P=0.039）。 3.單倍體型分析結(jié)果顯示7個(gè)位點(diǎn)組成的單倍型中GAAAGTG和GGAAGTG與冠心病發(fā)病風(fēng)險(xiǎn)相關(guān)（P0.05），攜帶GAAAGTG單倍型人群冠心病的發(fā)病風(fēng)險(xiǎn)可能降低，但攜帶GGAAGTG單倍型人群冠心病的發(fā)病風(fēng)險(xiǎn)可能增高。由6個(gè)SNP位點(diǎn)構(gòu)成的單倍型中有14種單倍型與冠心病的發(fā)病風(fēng)險(xiǎn)相關(guān)（P0.05），其中8種單倍型可能增加冠心病的發(fā)病風(fēng)險(xiǎn)，6種單倍型可能降低冠心病的發(fā)病風(fēng)險(xiǎn)。由5個(gè)SNP位點(diǎn)構(gòu)成的單倍型中有39種單倍型與冠心病的發(fā)病風(fēng)險(xiǎn)相關(guān)（P0.05），其中21種單倍型可能增加冠心病的發(fā)病風(fēng)險(xiǎn)，18種單倍型可能降低冠心病的發(fā)病風(fēng)險(xiǎn)。由4個(gè)SNP位點(diǎn)構(gòu)成的單倍型中有49種單倍型與冠心病的發(fā)病風(fēng)險(xiǎn)相關(guān)（P0.05），其中22種單倍型可能增加冠心病的發(fā)病風(fēng)險(xiǎn)，27種單倍型可能降低冠心病的發(fā)病風(fēng)險(xiǎn)。由3個(gè)SNP位點(diǎn)構(gòu)成的單倍型中有39種單倍型與冠心病的發(fā)病風(fēng)險(xiǎn)相關(guān)（P0.05），其中19種單倍型可能增加冠心病的發(fā)病風(fēng)險(xiǎn)，20種單倍型可能降低冠心病的發(fā)病風(fēng)險(xiǎn)。由2個(gè)SNP位點(diǎn)構(gòu)成的單倍型中有9種單倍型與冠心病的發(fā)病風(fēng)險(xiǎn)相關(guān)（P0.05），其中3種單倍型可能增加冠心病的發(fā)病風(fēng)險(xiǎn)，6種單倍型可能降低冠心病的發(fā)病風(fēng)險(xiǎn)。 4.位于SLC22A3基因上的rs9346816位點(diǎn)不同基因型間LDL-C、TC水平存在顯著差異（P0.05），LPA基因上的rs6415085位點(diǎn)不同基因型之間Lp(a)、LDL-C水平存在顯著差異（P0.05）。 結(jié)論： 1．吸煙、高血壓病、糖尿病、血清總膽固醇、低密度脂蛋白膽固醇、脂蛋白(a)水平可能與冠心病發(fā)病風(fēng)險(xiǎn)相關(guān)。 2. SLC22A3-LPAL2-LPA基因簇與中國(guó)東北部漢族人群冠心病發(fā)病風(fēng)險(xiǎn)及血脂水平相關(guān)。 3.在中國(guó)東北部漢族人群中位于LPA基因上的rs9364559位點(diǎn)可能參與冠心病的發(fā)生與發(fā)展。 4.多個(gè)SNPs位點(diǎn)同時(shí)存在可能對(duì)冠心病發(fā)病風(fēng)險(xiǎn)有不同的影響。 第二部分中國(guó)東北部漢族人群SLC22A3-LPAL2-LPA基因簇mRNA表達(dá)水平與冠心病發(fā)病風(fēng)險(xiǎn)的關(guān)系 目的： 分析SLC22A3, LPAL2和LPA基因mRNA表達(dá)水平與冠心病發(fā)病風(fēng)險(xiǎn)的關(guān)系；闡述SLC22A3-LPAL2-LPA基因簇遺傳變異對(duì)mRNA表達(dá)水平的影響。 方法： 選擇2012年在吉林大學(xué)第一醫(yī)院二部心血管內(nèi)科確診并進(jìn)行住院治療的92例冠心病患者為病例組，選擇同期在吉林大學(xué)第一醫(yī)院二部心血管內(nèi)科進(jìn)行診治的非冠心病患者32例為對(duì)照組。采用實(shí)時(shí)熒光定量PCR方法對(duì)SLC22A3, LPAL2和LPA基因mRNA的表達(dá)水平進(jìn)行測(cè)定。分析病例組與對(duì)照組之間及攜帶不同基因型病例組人群間目的基因mRNA表達(dá)水平的差異。以上統(tǒng)計(jì)學(xué)分析均采用SPSS16.0軟件。 結(jié)果： 1.病例組中吸煙、高血壓病人數(shù)均高于對(duì)照組，病例組患者低密度脂蛋白膽固醇、高密度脂蛋白膽固醇、脂蛋白(a)水平高于對(duì)照組，并且以上差異均具有統(tǒng)計(jì)學(xué)意義（P0.05）。 2.與對(duì)照組人群相比，冠心病患者外周血中LPA和SLC22A3基因mRNA的表達(dá)水平顯著增高（P0.05）；兩組間外周血中LPAL2mRNA表達(dá)水平無顯著差異（P0.05）。rs9346816、rs2221750、rs3127596、rs9364559、rs1367211、 rs6415085和rs9347438位點(diǎn)不同基因型患者外周血SLC22A3、LPAL2和LPAmRNA表達(dá)水平均無顯著差異（P0.05）。 結(jié)論： 1.外周血LPA和SLC22A3基因mRNA表達(dá)水平升高可能與中國(guó)東北部漢族人群冠心病的發(fā)病風(fēng)險(xiǎn)相關(guān)。 2.染色體6q26-27區(qū)域SLC22A3-LPAL2-LPA基因簇上rs9346816、rs2221750、rs3127596、rs9364559、rs1367211、rs6415085和rs9347438位點(diǎn)的多態(tài)性與冠心病患者外周血中SLC22A3、LPAL2、LPA基因mRNA的表達(dá)水平無關(guān)，因此，上述SNPs位點(diǎn)可能不是通過影響基因轉(zhuǎn)錄水平參與冠心病的發(fā)生。 第三部分SLC22A3-LPAL2-LPA基因簇蛋白表達(dá)與冠心病發(fā)病風(fēng)險(xiǎn)的關(guān)系 目的： 研究SLC22A3-LPAL2-LPA基因簇蛋白表達(dá)與冠心病發(fā)病風(fēng)險(xiǎn)的關(guān)系；闡明SLC22A3-LPAL2-LPA基因簇遺傳變異對(duì)其相鄰基因蛋白表達(dá)水平的影響。 方法： 選擇2012年在吉林大學(xué)第一醫(yī)院二部心血管內(nèi)科確診并進(jìn)行住院治療的55例冠心病患者為病例組，選擇同期在吉林大學(xué)第一醫(yī)院二部心血管內(nèi)科進(jìn)行健康體檢的正常人15例為對(duì)照組。采用western blot方法對(duì)外周血SLC22A3基因蛋白表達(dá)水平進(jìn)行測(cè)定。用Quantity One軟件對(duì)蛋白表達(dá)進(jìn)行半定量分析。采用SPSS16.0統(tǒng)計(jì)軟件包進(jìn)行統(tǒng)計(jì)學(xué)分析。 結(jié)果： 1.冠心病患者外周血中SLC22A3蛋白表達(dá)水平明顯高于對(duì)照組，具有顯著差異（P0.05）。 2.位于SLC22A3-LPAL2-LPA基因簇上rs9346816、rs2221750、rs3127596、rs9364559、rs1367211、rs6415085和rs9347438位點(diǎn)不同基因型間SLC22A3蛋白表達(dá)水平無顯著性差異（P0.05）。 結(jié)論： 1.冠心病患者外周血中SLC22A3蛋白表達(dá)水平增高可能是中國(guó)東北部漢族人群冠心病發(fā)病機(jī)制之一。 2. SLC22A3-LPAL2-LPA基因簇可能通過增加冠心病患者外周血中LPA和SLC22A3基因mRNA轉(zhuǎn)錄水平及SLC22A3蛋白表達(dá)水平影響冠心病發(fā)生。
[Abstract]:The relationship between the single nucleotide polymorphism of SLC22A3-LPAL2-LPA gene cluster and the risk of coronary heart disease and the level of blood lipids in the first part
Objective:
Objective to explore the relationship between rs9346816, rs2221750, rs3127596, rs9364559, rs1367211, rs6415085, rs9347438 and rs9355296 loci on the SLC22A3-LPAL2-LPA gene cluster and the risk of coronary heart disease and blood lipids in the Han population of Northeast China.
Method:
This study used a case-control study. The case group and the control group were 551 cases and 544 cases. The study population are Han nationality in Northeast Chinese population, and the individual unrelated cases. Population screening since 2009 ~2012 years in No.1 Hospital of Jilin University Department of cardiovascular medicine and diagnosis of two hospitalized patients with coronary heart disease in the same period. No.1 Hospital of Jilin University medical examination center of normal people as control group. Using Sequenom MassArray system on the SLC22A3-LPAL2-LPA gene cluster on rs9346816, rs2221750, rs3127596, rs9364559, rs1367211, rs6415085, rs9347438 and rs9355296 loci were genotyped and epidemiological data were collected at the same time. The research object of general data using statistical software SPSS16.0, and the allele the relationship between genotype and coronary heart disease, correlation analysis and different base SNPs and risk factors of coronary heart disease The relationship between blood lipid level was analyzed by SHEsis software. The relationship between haplotypes and coronary heart disease was analyzed by Haploview software. Linkage disequilibrium analysis was performed by using software. Multiple linear regression analysis was used to correct the influence of confounding factors on the results.
Result:
1. cases in the number of smokers was higher than the control group, and patients with hypertension, the number of patients with diabetes were more than the control group, serum total cholesterol group cases, low density lipoprotein cholesterol, high density lipoprotein cholesterol, lipoprotein (a) levels higher than the control group, and the above differences were statistically significant (P0.05).
2. after adjusting for confounding factors, there was significant difference in genotype distribution and allele distribution between rs9364559 locus and allele in SLC22A3-LPAL2-LPA group and control group (X2=7.126, P=0.028, X2=4.436, P=0.039).
3. haplotype analysis showed 7 loci haplotype in GAAAGTG and GGAAGTG and the risk for coronary heart disease (P0.05), relative risk of coronary heart disease with GAAAGTG haplotype groups may reduce the incidence of coronary heart disease, but the risk of carrying GGAAGTG haplotype population could increase. Consisting of 6 SNP loci haplotype in risk 14 haplotype and coronary heart disease (P0.05), of which 8 haplotypes may increase the risk of coronary heart disease, 6 haplotypes may reduce the risk of coronary heart disease. Consisting of 5 SNP loci haplotype in risk related 39 haplotypes with coronary heart disease (P0.05), of which 21 haplotypes may increase the risk of coronary heart disease, 18 haplotypes may reduce the risk of coronary heart disease. The risk of coronary heart disease and 49 haplotypes consisting of 4 SNP loci haplotype associated (P0.05) Among them, 22 haplotypes may increase the risk of coronary heart disease, 27 haplotypes may reduce the risk of coronary heart disease. Consisting of 3 SNP loci haplotype in risk related 39 haplotypes with coronary heart disease (P0.05), of which 19 haplotypes may increase the risk of coronary heart disease, 20 haplotypes may reduce the risk of coronary heart disease. Consisting of 2 SNP loci haplotype in risk related 9 haplotypes with coronary heart disease (P0.05), of which 3 haplotypes may increase the risk of coronary heart disease, 6 haplotypes may reduce the risk of coronary heart disease.
4., rs9346816 loci located on the SLC22A3 gene showed significant difference in LDL-C and TC levels among different genotypes (P0.05). Lp (a) and LDL-C level between different rs6415085 genotypes on LPA gene had significant difference (P0.05).
Conclusion:
1. smoking, hypertension, diabetes, serum total cholesterol, low density lipoprotein cholesterol (LDL), and lipoprotein (a) levels may be associated with the risk of coronary heart disease.
The 2. SLC22A3-LPAL2-LPA gene cluster is associated with the risk of coronary heart disease and the level of blood lipid in the Han population in the northeastern part of China.
3. the rs9364559 loci, located in the LPA gene in the Han population in northeastern China, may be involved in the development and development of coronary heart disease.
At the same time, more than 4. SNPs loci may have different effects on the risk of coronary heart disease.
The relationship between the expression level of SLC22A3-LPAL2-LPA gene cluster mRNA and the risk of coronary heart disease in the second part of the Han population in northeastern China
Objective:
Objective to analyze the relationship between mRNA expression level of SLC22A3, LPAL2 and LPA gene and the risk of coronary heart disease, and elaborate the influence of genetic variation of SLC22A3-LPAL2-LPA gene cluster on mRNA expression level.
Method:
In 2012 92 cases of hospitalized patients with coronary heart disease and the treatment of the case group in No.1 Hospital of Jilin University two Department of cardiovascular medicine were selected, were treated in No.1 Hospital of Jilin University Department of cardiovascular medicine two non coronary heart disease patients with 32 cases as control group. Using real-time quantitative PCR method of SLC22A3, the expression level of LPAL2 and LPA genes of mRNA were determined. The analysis between the case group and the control group and carrying different genotype differences in expression levels of mRNA gene groups. These cases statistical analysis was performed using SPSS16.0 software.
Result:
1., the number of smokers and hypertension patients in the case group was higher than that in the control group. The LDL cholesterol, high-density lipoprotein cholesterol and lipoprotein (a) level in the case group were higher than those in the control group, and the above differences were statistically significant (P0.05).
2. compared with the control group, the expression level of LPA and SLC22A3 in the peripheral blood of mRNA gene in patients with coronary heart disease were significantly higher (P0.05) between the two groups; the expression of LPAL2mRNA in peripheral blood level had no significant difference (P0.05).Rs9346816, rs2221750, rs3127596, rs9364559, rs1367211, SLC22A3, rs6415085 and rs9347438 loci in peripheral blood of patients with different genotypes LPAL2, and no significant difference in LPAmRNA expression level (P0.05).
Conclusion:
The increase of the expression level of LPA and SLC22A3 gene mRNA in peripheral blood may be associated with the risk of coronary heart disease in the Han population in northeastern China.
The 2. chromosome 6q26-27 region SLC22A3-LPAL2-LPA gene cluster on rs9346816, rs2221750, rs3127596, rs9364559, rs1367211, rs6415085 and rs9347438 loci polymorphism and coronary heart disease in patients with peripheral blood SLC22A3, LPAL2, LPA gene expression level of mRNA. Therefore, the SNPs locus may not be affected by the gene transcription level in coronary heart disease.
The relationship between the third part of SLC22A3-LPAL2-LPA gene cluster protein expression and the risk of coronary heart disease
Objective:
Objective to study the relationship between the expression of SLC22A3-LPAL2-LPA gene cluster and the risk of coronary heart disease (CHD), and clarify the influence of SLC22A3-LPAL2-LPA gene cluster genetic variation on the expression level of its adjacent gene protein.
Method:
In 2012 55 cases of hospitalized patients with coronary heart disease and the treatment of the case group in No.1 Hospital of Jilin University two Department of cardiovascular medicine diagnosis, normal people choose the same period the health examination in No.1 Hospital of Jilin University two Department of cardiovascular medicine. 15 cases as the control group. Using the Western blot method of peripheral blood SLC22A3 gene expression levels were determined by semi quantitative analysis of the protein. The expression of Quantity by One software. The data were analyzed by SPSS16.0 statistical software.
Result:
1. the expression level of SLC22A3 protein in peripheral blood of patients with coronary heart disease was significantly higher than that in the control group, with significant difference (P0.05).
2., on the SLC22A3-LPAL2-LPA gene cluster, there was no significant difference in the expression level of SLC22A3 protein between different genotypes among rs9346816, rs2221750, rs3127596, rs9364559, rs1367211, rs6415085 and rs9347438 locus (P0.05).
Conclusion:
1. the increase of SLC22A3 protein expression in peripheral blood of patients with coronary heart disease may be one of the pathogenesis of coronary heart disease in the Han population in northeastern China.
2., SLC22A3-LPAL2-LPA gene cluster may affect coronary heart disease by increasing the mRNA transcription level of LPA and SLC22A3 genes in peripheral blood and the expression level of SLC22A3 protein in patients with coronary heart disease.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R541.4

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本文編號(hào)：1762170