CX3CR1基因多态性与糖尿病肾病炎症介质的相关性

目的探讨趋化因子受体CX3CR1-V249I、CX3CR1-T280M基因多态性的与糖尿病肾病(DN)炎症介质核因子(NF)-κB、Fractalkine(FKN)、白细胞介素(IL)-6、肿瘤坏死因子(TNF)-α的相关性。方法应用聚合酶链反应-限制性片段长度多态性法检测及反向测序法检测80例DN患者(DN组)、119例糖尿病(DM组)患者和118例对照者(C组)的CX3CR1基因T280M、V249I多态性分布,ELISA法测定各组血清中NF-κB、FKN、IL-6、TNF-α浓度。结果等位基因V249I在C组中的分布频率(20.33%)明显高于DN组(17.23%)和DM组(8.75%)(P<0.05);等位基因T280M在各组中分布频率无明显差异(P>0.05)。DN组及DM组中V249I、T280M变异型患者血清中FKN浓度较野生型明显增加(P<0.05);DN组及DM组中V249I、T280M变异型患者血清中NF-κB浓度较野生型明显减少(P<0.05);DM组中突变型患者血清TNF-α浓度较野生型明显减少(P<0.05);DN组T280M突变型患者血清IL-6浓度较野生型浓度明显增多(P<0.05)。结论 CX3CR1-V249I突变可能减少了DN的发生,炎症因子NF-κB、FKN、TNF-α可能参与了此过程;而CX3CR1-T280M基因多态性和DN发生无明显关联,但IL-6加速DN的发生可能和T280M突变有关。     

CX3CR1基因249V/I多态性与早发冠心病及血脂比值的相关性

目的 探讨趋化因子Fractalkine受体CX3CR1基因位点249V/I多态性与早发冠心病以及血脂比值的相关性。方法 入选患者分为早发冠心病组（n149,年龄＜50岁）、晚发冠心病组（n150,年龄＞65岁）和健康对照组（n149,年龄47～93岁）,均接受血脂水平检测,计算总胆固醇/高密度脂蛋白胆固醇比值（TC/HDLC）、载脂蛋白B/载脂蛋白A1比值（ApoB/ApoA1）,应用聚合酶链反应和限制性片段长度多态性方法对CX3CR1基因位点249V/I多态性分布进行分析,比较CX3CR1基因多态性及血脂比值在三组之间的差异性。结果 等位基因I249在三组的分布频率比较差异有统计学意义（P<0.0001）;早发冠心病组TC/HDLC和ApoB/ApoA1比值明显高于晚发冠心病组（P<0.0001）,且独立于249V/I基因多态变异。结论 CX3CR1等位基因I249变异与冠心病的发病年龄存在相关性。高血脂比值与冠心病的发病年龄存在相关性。     

缺血性脑血管病患者趋化因子受体CX3CR1基因V249I多态性的研究

目的探讨缺血性脑血管病（ICVD）患者趋化因子受体CX3CR1基因V249I的多态性及其频率。方法采用聚合酶链反应和限制性片段长度多态性方法检测ICVD患者（脑梗死、腔隙性脑梗死、短暂性脑缺血发作）及健康对照者的CX3CR1基因V249I的多态性及频率。结果对照组CX3CR1基因V249I只有VV和Ⅵ基因型，ICVD组有VV、VI和Ⅱ3种基因型；ICVD组I等位基因频率明显高于对照组（P〈0．01）；CX3CR1基因型及I等位基因频率在不同类型ICVD患者之间无统计学差异。结论CX3CR1基因V249I多态性可能与ICVD有关。     

三磷酸腺苷结合盒转运子A1基因M883I多态性与冠心病的相关性研究

目的:探讨三磷酸腺苷结合盒转运子A1(ABCAI)基因M883I多态性与冠心病及血脂水平相关性.方法:冠心病组358例(维吾尔族180例,汉族178例);对照组160例(维吾尔族65例,汉族95例).用聚合酶链式反应限制性片段长度多态性(PCR-RFLP)方法,检测维吾尔族和汉族冠心病组及对照组ABCA1基因M883I多态性.结果:在冠心病组和对照组中,维吾尔族各基因型频率和等位基因频率与汉族比较差异均有统计学意义(P=0.000).M883I多态性基因型频率及等位基因频率在两个民族冠心病组和对照组间分布差异均无统计学意义(P>0.05),不同基因型间的血脂水平差异均无统计学意义(P>0.05).结论:ABCA1基因M883I多态性M等位基因频率在维吾尔族和汉族问有差异;ABCA1 M883I多态性与维吾尔族、汉族冠心病及血脂水平无明显相关.     

趋化因子CX3C受体1基因rs3732378多态性与急性冠状动脉综合征的相关性

目的探讨趋化因子CX3C受体1(CX3CR1)基因rs3732378单核苷酸多态性与急性冠状动脉综合征(ACS)的相关性。方法连续收集中国北方汉族人群951例,其中男性520例,女性431例,年龄35~75岁。根据冠状动脉造影(CAG)结果分为2组:(1)病例组(n=512):ACS患者;(2)对照组(n=439):非冠心病患者。病例组根据CAG检查血管病变支数分为3个亚组。采用测序法测定CX3CR1基因rs3732378单核苷酸多态位点的基因型。用多因素Logistic回归分析CX3CR1基因rs3732378多态性与ACS发病风险的关系。应用酶联免疫吸附法检测血浆中趋化因子CX3C配体1(CX3CL1)表达水平。结果两组CX3CR1基因rs3732378的基因型及等位基因的分布频率无显著性差异(P0.05)。rs3732378多态位点与ACS发病风险的总体和分层分析结果表明,CX3CR1基因rs3732378多态位点的3种基因型TT、TC和CC均不能增加ACS的发病风险(P0.05)。亚组分析显示,rs3732378多态位点的基因型和等位基因与冠状动脉血管病变支数无相关性(χ2=0.135,P=0.998;χ2=0.026,P=0.987)。病例组和对照组血浆中CX3CL1表达水平在rs3732378三种基因型无差异(P0.05)。结论 CX3CR1基因rs3732378多态位点不是ACS的易感基因,rs3732378多态性没有增加中国北方汉族人群ACS的风险。     

缺血性脑血管病患者趋化因子受体CX3CR1基因V2491多态性的研究

目的 探讨缺血性脑血管病(ICVD)患者趋化因子受体CX3CR1基因V2491的多态性及其频率.方法 采用聚合酶链反应和限制性片段长度多态性方法检测ICVD患者(脑梗死、腔隙性脑梗死、短暂性脑缺血发作)及健康对照者的CX3CR1基因V2491的多态性及频率.结果 对照组CX3CR1基因V2491只有ⅤⅤ和Ⅵ基因型,ICVD组有ⅤⅤ、Ⅵ和Ⅱ3种基因型;ICVD组Ⅰ等位基因频率明显高于对照组(P<0.01);CX3CR1基因型及Ⅰ等位基因频率在不同类型ICVD患者之间无统计学差异.结论 CX3CR1基因V2491多态性可能与ICVD有关.     

血管紧张素原及血管紧张素Ⅱ 1型受体基因多态性与冠心病的关系

目的研究血管紧张素原(AGT)基因M235T及血管紧张素Ⅱ1型受体(ATIR)基因A1166/C多态性与冠心病的关系.方法应用多聚酶链反应结合限制性内切酶法(PCR-RFLP)对100名经冠脉造影确诊为冠心病(CHD)的患者和52名冠造结果正常及18名门诊常规体检且无冠心病史者基因多态性进行分析.结果冠心病(CHD)组TT基因型和T等位基因频率显著高于对照组(分别为0.67、0.79和0.44、0.63,P＜0.05),而C等位基因频率在两组中差异则无统计学意义(分别为0.075和0.064,P＞0.05).结论AGT基因变异与CHD发病具有相关性.提示T等位基因可能是CHD的危险因素,而AT1R基因A1166/C多态性与冠心病则无关联.     

RAGE基因-374T/A多态性与中国汉族人群冠状动脉粥样硬化性心脏病的相关性研究

目的观察晚期糖基化终产物受体(receptor of advanced glycation end products,RAGE)基因启动区-374T/A多态性在中国汉人冠状动脉粥样硬化性心脏病(冠心病)人群和对照组人群中的分布特点,并比较两者之间的差异,分析RAGE基因启动区-374T/A多态性与冠心病的相关性。方法应用Tsp509 I限制性内切酶的多聚酶链反应-限制性片断长度多态性(PCR-RFLP)法,检测127例冠心病患者和88例对照组人群的RAGE多态性基因型。结果冠心病组与对照组间RAGE基因-374T/A多态性等位基因频率和基因型频率比较,差异均无统计学意义(P0.05);单因素logistic回归分析提示,AA基因型与冠心病无关联[OR=0.201,95%CI(0.201,4.220),P=0.9 155]。亚组分析显示,非糖尿病冠心病组与非糖尿病对照组RAGE基因-374T/A多态性等位基因频率和基因型频率比较,差异均无统计学意义(P0.05);单因素logistic回归分析提示,AA基因型与非糖尿病冠心病无关联[OR=1.415,95%CI(0.253,7.926),P=0.6 929]。结论 RAGE基因启动区-374T/A多态性可能与中国汉人冠心病的易感性无关联,其AA基因型可能不是中国汉人冠心病的保护因素。     

Fractalkine及其受体CX3CR1与冠心病

趋化因子fractalkine被炎症内皮细胞表达，与受体CX3CR1结合通过黏附和趋化作用、参与免疫及细胞间信息转导以及CX3CR1基因的多态性等多种途径影响动脉粥样硬化的发生和发展。通过对fractalkine蛋白及其受体CX3CR1 V249／I249基因水平的检测以及其作用机制的干预，可能成为冠状动脉粥样硬化性心脏病早期诊断和防治的新途径。     

肾素-血管紧张素系统基因多态性与冠心病的关系

目的探讨肾素-血管紧张素系统三个关键基因血管紧张素转化酶基因插入/缺失多态性、血管紧张素原基因M235T多态性及血管紧张素Ⅱ1型受体基因A1166/C多态性与冠心病的关系。方法应用多聚酶链反应-限制片长多态性方法对110例冠心病患者和80例健康人分别进行单基因和基因连锁分析。结果①冠心病组血管紧张素转化酶基因DD基因型(43.6%)及D等位基因频率(60.5%)明显高于正常对照组(分别为26.3%和44.4%,P<0.05);血管紧张素原基因TT基因型(66.4%)及T等位基因频率(78.6%)亦明显高于正常对照组(分别为42.5%和60.6%,P<0.05);与正常对照组相比,冠心病组血管紧张素Ⅱ1型受体基因的AA、AC基因型频率和A、C等位基因频率差异均无显著性(P>0.05)。②联合分析三个基因多态性罹患冠心病的相对风险,其OR为3.395,高于单基因血管紧张素转化酶DD型(OR为2.175)及血管紧张素原TT型(OR为2.669),低于血管紧张素转化酶DD型 血管紧张素原TT型(OR为6.098)。结论血管紧张素转化酶基因插入/缺失多态性及血管紧张素原基因M235T多态性与冠心病有关,而血管紧张素Ⅱ 1型受体基因A1166/C多态性可能与冠心病无关联。同时具有血管紧张素转化酶DD型及血管紧张素原TT型者发生冠心病的相对风险显著增高。     

Polymorphisms of Fractalkine receptor CX3CR1 and plasma levels of its ligand CX3CL1 in colorectal cancer patients

Background and aims The chemokine Fractalkine/CX3CL1, which is expressed by epithelial cells within normal colorectal mucosa and in colorectal cancer (CRC), is thought to have a crucial role in colorectal mucosal immunity by recruiting leucocytes via the receptor CX3CR1. The purpose of this study was to investigate two single-nucleotide polymorphisms of the Fractalkine receptor/CX3CR1 gene, V249I and T280M, in CRC to find out whether they occur more often in patients with CRC than in non-CRC individuals. In the search for tumour markers, we also intended to determine whether plasma levels of Fractalkine were correlated with parameters such as Dukes’ stage, tumour localisation, gender and age in CRC patients. Materials and methods Genomic deoxyribonucleic acid from 223 CRC patients and 229 controls was amplified by polymerase chain reaction, and the polymorphisms were detected by the restriction fragment length polymorphism analysis. Fractalkine/CX3CL1 was analysed in plasma from 62 CRC patients and 78 controls using enzyme-linked immunosorbent assay. Results The variant V249I was significantly different in genotype and allelic distribution between CRC patients and control subjects, P = 0.028 and P = 0.048, respectively. We also found that individuals with the I249 allele in homozygote state were less frequent in the CRC group (3.1%) compared with controls (9.2%; P = 0.008). No significant difference was observed regarding Fractalkine/CX3CL1 levels in plasma between patients and the control group. Conclusion Our results suggest that the lack of the allele I249 of the CX3CR1 gene may play a partial or minor role in CRC and that plasma Fractalkine/CX3CL1 does not seem to be a useful tumour marker that reflects the disease outcome of CRC.     

Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis

Fractalkine, a chemokine expressed by inflamed endothelium, induces leukocyte adhesion and migration via the receptor CX3CR1, and the CX3CR1 polymorphism V249I affects receptor expression and function. Here we show that this polymorphism is an independent risk factor for atherosclerotic coronary artery disease (CAD). Genotyping of the CX3CR1-V249I polymorphism was performed in a cohort of 339 white individuals who underwent cardiac catheterization (n=197 with and n=142 without CAD, respectively). In 203 patients, intracoronary acetylcholine 15 microg/min) and sodium nitroprusside (20 microg/min) were administered to test endothelium-dependent and -independent coronary vascular function, respectively. Change in coronary vascular resistance (DeltaCVR) was measured as an index of microvascular dilation. An association was observed between presence of the CX3CR1 I249 allele and reduced prevalence of CAD, independent of established CAD risk factors (odds ratio=0.54 [95% confidence interval, 0.30 to 0.96], P=0.03). Angiographic severity of CAD was also lower in these subjects (P=0.01). Furthermore, endothelium-dependent vasodilation was greater in these individuals compared with individuals homozygous for the CX3CR1-V249 allele (DeltaCVR during acetylcholine = -46+/-3% versus -36+/-3%, respectively, P=0.02), whereas DeltaCVR with sodium nitroprusside was similar in both groups (-55+/-2% versus -53+/-2%, P=0.45). The association between CX3CR1 genotype and endothelial function was independent of established risk factors and presence of CAD by multivariate analysis (P=0.02). Thus, the CX3CR1 I249 allele is associated with decreased risk of CAD and improved endothelium-dependent vasodilation. This suggests that CX3CR1 may be involved in the pathogenesis of CAD.     

血管紧张素转化酶基因插入/缺失多态性与冠心病发病的关系

目的 :探讨血管紧张素转化酶 (ACE)基因多态性与冠心病 (CHD)发病的关系。方法 :以人基因组DNA为模板 ,应用聚合酶链式反应 (PCR)检测 5 0例CHD组和 5 6例正常对照组ACE基因第 16内含子插入 /缺失 (I/D)多态性 ,并按性别分组计算各组基因型和等位基因频率。结果 :①在CHD组中 ,ACE基因DD基因型和D等位基因频率分别为 36 %和 6 0 % ,正常对照组分别为 16 %和 4 1% ,两者相比差异有统计学意义 (P <0 .0 1)。②男性CHD组DD基因型和D等位基因频率均显著高于对照组 (均P <0 .0 5 )。女性CHD组DD基因型频率显著高于对照组 (P <0 .0 1) ,D等位基因频率与对照组比较差异无统计学意义。结论 :CHD与ACE基因I/D多态性有显著相关性 ,不论男性和女性 ,ACE基因DD基因型均可能是CHD发生发展过程中重要的危险因素之一。     

The V249I polymorphism of the CX3CR1 gene is associated with fibrostenotic disease behavior in patients with Crohn's disease

OBJECTIVES: CX3CR1, the receptor of CX3CL1/fractalkine, is involved in regulation of inflammatory response and the CX3CR1-I249-M280 naturally occurring mutants are associated with altered binding to the ligand. Our aim was to evaluate the frequency of CX3CR1 V249I and T280M polymorphisms and NOD2/CARD15 mutations in Crohn's disease patients and to search for a relationship with phenotype. METHODS: Clinical data were retrospectively collected. V249I and T280M polymorphisms of CX3CR1 gene and NOD2/CARD15 mutations (R702W, G908R, 3020InsC) were identified. RESULTS: Two hundred and thirty-nine patients (140 females, 39.7+/-14.1 years) were included. About 37.4% were heterozygous and 8.8% were homozygous for the V249I CX3CR1 polymorphism, 18.1% were heterozygous and 1.3% homozygous for the T280M CX3CR1 polymorphism and 35.9% had at least one of the three mutations of NOD2/CARD15. The T280M CX3CR1 polymorphism was not associated with any phenotype. In univariate analysis, stenosis was significantly associated with both V249I CX3CR1 polymorphism and 3020InsC NOD2/CARD15 mutations. In smoker patients carrying the CX3CR1 allele I249, there was a significant increase in the frequency of fibrostenosing disease [P=0.005, odds ratio (OR): 3.25] whereas this relationship disappeared in the group of nonsmokers (P=0.72). In multivariate analysis, 3020InsC NOD2/CARD15 mutations and the V249I CX3CR1 polymorphism were independent risk factors for intestinal stenosis (P=0.046, OR: 1.8 and P=0.044, OR: 2.4, respectively). CONCLUSION: In Crohn's disease, V249I CX3CR1 polymorphism is associated with intestinal strictures, particularly in smokers. This association is independent of CARD15 mutations.     

血管紧张素转换酶和血管紧张素原基因多态性与冠心病的关系

目的探讨血管紧张素转换酶（ACE）插入／缺失（I／D）多态性和血管紧张素原（AGT）M235T基因多态性与冠心病（CHD）的关系。方法应用多聚酶链反应结合限制性内切酶法（PCR—RFLP）对110例冠心病患者、62例冠状动脉造影正常者以及18名门诊常规体检无冠心病史者基因多态性进行分析。结果①CHD组ACE基因DD基因型及D等位基因频率明显高于健康对照组（分别为43．6％、60．5％比26．3％、44．4％）,差异有统计学意义‘P〈0．05）。CHD组AGT基因TT基因型及T等位基因频率明显高于对照组（分别为66．4％、78．6％比42．5％、60．6％）,差异有统计学意义（尸〈0．05）。②男性CHD组ACE基因DD基因型和D等位基因频率以及AGT基因TT基因型和T等位基因频率均显著高于对照组（均P〈O．05）。女性CHD组ACE基因DD基因型和D等位基因频率以及AGT基因‘rr基因型和T等位基因频率与对照组比较差异无统计学意义（P〉0．05）。③联合分析ACEDD型及AGTTr型罹患冠心病的相对风险,其比数~L（OR）为4．904,高于单基因ACEDD型（2．175）及AGTTT型（2．669）。结论ACE基因I／D多态性及AGT基因M235T多态性与CHD有显著相关性,同时具有ACEDD型及AGT TT型发生冠心病的相对风险显著高于单基因ACEDD型及单基因AGT‘丌型。性别也可作为冠心病的危险因素。     

Increased expression of the chemokine fractalkine in Crohn's disease and association of the fractalkine receptor T280M polymorphism with a fibrostenosing disease Phenotype

BACKGROUND: The fractalkine receptor CX3CR1 has been shown to be involved in inflammation and immune response. Recently, two polymorphisms of CX3CR1 (V249I and T280M) were reported. AIMS: Our aim was to analyze fractalkine expression and the role of CX3CR1 polymorphisms in Crohn's disease (CD). METHODS: We determined fractalkine mRNA expression in the intestinal epithelial cell (IEC) line SW480 after stimulation with proinflammatory cytokines as well as in inflamed (n = 14) and noninflamed (n = 14) CD lesions by quantitative PCR. By restriction fragment length polymorphism analysis, genomic DNA from 206 patients with CD and 211 unrelated controls was analyzed for the two single nucleotide polymorphisms in the CX3CR1 gene, which result in the V249I and T280M substitutions. RESULTS: All proinflammatory stimuli (TNF-alpha, IL-1beta, LPS) significantly increased fractalkine mRNA expression in IEC. There was also a significant increase in fractalkine mRNA expression in inflamed lesions of CD patients when compared to noninflamed colonic mucosa (p = 0.02). Intestinal fractalkine mRNA levels correlated highly with IL-8 mRNA expression levels (r = 0.931). However, there was no difference in the V249I and T280M genotype frequencies between CD patients and the control group. In the CD group, 33.0% were heterozygous and 8.3% homozygous for the V249I polymorphism, while 23.3% were heterozygous and 4.4% homozygous for the T280M polymorphism. All T280M homozygotes were diagnosed of intestinal stenosis (p = 0.03 vs wildtype and heterozygous carriers) and had significantly more often ileocolonic involvement more often than patients with wildtype and heterozygous genotypes (p = 0.01). These associations were independent of the CARD15 genotype status. CONCLUSIONS: The expression of the chemokine fractalkine is upregulated by proinflammatory cytokines and enhanced in inflamed CD lesions. The CX3CR1 T280M polymorphism appears to influence CD phenotype and localization.     

肾上腺素能β3受体基因多态性与冠心病及冠状动脉病变程度的相关性研究

目的探讨肾上腺素能β3受体（β3-AR）基因多态性与冠心病及冠状动脉病变的相关关系。方法选择冠心病患者120例,114名健康者为对照。应用聚合酶链反应-限制性片段长度多态性（PCR—RFLP）检测分析肾上腺素能良受体基因型,比较对照组与冠心病组的基因型及等位基因频率之间的差异,同时对冠心病患者中不同β3肾上腺素能受体基因型的冠状动脉病变程度进行比较。结果①冠心病组和对照组Trp64Trp、Trp64Arg和Arg64Arg的基因型频率分别为68．3％、30．0％、1．6％和69．2％、29．8％、0．9％。冠心病组Arg等位基因频率（16．6％）与对照组频率（15．8％）近似（P〉0．05）,突变频率两组相比差异无统计学意义。②冠心病不同冠脉病变支数亚组间多态性分布差异无统计学意义（χ^2=0．471,P=0．790）。结论肾上腺素能艮受体基因多态性与冠心病及不同冠脉病变支数无相关性。     

Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease

Coronary atherosclerosis is a major cause of death in industrialized countries. Monocytes, which play a key role in atherosclerosis, migrate into the vessel wall, presumably guided by specific chemoattractant and adhesion molecules. A compelling candidate for this role is the chemokine receptor CX3CR1, which is expressed on monocytes and acts as either a chemotactic receptor or an adhesion molecule, depending on whether its ligand, fractalkine, is presented free or membrane bound. A common variant of CX3CR1 was recently identified, encoded by the alleles I249 and M280, which form a common I(249)M(280) haplotype. When CX3CR1 genotypes were analyzed in 151 patients with acute coronary syndromes and in 249 healthy controls, CX3CR1 I249 heterozygosity was associated with a markedly reduced risk of acute coronary events, independent of established acquired coronary risk factors (eg, smoking, diabetes). The adjusted odds ratio for this allele was 0.43 (95% confidence interval, 0.26-0.72; P =.001). Consistent with this, functional analysis of peripheral blood mononuclear cells showed that CX3CR1 I249 heterozygosity was associated with a significant decrease in the number of fractalkine binding sites per cell. The results show that CX3CR1 I249 is an independent genetic risk factor for coronary artery disease and that CX3CR1 may be involved in the pathogenesis of atherosclerotic disease. (Blood. 2001;97:1925-1928)     

载脂蛋白E基因多态性与冠心病的关系

目的 研究载脂蛋白E(ApoE)基因多态性与冠心病发病及对血脂代谢影响的关系。方法 对71例冠心病患者(CHD组)和69例正常对照者(对照组)的静脉全血白细胞提取DNA,应用PCR,HhaI酶切,用12％聚丙烯酰胺凝胶电泳,检测出其ApoE基因型及等位基因分布频率。结果 CHD组及对照组均检出4种基因型,分别是E