Hcy代谢相关酶基因、SAA基因与新疆维、汉两民族静脉血栓栓塞症的相关性研究

发布时间：2018-04-20 03:24

本文选题：静脉血栓栓塞症 + 同型半胱氨酸　；参考：《新疆医科大学》2016年博士论文

【摘要】：目的:(1)分析同型半胱氨酸(Hcy)、传统危险因素及饮食与VTE的关系,了解环境因素在维汉民族VTE患者中的差异,有助于个体化诊治。(2)探讨Hcy代谢相关酶基因,即MTHFR、MS、MSR基因位点多态性与VTE的关系,以及基因-基因、基因-环境因素对VTE的影响,为识别VTE的高危人群提供临床依据。(3)从炎症角度,初步探讨SAA及其基因多态性与VTE的关系,为阐明VTE的发病机制提供新思路。方法:(1)采用病例-对照研究,选择维族VTE162例、汉族VTE184例,性别和年龄匹配的健康体检者维族203例、汉族230例,收集所有研究对象的临床资料及食物摄入情况,应用ELESA法检测Hcy、叶酸、维生素B12水平,分析环境因素与VTE的关联性。(2)应用聚合酶链式反应-限制性片段长度多态性(PCR-PFLP)技术检测MTHFR基因C677T、A1298C、MS A2756G、MSR A66G位点多态性,分析基因位点多态性与VTE、Hcy的关系,采用叉生分析探讨基因-基因、基因-环境因素对VTE的交互作用。(3)应用ELESA法检测SAA水平,利用PCR-PFLP技术检测SAA基因rs12218和rs4638289多态性,分析其与VTE的关系。结果:(1)维汉民族VTE患者吸烟所占比例均较高,经t检验后有统计学意义,并在多因素回归分析中,得出吸烟是VTE的独立危险因素。相对于对照组,吸烟使得维吾尔族人群发生VTE风险增加2.199倍;汉族人群发生VTE的风险增加1.952倍。(2)维吾尔族VTE的BMI(27.69±4.07比25.77±4.17)kg/m2、腰围(85.08±9.60比81.54±9.94)cm高于对照组,且差异有统计学意义(P0.05);腹型肥胖是VTE的独立危险因素,OR=4.114,95%CI:2.242-7.549;而汉族VTE的腰围(83.31±10.13比80.01±10.64)cm高于对照组,且差异有统计学意义(P0.05),而BMI(24.91±3.63比24.45±3.44)kg/m2在两组间无差别,腹型肥胖同样是汉族VTE的危险子,OR=1.676,95%CI:1.060-2.650。(3)第一部分中,维吾尔族VTE人群的CRP高于正常对照组(6.44±4.17比4.75±3.54)mg/L,经非条件logistic回归分析后,提示CRP不是维吾尔族VTE的独立危险因素(OR=1.030,95%CI:0.968-1.096,P=0.352)。但在汉族人群中,VTE的CRP高于正常对照组(6.33±4.34比4.60±3.13)mg/L,且差异有统计学意义(P0.05),校正后,CRP是VTE的独立危险因素(OR=1.174,95%CI:1.100-1.253,P0.001)。(4)与对照组比较,无论维吾尔族还是汉族人群,VTE组的Hcy水平均明显升高,且有统计学意义,分别为(13.36±7.84比11.03±3.92)umol/L和(13.26±4.54比10.56±3.16)umol/L,P0.05;VTE组的叶酸水平都降低,分别为(20.29±8.39比22.57±10.09)nmol/L和(20.02±7.86比23.31±9.49)nmol/L,P0.05;而维生素B12的浓度分别在维汉民族的两组中均无显著性差异,P0.05。(5)Hcy水平升高是维汉民族的独立危险因素,其中维吾尔族人群中,高Hcy血症增加VTE发生风险的OR值=1.879,95%CI1.023-3.450;汉族人群中高Hcy血症增加VTE发生风险的OR值=2.113,95%CI1.283-3.480。(6)维吾尔族VTE组红肉及加工肉类摄入量高于对照组(274.79±114.54比203.39±97.709)g/天,差异有统计学意义,经非条件Logistic多因素分析,红肉及加工肉类是维吾尔族VTE的独立危险因素之一。汉族人群的红肉及加工肉变量在VTE组明显高于对照组,经非条件Logistic分析,显示不是汉族人群VTE的危险因素之一。(7)汉族VTE组蔬菜类摄入量比对照组少(405.83±101.46比442.89±114.35)g/day,差异有统计学意义,且蔬菜类为VTE的保护性因素。(8)维吾尔族人群,消除吸烟、腹型肥胖、Hcy、TG等危险因素之后,多因素回归分析显示,MTHFR C677T基因的隐性模型与VTE具有相关性(OR=2.182,P=0.011),而其显性模型没有显示与VTE有关联性(OR=1.359,P=0.406)。同样,针对汉族人群进行多因素回归分析,MTHFR C677T基因的隐性模型是VTE的危险因素之一(OR=1.831,P=0.010)。而MTHFR A1298C、MS A2756G和MSR A66G基因多态性及各遗传模型均与VTE不存在相关性。(9)MTHFR C677T基因型与Hcy、Vit B12、叶酸水平的关系显示,Hcy水平在校正前及校正性别、民族、吸烟及腹型肥胖等混杂因素后,显性模型、隐性模型差别均有统计学意义(P0.05)。(10)维族MTHFR C677T的TT型与MSR A66G的GG型同时存在时的OR为3.977,95%CI:1.033-15.585,P=0.002;维族MTHFR 677TT型和吸烟同时暴露时的OR=4.223,95%CI:1.404-12.695,P=0.001;汉族MTHFR 677TT型和吸烟同时暴露时的OR=4.272,95%CI:1.798-10.153,P0.001。(11)与对照组比较,维汉族人群的VTE组的SAA水平均升高,分别为(6.52±4.07比5.45±2.79)mg/L和(8.29±5.33比6.78±3.27)mg/L,P0.05,经回归分析显示SAA水平不是维、汉族VTE的独立危险因子。(12)SAA基因rs12218和rs4638289多态性在维、汉民族中的分布不存在民族异质性;SAA基因rs12218和rs4638289多态性在VTE组和正常对照组分布差异无统计学意义,均不是VTE的危险因子。结论:(1)行为习惯方面,吸烟是维汉民族VTE的共同危险因素。(2)饮食方面,红肉及加工肉类摄入增多是维族VTE的独立危险因子,而蔬菜类摄入增加是汉族VTE的保护性性因子。(3)VTE患者的Hcy和CRP水平均升高,Hcy是维汉民族共同的危险因素之一,而CRP是汉族VTE的危险因子。(4)MTHFR 677TT型是VTE的独立危险因素,且TT型患者的Hcy水平较高,提示TT基因型及T等位基因可能通过增加血浆Hcy水平,促进血栓形成发展,是VTE的发病机制之一。(5)维族人群MTHFR 677TT型和MSR 66GG型并存时增加VTE发生风险;维汉族MTHFR 677TT型和吸烟并存时同样增加VTE发生风险,为识别高危人群提供帮助。(6)炎症角度,尽管本研究SAA水平及其基因多态性与VTE未显示相关性,但是进一步扩大样本量检测分析可能有新的发现。
[Abstract]:Objective: (1) to analyze the relationship between homocysteine (Hcy), traditional risk factors and diet and VTE, to understand the differences of environmental factors in the VTE patients in the Uygur nationality, and to help the individual diagnosis and treatment. (2) to explore the relationship between Hcy metabolism related enzymes, that is, the relationship between the polymorphisms of MTHFR, MS, MSR loci and VTE, and gene gene, gene and environmental factors on VTE Influence, provide clinical basis for identifying high risk population of VTE. (3) from the point of view of inflammation, the relationship between SAA and its gene polymorphism and VTE is preliminarily explored to provide new ideas for clarifying the pathogenesis of VTE. Methods: (1) a case control study was used to select the VTE162 cases of the Uygur ethnic group, the Han nationality VTE184, the gender and age matched health examiners, 203 cases of the Han nationality, the Han nationality, and the Han nationality 230 cases, the clinical data and food intake of all the subjects were collected, the levels of Hcy, folic acid, vitamin B12 were detected by ELESA, and the correlation between the environmental factors and VTE was analyzed. (2) the polymerase chain reaction restriction fragment length polymorphism (PCR-PFLP) technique was used to detect the MTHFR gene C677T, A1298C, MS A2756G, MSR A66G locus polymorphism. The relationship between gene locus polymorphism and VTE, Hcy, the interaction of gene gene, gene and environment factor on VTE was investigated by cross analysis. (3) SAA level was detected by ELESA method, PCR-PFLP technique was used to detect SAA gene rs12218 and rs4638289 polymorphism, and the relationship between the SAA gene and VTE was analyzed. (1) the proportion of smokers in the Uygur nationality VTE patients were all in proportion. Higher, after t test, there were statistical significance, and in multiple regression analysis, smoking was an independent risk factor for VTE. Compared with the control group, the risk of VTE increased by 2.199 times in Uygur population, and the risk of VTE in the Han population increased 1.952 times. (2) BMI (27.69 + 4.07 to 25.77 + 4.17) kg/m2 and waist circumference (8). 5.08 + 9.60 ratio 81.54 + 9.94) cm higher than the control group, and the difference was statistically significant (P0.05); abdominal obesity was an independent risk factor for VTE, OR=4.114,95%CI:2.242-7.549, while the waist circumference of the Han VTE (83.31 + 10.13 to 80.01 + 10.64) cm was higher than the control group, and the difference was statistically significant (P0.05), and BMI (24.91 + 3.63 / 24.45 + 3.44) kg/m2 was among the two groups. No difference, abdominal obesity was also the risk child of VTE in the Han nationality. In the first part of OR=1.676,95%CI:1.060-2.650. (3), the CRP of Uygur VTE was higher than that of normal control group (6.44 + 4.17 / 4.75 + 3.54) mg/L. After unconditional logistic regression analysis, CRP was not an independent risk factor for Uygur VTE (OR=1.030,95%CI:0.968-1.096, P=0.352). But in the Han population, the CRP of VTE was higher than that of the normal control group (6.33 + 4.34 / 4.60 + 3.13) mg/L, and the difference was statistically significant (P0.05). After correction, CRP was an independent risk factor of VTE (OR=1.174,95%CI:1.100-1.253, P0.001). (4) compared with the control group, the Hcy level of the VTE group was significantly increased, and there was a series of differences compared with the control group. The significance of the study was (13.36 + 7.84 to 11.03 + 3.92) umol/L and (13.26 + 4.54 to 10.56 + 3.16) umol/L, P0.05, and VTE group of folic acid decreased, respectively (20.29 + 8.39 / 22.57 + 10.09) nmol/L and nmol/L, P0.05, respectively, and there was no significant difference in the concentration of vitamin B12 in the groups of the Uygur nationality, P0.05 (5) the elevation of Hcy level is an independent risk factor for the Uygur ethnic group. Among the Uygur population, high Hcy hyperemia increases the OR value =1.879,95%CI1.023-3.450 of the risk of VTE, and the OR value =2.113,95%CI1.283-3.480. (6) in the Han population, which increases the risk of VTE, is higher than that of the control group (274 .79 + 114.54 to 203.39 + 97.709) g/ days, the difference was statistically significant. Red meat and processed meat were one of the independent risk factors for Uygur VTE by unconditional Logistic multiple factors analysis. The red meat and processed meat variables in the Han population were significantly higher in the VTE group than in the control group. The non conditional Logistic analysis showed that the risk factors of VTE in the Han population were not the cause. (7) the intake of vegetable and vegetable in the VTE group of Han nationality was less than that of the control group (405.83 + 101.46 / 442.89 + 114.35) g/day, and the difference was statistically significant, and the vegetable was the protective factor of VTE. (8) the Uygur population, after the elimination of smoking, abdominal obesity, Hcy, TG and other risk factors, the recessive model and V of the MTHFR C677T gene showed that the MTHFR C677T gene was the recessive model and V. TE has correlation (OR=2.182, P=0.011), and its dominant model does not show association with VTE (OR=1.359, P=0.406). Similarly, the recessive model of the MTHFR C677T gene is one of the risk factors of VTE (OR=1.831, P=0.010) for the Han population. There was no correlation between the model and VTE. (9) the relationship between the MTHFR C677T genotype and Hcy, Vit B12, folic acid level showed that the dominant model and the recessive model were statistically significant (P0.05) after Hcy level and the correction of gender, nationality, smoking and abdominal obesity (P0.05). (10) the TT type of the MTHFR C677T was at the same time as the MSR type. The presence of OR was 3.977,95%CI:1.033-15.585, P=0.002, Uygur MTHFR 677TT and OR=4.223,95%CI:1.404-12.695, P=0.001, MTHFR 677TT and cigarette exposure at the same time, P0.001. (11), compared with the control group, the level of the VTE group in the Han population increased, respectively (6.52 Mg/L and (8.29 + 5.33 / 6.78 + 3.27) mg/L, P0.05, and P0.05. The regression analysis showed that SAA level was not a dimension, the independent risk factor of VTE in Han nationality. (12) the polymorphism of rs12218 and rs4638289 in the SAA gene was in the dimension, the distribution of the Han nationality did not exist, and the SAA based polymorphism of rs12218 and rs4638289 was distributed in the VTE group and the normal control group. The difference was not statistically significant and not the risk factor of VTE. (1) smoking is a common risk factor for the VTE of the Uygur nationality. (2) the increasing intake of red meat and processed meat is an independent risk factor for the Uygur VTE, while the increase in vegetable intake is the protective factor of the Han VTE. (3) the level of Hcy and CRP in VTE patients. Hcy is one of the common risk factors of the Uygur Han nationality, and CRP is a dangerous factor of VTE in Han nationality. (4) MTHFR 677TT is an independent risk factor of VTE, and the Hcy level of TT type patients is higher. It suggests that the TT genotype and T allele may promote the development of thrombus by increasing the Hcy level of plasma, which is one of the pathogenesis of VTE. (5) Uygur nationality The co-existence of MTHFR 677TT and MSR 66GG in the population increases the risk of VTE; the co-existence of MTHFR 677TT and smoking in the Han nationality also increases the risk of VTE to help identify high-risk groups. (6) the inflammatory angle, although the level of SAA and its genetic polymorphisms are not associated with VTE, but further enlargement of sample measurement and analysis can be made. There's a new discovery.

【学位授予单位】：新疆医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R543.6

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