發(fā)布時(shí)間：2018-04-20 03:24

  本文選題：靜脈血栓栓塞癥 + 同型半胱氨酸��； 參考：《新疆醫(yī)科大學(xué)》2016年博士論文

【摘要】：目的:(1)分析同型半胱氨酸(Hcy)、傳統(tǒng)危險(xiǎn)因素及飲食與VTE的關(guān)系,了解環(huán)境因素在維漢民族VTE患者中的差異,有助于個(gè)體化診治。(2)探討Hcy代謝相關(guān)酶基因,即MTHFR、MS、MSR基因位點(diǎn)多態(tài)性與VTE的關(guān)系,以及基因-基因、基因-環(huán)境因素對VTE的影響,為識別VTE的高危人群提供臨床依據(jù)。(3)從炎癥角度,初步探討SAA及其基因多態(tài)性與VTE的關(guān)系,為闡明VTE的發(fā)病機(jī)制提供新思路。方法:(1)采用病例-對照研究,選擇維族VTE162例、漢族VTE184例,性別和年齡匹配的健康體檢者維族203例、漢族230例,收集所有研究對象的臨床資料及食物攝入情況,應(yīng)用ELESA法檢測Hcy、葉酸、維生素B12水平,分析環(huán)境因素與VTE的關(guān)聯(lián)性。(2)應(yīng)用聚合酶鏈?zhǔn)椒磻?yīng)-限制性片段長度多態(tài)性(PCR-PFLP)技術(shù)檢測MTHFR基因C677T、A1298C、MS A2756G、MSR A66G位點(diǎn)多態(tài)性,分析基因位點(diǎn)多態(tài)性與VTE、Hcy的關(guān)系,采用叉生分析探討基因-基因、基因-環(huán)境因素對VTE的交互作用。(3)應(yīng)用ELESA法檢測SAA水平,利用PCR-PFLP技術(shù)檢測SAA基因rs12218和rs4638289多態(tài)性,分析其與VTE的關(guān)系。結(jié)果:(1)維漢民族VTE患者吸煙所占比例均較高,經(jīng)t檢驗(yàn)后有統(tǒng)計(jì)學(xué)意義,并在多因素回歸分析中,得出吸煙是VTE的獨(dú)立危險(xiǎn)因素。相對于對照組,吸煙使得維吾爾族人群發(fā)生VTE風(fēng)險(xiǎn)增加2.199倍;漢族人群發(fā)生VTE的風(fēng)險(xiǎn)增加1.952倍。(2)維吾爾族VTE的BMI(27.69±4.07比25.77±4.17)kg/m2、腰圍(85.08±9.60比81.54±9.94)cm高于對照組,且差異有統(tǒng)計(jì)學(xué)意義(P0.05);腹型肥胖是VTE的獨(dú)立危險(xiǎn)因素,OR=4.114,95%CI:2.242-7.549;而漢族VTE的腰圍(83.31±10.13比80.01±10.64)cm高于對照組,且差異有統(tǒng)計(jì)學(xué)意義(P0.05),而BMI(24.91±3.63比24.45±3.44)kg/m2在兩組間無差別,腹型肥胖同樣是漢族VTE的危險(xiǎn)子,OR=1.676,95%CI:1.060-2.650。(3)第一部分中,維吾爾族VTE人群的CRP高于正常對照組(6.44±4.17比4.75±3.54)mg/L,經(jīng)非條件logistic回歸分析后,提示CRP不是維吾爾族VTE的獨(dú)立危險(xiǎn)因素(OR=1.030,95%CI:0.968-1.096,P=0.352)。但在漢族人群中,VTE的CRP高于正常對照組(6.33±4.34比4.60±3.13)mg/L,且差異有統(tǒng)計(jì)學(xué)意義(P0.05),校正后,CRP是VTE的獨(dú)立危險(xiǎn)因素(OR=1.174,95%CI:1.100-1.253,P0.001)。(4)與對照組比較,無論維吾爾族還是漢族人群,VTE組的Hcy水平均明顯升高,且有統(tǒng)計(jì)學(xué)意義,分別為(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組的葉酸水平都降低,分別為(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;而維生素B12的濃度分別在維漢民族的兩組中均無顯著性差異,P0.05。(5)Hcy水平升高是維漢民族的獨(dú)立危險(xiǎn)因素,其中維吾爾族人群中,高Hcy血癥增加VTE發(fā)生風(fēng)險(xiǎn)的OR值=1.879,95%CI1.023-3.450;漢族人群中高Hcy血癥增加VTE發(fā)生風(fēng)險(xiǎn)的OR值=2.113,95%CI1.283-3.480。(6)維吾爾族VTE組紅肉及加工肉類攝入量高于對照組(274.79±114.54比203.39±97.709)g/天,差異有統(tǒng)計(jì)學(xué)意義,經(jīng)非條件Logistic多因素分析,紅肉及加工肉類是維吾爾族VTE的獨(dú)立危險(xiǎn)因素之一。漢族人群的紅肉及加工肉變量在VTE組明顯高于對照組,經(jīng)非條件Logistic分析,顯示不是漢族人群VTE的危險(xiǎn)因素之一。(7)漢族VTE組蔬菜類攝入量比對照組少(405.83±101.46比442.89±114.35)g/day,差異有統(tǒng)計(jì)學(xué)意義,且蔬菜類為VTE的保護(hù)性因素。(8)維吾爾族人群,消除吸煙、腹型肥胖、Hcy、TG等危險(xiǎn)因素之后,多因素回歸分析顯示,MTHFR C677T基因的隱性模型與VTE具有相關(guān)性(OR=2.182,P=0.011),而其顯性模型沒有顯示與VTE有關(guān)聯(lián)性(OR=1.359,P=0.406)。同樣,針對漢族人群進(jìn)行多因素回歸分析,MTHFR C677T基因的隱性模型是VTE的危險(xiǎn)因素之一(OR=1.831,P=0.010)。而MTHFR A1298C、MS A2756G和MSR A66G基因多態(tài)性及各遺傳模型均與VTE不存在相關(guān)性。(9)MTHFR C677T基因型與Hcy、Vit B12、葉酸水平的關(guān)系顯示,Hcy水平在校正前及校正性別、民族、吸煙及腹型肥胖等混雜因素后,顯性模型、隱性模型差別均有統(tǒng)計(jì)學(xué)意義(P0.05)。(10)維族MTHFR C677T的TT型與MSR A66G的GG型同時(shí)存在時(shí)的OR為3.977,95%CI:1.033-15.585,P=0.002;維族MTHFR 677TT型和吸煙同時(shí)暴露時(shí)的OR=4.223,95%CI:1.404-12.695,P=0.001;漢族MTHFR 677TT型和吸煙同時(shí)暴露時(shí)的OR=4.272,95%CI:1.798-10.153,P0.001。(11)與對照組比較,維漢族人群的VTE組的SAA水平均升高,分別為(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,經(jīng)回歸分析顯示SAA水平不是維、漢族VTE的獨(dú)立危險(xiǎn)因子。(12)SAA基因rs12218和rs4638289多態(tài)性在維、漢民族中的分布不存在民族異質(zhì)性;SAA基因rs12218和rs4638289多態(tài)性在VTE組和正常對照組分布差異無統(tǒng)計(jì)學(xué)意義,均不是VTE的危險(xiǎn)因子。結(jié)論:(1)行為習(xí)慣方面,吸煙是維漢民族VTE的共同危險(xiǎn)因素。(2)飲食方面,紅肉及加工肉類攝入增多是維族VTE的獨(dú)立危險(xiǎn)因子,而蔬菜類攝入增加是漢族VTE的保護(hù)性性因子。(3)VTE患者的Hcy和CRP水平均升高,Hcy是維漢民族共同的危險(xiǎn)因素之一,而CRP是漢族VTE的危險(xiǎn)因子。(4)MTHFR 677TT型是VTE的獨(dú)立危險(xiǎn)因素,且TT型患者的Hcy水平較高,提示TT基因型及T等位基因可能通過增加血漿Hcy水平,促進(jìn)血栓形成發(fā)展,是VTE的發(fā)病機(jī)制之一。(5)維族人群MTHFR 677TT型和MSR 66GG型并存時(shí)增加VTE發(fā)生風(fēng)險(xiǎn);維漢族MTHFR 677TT型和吸煙并存時(shí)同樣增加VTE發(fā)生風(fēng)險(xiǎn),為識別高危人群提供幫助。(6)炎癥角度,盡管本研究SAA水平及其基因多態(tài)性與VTE未顯示相關(guān)性,但是進(jìn)一步擴(kuò)大樣本量檢測分析可能有新的發(fā)現(xiàn)。
[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.

【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R543.6

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