纤维蛋白原Bβ基因多态性研究

纤维蛋白原Bβ基因多态性可影响血浆中的纤维蛋白原水平,并可能是心脑血栓性疾病的遗传性危险因素,本重点综述了目前已发现的纤维蛋白原Bβ基因多态性位点及相互间关系,以及纤维蛋白原Bβ基因多态性影响血浆中的纤维原水平的机制。     

纤维蛋白原Bβ基因多态性研究

纤维蛋白原 Bβ基因多态性可影响血浆中的纤维蛋白原水平 ,并可能是心脑血栓性疾病的遗传性危险因素。本文重点综述了目前已发现的纤维蛋白原 Bβ基因多态性位点及相互间关系 ,以及纤维蛋白原 Bβ基因多态性影响血浆中的纤维蛋白原水平的机制     

血浆纤维蛋白原Bβ链基因多态性与血浆Fg功能表达的相关性研究

目的分析纤维蛋白原-1420G/A、-993C/T、BsmAIG/C位点基因多态性的分布特征及其对血浆Fg浓度和分子活性等功能表达的影响。方法采用整体抽样的方法选取开滦集团职工1248人,均抽取清晨空腹静脉血测定生化指标及Fg浓度、Fg单体聚合反应速率(FMPV)等指标,并检测基因型。结果 Fg浓度、FMPV、Amax、FMPV/Ama在3位点的野生型与变异型组间无差异(P>0.05);男性组FMPV/Amax低于女性组(P<0.05);高UA组中-1420的GA+AA基因型、-993的CT+TT基因型、Bs-mAI的GC+CC基因型分布频率均高于正常组(P<0.01);在无高血压病史人群中-1420 GA+AA组的FMPV/Amax高于GG组(P<0.05)。结论 -1420和-993位点与BsmAI位点之间具有特殊的链锁不平衡关系,这3个SNPs对于血浆Fg浓度和分子功能表达没有直接的影响;但它们可通过引发血UA等特定因子的变化,而影响血浆Fg分子功能的表达。     

纤维蛋白原Bβ多位点基因多态性与其功能表达和脑梗死类型的关系

目的:研究人体纤维蛋白原(Fibrinogen,Fg)Bβ-854G/A、-455G/A、-249C/T、-148C/T、448G/A和Bcl-1G/A的基因多态性与血浆Fg浓度、分子聚合活性等功能表达指标和脑梗死类型的关系。方法:采用病例对照研究,选取2002年7月-2003年6月在开滦医院神经内科住院的急性脑梗死患者160例,其中脑动脉主干支梗死组(MCI)54例、脑动脉穿通支梗死组(PCI)106例,选取同期在开滦医院健康查体且结果均正常的志愿者160例为对照组,测定所有样本的血浆Fg浓度、纤维蛋白单体聚合反应速率(FMPV)、最大吸光度(Amax)及其比值(FMPV/Amax)等反映Fg分子聚合功能参数和甘油三酯(TG)、极低密度脂蛋白(VLDL)等血液生化指标,应用聚合酶链反应-限制性内切酶片段长度多态性技术进行FgBβ链六位点的基因多态性检测。结果:MCI组Fg浓度、FMPV、FMPV/Amax及PCI组TG、VLDL、FMPV均高于对照组(P0.05);FgBβ-854 A和Bcl-1 A等位基因在三组间分布频率有统计学差异,且MCI和PCI组的GA、AA型分布频率高于对照组(P0.05),其余位点等位基因及基因型分布在三组间均无显著性差异(P0.05);MCI组FgBβ-249T携带者人群Fg、FMPV低于CC型(P0.05);PCI组-148T携带者人群FMPV/Amax高于CC型(P0.05);对照组Bcl-1A携带者人群Fg浓度高于GG型(P0.05),而PCI组此人群则FMPV高于GG型(P0.05)。结论:FgBβ链5’端启动子区-249多态性位点可影响血浆FMPV功能的表达,-148位点是调控血浆Fg分子聚合功能表达的重要部位;3’端Bcl-1是血浆Fg浓度的重要基因调控位点,其变异基因型人群是MCI的遗传易感人群;血浆Fg浓度、FMPV/Amax和FMPV同时异常是MCI的重要危险因素,而仅FMPV和TG异常则易发PCI。     

海南汉族人群九个纤维蛋白原基因多态性及其与血浆纤维蛋白原水平的关系

目的 调查海南汉族健康人群αTaqⅠ和βBclⅠ、HinfⅠA／C、448G／A、βBsmA ⅠG／C、＋1689T／G、-148C／T、-249C／T、-455G／A多态性的等位基因频率及其与血浆纤维蛋白原（fibrinogen，Fg）水平的关系。方法 用比浊法测定238名健康个体的血浆Fg浓度，用PCR-限制性片段长度多态性方法及测序法分析多态性基因型，并用协方差分析比较9个位点的基因型与血浆Fg水平的关系。结果 海南汉族人群αTaqⅠ、βBclⅠ、HinfⅠA／C、C448、βBsmAⅠG／C、＋1689T／G、-148C／T、-249C／T、-455G／A稀有位点的等位基因频率分别为0．445、0．239、0．134、0．235、0．273、0．241、0．265、0．441、0．254，9个位点之间存在连锁不平衡；在总人群中，-455GA和AA基因型、-148CT和TT基因型、αTaqⅠT1T1基因型组的血浆Fg水平比野生型组高（P值均〈0．01）；在男性人群中，-455GA和AA基因型、-148CT和TT基因型、αTaqⅠT1T1、αTaqⅠT1T2基因型组的血浆Fg水平比野生型组高（P值均〈0．01）。在女性人群中，携带稀有位点A^-455、T^-148、αTaⅠT1的基因型组与野生型组之间的血浆赡水平差异无统计学意义。结论 在9个多态性位点之间存在连锁不平衡；A^-455、T^-148、αTaqⅠT1位点与血浆Fg水平增高关联，β-Fg-455G／A、-148C／T及α-TaqⅠ多态性与男性血浆Fg水平关联。     

FgBβ1689T/G、I6I/D、345C/T和HinfIA/C基因多态性与血浆Fg功能表达的相关性研究

目的:分析血浆纤维蛋白原(Fg)Bβ1689T/G、I6I/D、345C/T和Hinf IA/C多态性位点对Fg浓度和分子聚合活性等功能表达指标的影响。方法:采用整群抽样的方法选取开滦集团职工1 021人,均留取清晨空腹静脉血测定血糖、尿酸等生化指标;分别应用PCR-RFLP和基因测序技术确定四位点的基因型;采用微机辅助血浆Fg功能自动监测系统测定血浆Fg浓度和Fg单体聚合反应速率(FMPV)、最大光密度(Amax)、FMPV/Amax等反映Fg分子聚合功能参数。结果:Fg浓度、FMPV、Amax及FMPV/Amax在Bβ1689、I6、345、Hinf I各基因型组间比较均无显著性差异(P>0.05);FMPV/Amax指标在两性之间的差异有统计学意义(P<0.05);在无高血压病的人群中BβHinf I的AA组FMPV/Amax高于CC+AC组(P<0.05),在无脑梗死的人群中Bβ1689的GG+TG组的FMPV/Amax高于TT组(P<0.05)。结论:Bβ1689位点在特定条件下具有参与和影响调解Fg分子聚合活性表达的作用;BβHinf IA/C发生变异时可以使血浆Fg分子活性降低。     

突发性聋发病机理与纤维蛋白原分子功能的关系研究

目的 :通过检测纤维蛋白原 (Fbg)含量及分子功能 ,探讨血液高凝状态在突发性聋发病机理及预后中的意义。方法 :利用微机扫描检测纤维蛋白单体聚合速率 ,获得纤维蛋白原含量及分子功能参数。结果 :突聋患者纤维蛋白原含量及分子功能较正常对照组明显增强 ,有 75 .9%的患者治疗前纤维蛋白原高于正常值 ,治愈组、治疗好转组治疗前纤维蛋白原质量有明显差异 (FMPV ,P <0 .0 5 ;Fbg :P <0 .0 1)。结论 :部分突聋患者有明显纤维蛋白原含量增高及分子功能增强 ,提示存在易发血栓形成因素 ,疾病预后可能与治疗前纤维蛋白原含量与功能改变程度有关 ,在抗栓治疗中应警惕出血并发症的发生。     

白介素和FgBβ-1420G/A、-993C/T、1689T/G、BsmAIG/C、I6I/D、345C/T、HinfIA/C基因多态性与血浆Fg浓度及分子功能的相关性研究

目的:分析白介素(IL)等细胞因子与纤维蛋白原(Fg)Bβ链-1420G/A、-993C/T、1689T/G、BsmAIG/C、I6I/D、345C/T、HinfIA/C 7个基因多态性位点的关系及其对血浆Fg浓度和分子活性系列指标的影响。方法:采用整群抽样方法选取开滦集团离退休职工864人进行体检和问卷调查,抽取静脉血检测血生化及血高敏C反应蛋白(hsCRP)、肿瘤坏死因子(TNF-α)和IL-6、IL-8、IL-10,同时测定血浆Fg浓度和纤维蛋白单体聚合反应速率(FMPV)、最大光密度(Amax)、FMPV/Amax等反映Fg分子聚合功能指标,并应用等位基因特异性聚合酶联反应(AS-PCR)和限制性内切酶片段长度多态性技术及直接基因测序分析检测上述7位点的基因多态性。结果:FgBβHinfI为AC+CC型人群TNF-α水平高于AA人群(P<0.05),其他细胞因子在各位点野生基因型与变异基因型组间均无显著性差异(P>0.05)。以FMPV/Amax为因变量进行多元逐步回归分析,依次筛选出年龄、HDL、UA、hsCRP、口服阿司匹林,标准回归系数(β)为-0.089、-0.094、-0.098、0.091、-0.081(P<0.05);以IL-6为因变量则筛选出IL-8、性别、糖尿病史、TNF-α及HinfI基因型,β分别为0.277、-0.136、0.134、0.125、-0.088(P<0.05);以TNF-α为因变量,则筛选出IL-10、IL-6、BsmAI、UA、1689位点,β分别为0.157、0.127、0.202、0.089、-0.130(P<0.05)。结论:白介素、TNF-α等细胞因子水平与FgBβ链基因多态性具有很强的关联性,它们可以通过影响FgBβ链某些位点的白介素反应元件而具有潜在的调节人类血浆Fg浓度和分子活性表达水平的作用。     

纤维蛋白原β基因-148C/T多态性与脑梗死的关系

目的探讨纤维蛋白原（fibrinogen，Fg）β基因启动子区-148C／T多态性、血浆Fg水平与急性动脉粥样硬化性脑梗死的关系。方法用多聚酶链反应．限制性片段长度多态性方法对151例脑梗死患者和101名健康对照进行Fgβ-148C／T基因多态性分析，并应用凝血酶原时间衍生法检测血浆Fg水平。结果脑梗死组血浆Fg水平明显高于对照组（P〈0．01）；T等位基因携带者较CC基因型者血浆Fg水平明显增高（P〈0．01）；按性别分组后差异仍有统计学意义；按年龄段分组后，病例组各组T等位基因携带者较CC基因型者血浆Fg水平增高（P〈0．05）。中年梗死组较中年对照组T等位基因频率的差异有统计学意义（P〈0．05）。结论Fgβ-148C／T基因多态性影响血浆Fg水平，T等位基因可能独立或通过与其它血栓危险因素或环境因素协同作用增高血浆Fg水平，成为脑动脉血栓形成的危险因素。     

纤维蛋白原Bβ链基因多态性与肥胖影响因素的关联分析

目的 研究纤维蛋白原(fibrinogen,Fg)Bβ链-854G/A、-455G/A、-249C/T、-148C/T、448G/A和Bcl-1G/A位点基因多态性与肥胖症的影响因素及血浆Fg含量和聚合功能表达的关系.方法 选取开滦集团离退休职工1391人,依体重指数将其分为体重正常、超重及肥胖组,抽取静脉血测定血生化、血浆Fg浓度和纤维蛋白单体聚合反应速率(fibrin monomer polymerized velocity,FMPV)、最大光密度(Amax)、FMPV/Amax等反映Fg聚合功能的指标,应用聚合酶链反应-限制性片段长度多态技术进行Bβ链6个位点多态性检测.结果 Fg Bβ6个位点中仅Bcl-1A等位基因和变异基因型在超重组的频率分布明显高于正常体重组(P＜0.01);3组均为Fg Bβ-854变异基因型人群Fg浓度、FMPV、FMPV/Amax显著高于野生型(P＜0.01),超重组Bβ-455变异基因型人群FMPV/Amax以及Bβ-249变异基因型人群FMPV分别高于野生型(P＜0.05).结论 Fg BβBcl-1A等位基因及其变异基因型人群是易发体重超重的高危人群,Bβ-455和-249的变异基因型可通过调控血浆Fg聚合功能的表达而成为发生超重的累效基因.     

人类早期胚胎体外发育的分子基础

人类早期胚胎的发育过程是一个复杂的过程,不同的发育阶段的营养需求及代谢类型是在不断变化,并且基因表达也有所转变。胚胎在由母型调节向合子型调节转变的过渡期间细胞水平和分子水平上都发生了一系列复杂的变化,调节着胚胎的发育进程。     

急性心肌缺血时冠状窦血浆纤维蛋白原的改变及意义

通常人们认为,急性心肌缺血可引起血浆纤维蛋白原(Fg)的增高;但是在缺血区局部Fg的变化并不清楚。本文在17条犬上,以自制微米缩窄器造成冠脉左旋支狭窄与梗塞,观察了冠状窦Fg和血小板数(PC)的改变。结果表明:当冠脉狭窄大于75%后,急性心肌缺血可引起Fg含量的减少,当冠脉大狭窄于90%后,PC也出现减少。病理组织学检查在狭窄部位有内皮细胞的损伤、血小板的粘附及冠状动脉血栓和微血栓的形成。这一结果提示:急性心肌缺血可引起血浆Fg的减少,Fg的减少与血小板的聚集及血栓的形成有关。     

Comparison between cytokine concentration in follicular fluid of poor and high responder patients and their influence of ICSI-outcome

OBJECTIVE: The aim of this study was to compare the cytokine concentration in follicular fluid (FF) of low and high responder intracytoplasmic sperm injection (ICSI) patients and to find out the impact of these cytokines in FF on ICSI outcome. DESIGN: The levels of insulin-like growth factor (IGF)-I, IL-6, IL-8, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), granulocyte-macrophage-colony stimulating factor (GM-CSF) were measured from low and high responder ICSI patients, the results were compared between the two groups and their influence on ICSI outcome was analysed. MATERIAL AND METHODS: A total of 49 low (G.I) and 34 high (G.II) responder patients were enrolled in this study. FF was collected at the time of oocyte retrieval and measured either by enzyme-linked immunosorbent assay (IL-6, IL8, EGF, PDGF, GM-CSF) or radio immuno assay (IGF-I). RESULTS: The concentration of IL-6 (pg/mL), IL-8 (pg/mL), IGF-I (ng/mL), PDGF (pg/mL), EGF (pg/mL), GM-CSF (pg/mL) in G.I was 6.0 +/- 4.3, 288.1 +/- 139.2, 0.416 +/- 0.089, 249.8 +/- 150.1, 9.12 +/- 5.5 and 1.45 +/- 2.10 and the corresponding value in G.II was 7.4 +/- 4.8, 208.6 +/- 64.0, 0.431 +/- 0.094, 387.6 +/- 36.0, 8.9 +/- 5.4 and 1.8 +/- 3.3, respectively. Only the PDGF concentration showed a significant (P = 0.007) difference between the two groups. Besides, negative correlations were found between PDGF and fertilization rate (r = -0.287; P = 0.046) of G.I. The mean number of retrieved (6.4 +/- 2.3 versus. 15.7 +/- 5.4) and fertilized (3.6 +/- 1.6 versus 7.0 +/- 4.5) oocytes differ significantly (P = 0.001) between the two groups. The fertilization rate was significantly higher in G.I than in G.II (60.9 +/- 25.1 versus 43.4 +/- 20.7%). CONCLUSION: There was no significant difference between IGF-I, IL-6, IL-8, EGF and GM-CSF concentrations of low and high responder patients. Besides, PDGF was significantly (P = 0.007) higher in high responder compared with low responder patients. Moreover, in poor responder patients, a negative correlation was found between PDGF and fertilization rate. However, the cytokine levels in FF of the patients undergoing controlled ovarian hyperstimulation for ICSI could not be used as a marker of oocyte fertilization and implantation potential.     

Relationship between ovarian stimulation regimen and cytokine concentration in follicular fluid and their effect on fertilization and pregnancy outcome of patients undergoing ICSI program

PROBLEM: The aims of this study were to evaluate the presence of insulin-like growth factor (IGF)-I, platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) in pre-ovulatory follicular fluid (FF) in patients undergoing ovarian hyperstimulation for intra-cytoplasmic sperm injection (ICSI) treatment, to determine the differences between the concentrations of these cytokines in relation to ovarian stimulation regimens, and to find the relationship between these parameters and estradiol 17-beta, progesterone, and luteinizing hormone (LH) concentration in serum, as well as ICSI outcome. METHOD: IGF-I and PDGF were measured in the FF of 85 patients. The IGF-I levels were measured by radioimmunoassay, whereas the concentrations of PDGF and EGF were measured by enzyme-linked immunosorbent assay technique, using commercially available kits. RESULTS: IGF-I (0.42 +/- 0.09 ng/mL), PDGF (307.3 +/- 274.5 pg/mL), and EDF (8.88 +/- 6.4 pg/mL) were present in pre-ovulatory FF in patients undergoing ovarian hyperstimulation for ICSI treatment. The mean concentration of IGF-I in the follicle-stimulating hormone (FSH) group was significantly higher (P = 0.036) than that found in the human menopausal gonadotrophin (hMG)/FSH group, whereas no significant difference in the mean concentrations of PDGF (P = 0.58) and EGF was shown between all investigated groups. CONCLUSION: Controlled ovarian stimulation regimens affect only IGF-I levels in FF and the cytokine concentrations of all investigated groups, in turn, showed no correlation either with steroid hormones in serum or ICSI outcome.     

The effect of serum concentration of leukaemia inhibitory factor on in vitro fertilization treatment outcome

PROBLEM: To evaluate the association of peripheral leukaemia inhibitory factor (LIF) levels on implantation and miscarriage rates after in vitro fertilization (IVF) treatment. METHODS: Prospective observational study of 120 randomly selected women who underwent IVF treatment. The concentration of LIF in serum was determined by enzyme-linked immunosorbent assay. RESULTS: There was no significant differences with regard to the systemic mean LIF concentration between the pregnant (42 patients, LIF: 11.55 pg/mL +/- 5.3 S.D.) and non-pregnant (66 patients, LIF: 13.47 pg/mL +/- 5.1 S.D.) women after IVF treatment. Likewise, for those women who have positive pregnancy after IVF treatment, the systemic mean LIF levels were not significantly different between women who have an ongoing pregnancy (34 ongoing pregnancy, LIF: 11.26 pg/mL +/- 5.2 S.D.) and those who had miscarriage (eight miscarriage, LIF: 12.78 pg/mL +/- 5.6 S.D.). CONCLUSION: The systemic levels of LIF concentration have no association with implantation rate or miscarriage rate in women undergoing IVF treatment. Measuring serum LIF concentration prior to embryo transfer in IVF treatment has no predictive value of implantation rate or miscarriage rate.     

2型糖尿病的分子遗传学研究进展和预防策略

2型糖尿病是一种由遗传因素和环境因素相互作用所导致的复杂疾病。研究表明胰岛β细胞功能缺陷和胰岛素抵抗是导致2型糖尿病发生和发展的重要原因。与胰岛β细胞功能缺陷有关的基因主要有 CDKAL 1、CDKN 2 A／2 B、TCF 7 L 2等,而与胰岛素抵抗有关的基因主要有 PPAR-γ、HHEX、KCNQ 1等。众多大型临床试验研究结果显示,通过改变生活方式以及药物干预可以预防或延缓2型糖尿病的发生。本文综述了基因及其多态性与2型糖尿病胰岛β细胞功能缺陷和胰岛素抵抗的相关性及其作用机制的研究进展,并总结了在世界范围内预防2型糖尿病的基本策略。     

Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro

Alemtuzumab is a humanized monoclonal antibody specific for the CD52 protein present at high levels on the surface of B and T lymphocytes. In clinical trials, alemtuzumab has shown a clinical benefit superior to that of interferon‐β in relapsing–remitting multiple sclerosis patients. Treatment with alemtuzumab leads to the depletion of circulating lymphocytes followed by a repopulation process characterized by alterations in the number, proportions and properties of lymphocyte subsets. Of particular interest, an increase in the percentage of T cells with a regulatory phenotype (Treg cells) has been observed in multiple sclerosis patients after alemtuzumab. Since Treg cells play an important role in the control of autoimmune responses, the effect of alemtuzumab on Treg cells was further studied in vitro. Alemtuzumab effectively mediated complement‐dependent cytolysis of human T lymphocytes and the remaining population was enriched in T cells with a regulatory phenotype. The alemtuzumab‐exposed T cells displayed functional regulatory characteristics including anergy to stimulation with allogeneic dendritic cells and ability to suppress the allogeneic response of autologous T cells. Consistent with the observed increase in Treg cell frequency, the CD25^hi T‐cell population was necessary for the suppressive activity of alemtuzumab‐exposed T cells. The mechanism of this suppression was found to be dependent on both cell–cell contact and interleukin‐2 consumption. These findings suggest that an alemtuzumab‐mediated increase in the proportion of Treg cells may play a role in promoting the long‐term efficacy of alemtuzumab in patients with multiple sclerosis.     

The effect of taste familiarity on intake and taste reactivity in infant rats

With infant rats, unlike with adults, increased intake of a taste after mere exposure to this stimulus is not consistently found; this has sometimes been interpreted as a failure by the immature subject to recognize tastes as familiar. We studied the effect of preexposure to a tastant, measuring taste reactivity and intake in 14‐day‐old rats. Familiarity increased hedonic response to sucrose, but also increased aversive response to quinine and ethanol. With the sucrose‐quinine compound, familiarity increased both the hedonic and the aversive reaction to the stimulus. In no case was a differential reactivity to water observed. Significant increased intake after familiarization was only found with quinine or the sucrose‐quinine compound. Results indicate that in infant rats, and with the present parameters, taste familiarity enhances responsiveness to these stimuli, an effect not always accompanied by detectable changes in intake. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 52:109–120, 2010