本文選題：子癇前期 + VCAM-1　； 參考：《南方醫(yī)科大學(xué)》2014年碩士論文

【摘要】：研究背景 子癇前期是妊娠期特有的疾病,以高血壓、蛋白尿、全身內(nèi)皮細胞激活受損及過度的炎癥反應(yīng)為特征的一組綜合征,在我國發(fā)病率為9.4%-10.4%。該病病情嚴重時患者可因抽搐、昏迷、心腦血管意外、心功能衰竭、肺水腫、肝腎功能衰竭、彌漫性血管內(nèi)出血等而導(dǎo)致死亡；圍產(chǎn)兒可出現(xiàn)胎兒生長受限、胎兒宮內(nèi)窘迫、胎死宮內(nèi)、早產(chǎn)、新生兒窒息等不良結(jié)局,是臨床上導(dǎo)致孕產(chǎn)婦及圍產(chǎn)兒死亡的重要產(chǎn)科疾病,也是我國孕產(chǎn)婦死亡的第二大原因。半個世紀以來,研究者們嘗試從不同角度闡明子癇前期的發(fā)病機制,希望通過對該病的病因?qū)W研究,找到有效的預(yù)測、預(yù)防和治療的方法,然而迄今為止其病因及發(fā)病機制仍未清楚,故對于子癇前期的預(yù)測、預(yù)防仍較為困難。在被廣泛認可的各種病因?qū)W說中,遺傳易感性在子癇前期的發(fā)病中可能扮演著重要角色。作為一種復(fù)雜性疾病,子癇前期的易感基因可以有很多。目前研究較多的子癇前期的易感基因有：(1)內(nèi)皮細胞損傷和血管張力改變易感基因；(2)參與脂類代謝的易感基因；(3)遺傳血凝基因；(4)人白細胞抗原HLA-DR4基因；(5)線粒體基因等。然而,由于子癇前期的“異質(zhì)性”特點,基因易感性在不同人種基因組之間、不同地區(qū)之間也存在差異性分布,加之基因與基因、基因與環(huán)境之間的相互作用,使得尋找易感基因面臨很大挑戰(zhàn)。 粘附分子是介導(dǎo)細胞與細胞之間、細胞與胞外基質(zhì)間相互結(jié)合的細胞表面受體,參與細胞的識別、活化和信號轉(zhuǎn)導(dǎo),在免疫應(yīng)答、炎癥發(fā)生及血栓形成等方面起著重要的作用。血管細胞粘分子-1(vascular cellular adhesion molecule-1VCAM-1)、細胞間粘附分子-1(intercellular adhesion molecule-1, ICAM-1)和血小板內(nèi)皮細胞粘附分子-1(platelet endothelial cell adhesion molecule-1PECAM-1)是細胞粘附分子中的免疫球蛋白超家族成員。細胞表面粘附分子異常表達可能與子癇前期的發(fā)生有重要影響。研究發(fā)現(xiàn)在子癇前期患者血中VCAM-1、ICAM-1和PECAM-1的水平較正常對照組有明顯差異。其機制可能與VCAM-1、ICAM-1和PECAM-1基因參與的炎癥反應(yīng)導(dǎo)致血管內(nèi)皮細胞的損傷,進而引起一系列的病理變化有關(guān)。VCAM-1、ICAM-1和PECAM-1基因均存在著變異和多態(tài)性。這些基因多態(tài)性是否會通過影響子癇前期患者血漿水平的表達而影響子癇前期的發(fā)生、發(fā)展,目前尚不清楚。當(dāng)前對于子癇前期與粘附分子VCAM-1、ICAM-1及PECAM-1的相關(guān)性的研究均局限于蛋白水平,而從基因?qū)W角度去探討其關(guān)系的研究,除Kwon和Tabatabai等報道了ICAM-1基因K469E多態(tài)性與子癇前期相關(guān)性的研究外,尚未見其他文獻報道。而且,由于基因多態(tài)性的種族差異及地域性差異,結(jié)果也可能不同。 目的 本研究旨在探討細胞粘附分子VCAM-1基因rs1041163和rs3181092、ICAM-1基因rs5498及PECAM-1基因rs211865545單核苷酸多態(tài)性與子癇前期的相關(guān)關(guān)系,尋找我國南方地區(qū)漢族人群子癇前期的易感基因,了解子癇前期的發(fā)病機制,為子癇前期的防控和對癥性治療提供依據(jù)。 方法 選擇2011年12月至2013年10月南方醫(yī)院婦產(chǎn)科病房收治的子癇前期患者110例及同一時期健康足月孕婦110例作為對照組。所有入選者均為我國南方地區(qū)漢族人群,單胎妊娠且無血緣關(guān)系的散發(fā)病例,排除輔助生殖技術(shù)妊娠、慢性高血壓疾病、腎病、胎膜早破、妊娠期糖尿病、糖尿病及抗磷脂抗體陽性等免疫系統(tǒng)性疾病的病史者。收集納入研究對象的臨床指標(biāo)(年齡、身高、孕前體重、孕產(chǎn)次、入院時的血壓、子癇前期的發(fā)病孕周或健康足月孕婦的分娩孕周、白細胞計數(shù)、血小板計數(shù)及24h尿蛋白定量)進行比較分析。采用候選基因法選擇VCAM-1基因rs1041163和rs3181092、ICAM-1基因rs5498及PECAM-1基因rs211865545單核苷酸多態(tài)性,用聚合酶鏈反應(yīng)-限制性片段多態(tài)性(PCR-RFLP)方法對這些多態(tài)性位點進行基因分型及DNA序列測序法對PCR-RFLP基因分型的準(zhǔn)確性進一步驗證。運用單因素Logistic回歸分析子癇前期的高危因素及多因素Logistic回歸分析以校正這些高危因素對基因多態(tài)性與子癇前期相關(guān)性造成的影響。并且比較子癇前期組中與子癇前期相關(guān)聯(lián)的多態(tài)性位點各基因型對其發(fā)病孕周、血壓、蛋白尿、白細胞及血小板水平的影響。 結(jié)果 1.通過比較兩組研究對象臨床資料后發(fā)現(xiàn)：孕產(chǎn)婦年齡、孕次、產(chǎn)次及孕前BMI在兩組人群中有統(tǒng)計學(xué)差異,其中,子癇前期組35歲的高齡孕產(chǎn)婦、初孕婦及初產(chǎn)婦都較對照組明顯增多,孕前BMI也較對照組顯著增大。 2. rs1041163、rs3181092、rs5498及rs281865545各單核苷酸多態(tài)性位點的基因型頻率分布都符合Hardy Weinberg平衡定律(p0.05),表明所研究對象來自同一個群體,具有群體代表性。 3. VCAM-1基因rs3181092位點各基因型中,晚發(fā)型子癇前期組AA基因型頻率(40.3%)和AA+AG基因型頻率(91%)高于對照組(22.7%和78.2%),其分布差異在兩組均存在顯著性(p0.05)；基因型頻率相對鳳險顯示攜帶AA基因型和AA+AG基因型者發(fā)生晚發(fā)型子癇前期的風(fēng)險分別是攜帶GG基因型者的4.320倍(OR=4.320,95%CI:1.516-12.308)和2.837倍(OR=2.837,95%CI：1.094-7.357)。晚發(fā)型子癇前期組A等位基因頻率(65.7%)高于對照組(50.5%),其分布差異在兩組存在顯著性(p0.05)；等位基因頻率相對風(fēng)險顯示攜帶A等位基因者發(fā)生晚發(fā)型子癇前期的風(fēng)險是攜帶G等位基因的1.879倍(OR=1.879,95%CI:1.205-2.928)。 4. PECAM-1基因rs281865545位點各基因型中,早發(fā)型子癇前期組CG基因型頻率(65.1%)高于對照組(45.5%),其分布差異在兩組中均存在顯著性(p0.05)；基因型頻率相對風(fēng)險顯示攜帶CG基因型者發(fā)生早發(fā)型子癇前期的風(fēng)險是攜帶CC基因型的2.240倍(OR=2.240,95%CI:1-5.018)。早發(fā)型子癇前期組CG+GG基因型頻率(74.4%)和G等位基因頻率(41.9%)高于對照組(60%和37.3%),但其分布在兩組中均無統(tǒng)計學(xué)差異(p0.05)。 5. VCAM-1基因rs1041163位點各基因型頻率和等位基因頻率在子癇前期組和對照組中的分布差異無顯著性(p0.05)。ICAM-1基因rs5498位點各基因型中,子癇前期組AG基因型頻率(49.1%)高于對照組(41.8%),但其分布在兩組中無顯著差異(p0.05)；G等位基因頻率(27.3%)高于對照組(24.5%),但其分布在兩組中亦無統(tǒng)計學(xué)差異(p0.05)。 6.通過單因素Logistic回歸分析發(fā)現(xiàn),高齡、初孕、初產(chǎn)及孕前BMI是影響子癇前期發(fā)生的危險因素,可增加子癇前期發(fā)病的風(fēng)險。經(jīng)過多因素Logistic回歸分析調(diào)整高齡、初孕、初產(chǎn)及孕前BMI后,VCAM-1基因rs3181092單核苷酸多態(tài)性的AA基因型仍是影響晚發(fā)型子癇前期發(fā)生的獨立危險因素(p0.05)。調(diào)整后的基因型頻率相對風(fēng)險顯示攜帶rs3181092單核苷酸多態(tài)性AA基因型者發(fā)生晚發(fā)型子癇前期的風(fēng)險是攜帶GG基因型者的3.927倍(OR=3.927,95%CI:1.195-12.905)。經(jīng)過多因素Logistic回歸分析調(diào)整高齡、初孕、初產(chǎn)及孕前BMI后,PECAM-1基因rs281865545多態(tài)性位點的CG基因型仍然是影響早發(fā)型子癇前期發(fā)生的獨立危險因素(p0.05),調(diào)整后的基因型頻率相對風(fēng)險顯示攜帶rs281865545多態(tài)性位點的CG基因型者發(fā)生早發(fā)型子癇前期的風(fēng)險是攜帶CC基因型者的4.193倍(OR=4.193,95%CI：1.456-12.079)。 7.白細胞和血小板在子癇前期患者VCAM-1基因rs3181092位點各基因型間的分布差異存在顯著性(p0.05),AA基因型攜帶者的白細胞和血小板水平低于GG基因型和AG基因型攜帶者,而各基因型間發(fā)病孕周、血壓及尿蛋白并無明顯差異；PECAM-1基因rs281865545位點各基因型間各臨床指標(biāo)差異亦無統(tǒng)計學(xué)意義。 結(jié)論 1.首次發(fā)現(xiàn)VCAM-1基因rs3181092單核苷酸多態(tài)性AA基因型和AA+AG基因型與我國南方地區(qū)漢族人群子癇前期,特別是晚發(fā)型子癇前期的發(fā)生有關(guān),AA基因型可能是我國南方地區(qū)漢族人群晚發(fā)型子癇前期的易感基因型,A等位基因的攜帶者與晚發(fā)型子癇前期有較高的遺傳易感性。 2.首次發(fā)現(xiàn)了PECAM-1基因rs281865545單核苷酸多態(tài)性CG基因型與我國南方地區(qū)漢族人群子癇前期,尤其是早發(fā)型子癇前期的發(fā)生有關(guān),CG基因型可能是我國南方地區(qū)漢族人群早發(fā)型子癇前期的易感基因型。 3. VCAM-1基因rs1041163單核苷酸多態(tài)性及ICAM-1基因rs5498單核苷酸多態(tài)性與我國南方地區(qū)漢族人群子癇前期無關(guān)聯(lián)。 4. VCAM-1基因rs3181092單核苷酸多態(tài)性AA基因型可影響子癇前期患者白細胞及血小板的水平。 5.高齡、初孕、初產(chǎn)及孕前BMI也是影響子癇前期發(fā)生的危險因素,可增加子癇前期發(fā)病的風(fēng)險；子癇前期是多因素互相影響和共同作用的結(jié)果。
[Abstract]:Background of the study

Preeclampsia is a group of syndrome characterized by pregnancy - specific diseases , such as hypertension , proteinuria , activation of systemic endothelial cells and excessive inflammatory response . In China , the incidence rate is 9.4 % - 10.4 % . In severe cases , the patient can cause death due to convulsions , coma , cardiovascular and cerebrovascular accidents , cardiac failure , pulmonary edema , liver and kidney function failure , diffuse vascular hemorrhage , etc .
In half a century , researchers have tried to clarify the pathogenesis of pre - eclampsia and find effective methods of prediction , prevention and treatment .
( 2 ) the susceptible genes involved in lipid metabolism ;
( 3 ) genetic blood coagulation gene ;
( 4 ) HLA - DR4 gene of human leukocyte antigen ;
( 5 ) mitochondrial gene and so on . However , due to the " heterogeneity " in the early - eclampsia , there is a difference distribution between different regions of the gene , and the interaction between the gene and the gene , gene and environment makes it difficult to find the susceptible gene .

Vascular cell adhesion molecule - 1 ( VCAM - 1 ) , intercellular adhesion molecule - 1 ( ICAM - 1 ) and platelet endothelial cell adhesion molecule - 1 ( platelet endothelial cell adhesion molecule - 1 PECAM - 1 ) have a significant effect on the occurrence and development of VCAM - 1 , ICAM - 1 and PECAM - 1 .

Purpose

The purpose of this study was to investigate the relationship between the single nucleotide polymorphism of the VCAM - 1 gene rs1041163 and rs181092 , the ICAM - 1 gene rs5498 and the PECAM - 1 gene , rs2118655 45 , in the early stage of eclampsia .

method

The clinical indexes ( age , height , pre - pregnancy weight , pregnancy birth time , blood pressure during pregnancy , gestational age , gestational age , gestational age , gestational age , gestational diabetes , diabetes mellitus and anti - phospholipid antibody positive ) were analyzed by using single - factor logistic regression analysis .

Results

1 . After comparing the clinical data of the two groups , it was found that the maternal age , the pregnancy time , the birth time and the pre - pregnancy BMI were significantly different in the two groups . Among them , the 35 - year - old pregnant woman , the early pregnant woman and the pregnant woman in the pre - eclampsia group were obviously increased compared with the control group , and the BMI of the pregnant women was also significantly increased compared with the control group .

2 . The genotype frequency distribution of rs1041163 , rs181092 , rs5498 and rs2818655 45 single nucleotide polymorphism loci was in accordance with Hardy ' s equilibrium law ( p0.05 ) , indicating that the subjects were from the same group and were representative of population .

3 . The frequencies of AA genotype ( 40.3 % ) and AA + AG genotype frequencies ( 91 % ) in the early - onset pre - eclampsia group were higher than those in the control group ( 22 . 7 % and 78.2 % ) .
Compared with control group ( OR = 4.320 , 95 % CI : 1.516 - 12.308 ) and 2.837 - fold ( OR = 2.837 , 95 % CI : 1.094 - 7.357 ) , the frequency of late - onset pre - eclampsia ( 65.7 % ) was higher than that of the control group ( 50.5 % ) .
The relative risk of allele frequencies showed that the risk of late onset of onset of late onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of onset of pre - eclampsia was 1.879 times ( OR = 1.879 , 95 % CI : 1.205 - 2.928 ) carrying the G allele .

4 . The frequency of CG genotype in early - onset pre - eclampsia group ( 65.1 % ) was higher than that in the control group ( 45.3 % ) , and the distribution difference was significant ( p < 0.05 ) .
The relative risk of genotype frequency showed that the risk of early onset of pre - eclampsia was 2.240 times ( OR = 2.240 , 95 % CI : 1 - 5.018 ) of CC genotype . The frequency of CG + GG genotype ( 74.4 % ) and G allele frequency ( 41.9 % ) in early - onset pre - eclampsia group were higher than those in control group ( 60 % and 37.3 % ) , but their distribution was not statistically significant in both groups ( p . 05 ) .

5 . There was no significant difference in the frequency and allele frequencies of the rs1041163 locus of VCAM - 1 gene in the pre - eclampsia group and the control group ( p < 0.05 ) . The frequency of the AG genotype in the early - eclampsia group ( 49.1 % ) was higher than that in the control group ( 41.8 % ) , but the distribution of the distribution of the genotype frequencies and allele frequencies in the early - eclampsia group was higher than that in the control group ( 41.8 % ) .
The frequency of G allele ( 27.3 % ) was higher than that of the control group ( 24.5 % ) , but its distribution was not statistically significant in both groups ( p < 0.05 ) .

6 . A single - factor logistic regression analysis showed that the risk factors of early onset of pre - eclampsia were the age , early pregnancy , early pregnancy and pre - pregnancy BMI , which could increase the risk of pre - eclampsia . After multivariate logistic regression analysis , the genotype of the single nucleotide polymorphism of rs2818655 was 3.927 times ( OR = 3.927 , 95 % CI : 1.195 - 12.905 ) . The risk of genotype frequency after adjustment showed that the risk of early - onset pre - eclampsia was 4.193 times that of CC genotype ( OR = 4.193 , 95 % CI : 1.456 - 12.079 ) .

7 . There was a significant difference in the distribution of VCAM - 1 gene rs181092 in patients with pre - eclampsia ( p < 0.05 ) . The levels of leukocyte and platelet in AA genotype carriers were lower than those of GG genotype and AG genotype carriers , but there was no significant difference in the gestational weeks , blood pressure and urinary protein among the genotypes .
There was no significant difference in clinical parameters between the genotypes of PECAM - 1 and rs2818655 .

Conclusion

1 . The single nucleotide polymorphism AA genotype and AA + AG genotype of the VCAM - 1 gene were found to be related to the pre - eclampsia of Han population in the southern region of China , especially in the pre - eclampsia , AA genotype could be the susceptible genotype of late - onset pre - eclampsia in the Han population in the southern region of China .

2 . The polymorphism of the single nucleotide polymorphism of the PECAM - 1 gene rs2818655 45 was first found to be related to the pre - eclampsia of Han population in the southern region of China , especially in the early - onset pre - eclampsia , and the CG genotype could be the susceptible genotype of early - onset pre - eclampsia in the Han population in the southern region of China .

3 . The single nucleotide polymorphism of the VCAM - 1 gene rs1041163 and the single nucleotide polymorphism of the ICAM - 1 gene rs5498 were not associated with the pre - eclampsia in the Han population in the southern region of China .

4 . The single nucleotide polymorphism of the single nucleotide polymorphism of the VCAM - 1 gene rs181092 can affect the level of white blood cells and platelets in patients with pre - eclampsia .

5 . Age , early pregnancy , early birth and pre - pregnancy BMI are also the risk factors which affect the pre - eclampsia , which can increase the risk of pre - eclampsia .
Preeclampsia is the result of multi - factor interaction and coaction .

【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R714.244

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本文編號：1760825