血管内皮细胞生长因子受体基因启动子区多态与脑卒中复发的关系

目的:探讨血管内皮细胞生长因子受体(VEGFR-2)基因启动子区多态与颈动脉粥样硬化以及脑卒中复发风险的关系.方法:对1849例脑卒中患者进行前瞻性随访4.5年(中位数,范围0.1～6.0年),Cox生存回归模型分析基因多态与脑卒中复发风险的关联性.并在一个横断面队列研究中随机人选1123名无心脑血管病史的参加者,检测颈动脉内膜-中膜厚度,观察基因多态与动脉粥样硬化的关系.结果:长期随访过程中,355例患者发生脑卒中复发事件.携带-604TC和CC基因型的脑卒中患者4.5年累积复发率为17.1%(159/929,复发/总例数),而-604TT基因型携带者的累积复发率为21.3%(196/920,复发/总例数).Cox生存回归模型校正了年龄、性别和其他心血管危险因素后,-604TC和CC基因型与降低的脑卒中复发风险相关,风险比0.71(95%可信区间,0.58～0.89;P=0.002);这种保护作用对动脉粥样硬化性血栓性脑梗塞患者更为显著,降低复发风险达35%.多元线性回归分析表明-604C等位基因与颈动脉内膜-中膜厚度呈显著负相关(标化回归系数β=0.125;P<0.001).结论:VEGFR-2基因启动子多态-604TC和CC基因型携带者与-604TT基因型相比,脑卒中复发风险相对较低,尤其在动脉粥样硬化性血栓性脑梗塞患者中作用更显著.其机制可能与影响动脉粥样硬化的进展有关.     

血管内皮细胞生长因子受体基因编码区变异与脑卒中复发及心血管病死率的研究

目的:血管发育异常、损伤修复能力下降等将影响血管的正常结构与功能,与心脑血管疾病的发生及预后密切相关.本文探讨血管内皮细胞生长因子受体(VEGFR-2)基因编码区变异Val297Ile对脑卒中复发风险及心血管病死率的影响.方法:自2000-2001年在全国7个临床中心入选1849例脑卒中患者(35～74岁),进行前瞻性随访4.5年(中位数,范围0.1～6.0年),收集脑卒中复发和死亡事件.Cox生存回归模型分析基因变异与脑卒中复发及病死率的关系.结果:长期随访过程中,355例发生脑卒中复发事件,180例死于心血管病事件.携带297Ile等位基因的脑卒中患者4.5年累积复发率为24.3%,心血管病死率为13.6%,显著高于297Val携带者(分别为17.4%和 8.4%).Cox生存回归模型校正了年龄、性别和其他心血管危险因素后,297Ile等位基因与增加的脑卒中复发风险(RR:1.40,95%CI 1.12～1.75;P=0.003)和心血管病死率(RR:1.64,95% CI 1.21～2.23;P=0.002)相关.结论:VEGFR-2基因编码区变异297Ile是一个与脑卒中高复发风险和心血管病死率相关的新的预测因子,其机制与受损血管内皮的修复能力下降有关.     

血管内皮细胞生长因子受体基因启动子区多态性与脑卒中的关系

目的:探讨血管内皮细胞生长因子受体(VEGFR-2)基因启动子区多态性与脑卒中患病风险的关系。方法:利用多中心病例—对照研究,对1849例脑卒中患者(血栓形成性脑梗塞812例,腔隙性脑梗塞530例,脑出血507例)和1798例对照检测VEGFR-2基因启动子多态-604T/C的频率分布,Logistic回归模型分析多态与脑卒中的相关性。测定荧光素酶活性,分析突变型多态对VEGFR-2基因转录活性的影响。结果:VEGFR-2基因多态-604TC和CC基因型频率在脑梗塞组显著低于对照组(脑梗塞者:TC36.7%,CC8.4%;对照组:TC41.8%,CC10.3%;P<0.01),脑梗塞者C等位基因频率显著低于对照组(26.7%比31.2%,P<0.01),均有显著性差异。-604C等位基因与脑梗塞的低发病风险相关(OR:0.78;95%CI:0.65～0.95;P<0.05)。多态-604C与野生型-604T相比,降低该基因的转录活性2.93倍。结论:VEGFR-2基因启动子变异-604C降低该基因的转录活性,并与降低脑梗塞的发病风险相关。其分子机制可能是由于VEGF/VEGFR-2信号通路下调,降低斑块内的新生血管化程度,从而延迟或减轻动脉粥样硬化的进展。     

血管内皮细胞生长因子基因多态与血浆浓度及脑卒中易感性研究

目的:探讨血管内皮细胞生长因子(VEGF)基因多态与血浆VEGF浓度以及脑卒中患病风险的关系。方法:采用PCR和限制性酶切片段长度多态性(RFLP)的方法,对1849例脑卒中患者和1798例对照者检测了VEGF基因启动子多态-460T/C、-116G/A和 405G/C的频率分布。Logistic回归模型校正传统危险因素后分析多态与脑卒中的独立相关性。ELISA法检测血浆VGEF浓度。结果:脑卒中组血浆VEGF水平显著高于对照组[分别为(291±61.9)ng/L、(225±56.3)ng/L;P<0.01];VEGF基因多态-460T/C,-116G/A和 405G/C与血浆VEGF浓度不相关(相关系数分别是:r=-0.119,P>0.05;r=0.173,P>0.05;r=0.144,P>0.05)。未发现VEGF基因多态与脑卒中的患病风险具有相关性。结论:脑卒中组血浆VEGF水平升高支持VEGF在脑卒中发病过程中的作用,但VEGF基因5'-调控区多态与脑卒中的易感性不相关。     

ALOX5AP基因多态2354T/A和MTHFR基因多态677C/T的协同作用显著增加脑梗塞的易患性

目的研究MTHFR多态性和编码5-脂氧合酶激活蛋白的基因ALOX5AP多态性，尤其是基因之间的相互作用，是否与脑卒中的易患性相关。方法采用PCR．RFLP方法，对来自7个临床中心的1823名对照和1832名脑卒中患者检测了基因ALOX5AP和MTHFR的3个多态性，基因分型结果经测序进一步确证。多元logistic回归方法校正了传统危险因素后分析基因多态性与脑卒中的独立相关性。检测7个与脑卒中不相关的微卫星多态标记在病例一对照人群的频率分布以评估人群层化程度。结果MTHFR677TT基因型与男性脑梗塞的发病风险呈弱相关（OR，1．45；95％CI：1．04-2．02；P=0．020），ALOX5AP2354AA基因型也增加男性脑梗塞1．55倍的发病风险（95％CI：1．03．2．35；PP=0．038）。当个体同时携带MTHFR677TT和ALOX5AP2354AA基因型时，男性脑梗塞的相对患病风险率显著增加至3．58倍（（95％CI：1．72-7．43；P=0．001）。微卫星多态性标记的各主要等位基因片段的频率在病例和对照组无显著性差异。结论MTHFR677TT基因型和ALOX5AP2354AA基因型的协同作用与增加的男性脑梗塞患病风险呈显著相关。对于多因素复杂性疾病，综合分析弱效基因的相互作用有助于了解个体易患脑卒中的遗传背景。     

GSTP1基因多态性与急性髓系白血病易感性的关系

目的:研究甘肃汉族人群谷胱甘肽-S-转移酶P1(GSTP1)基因多态性和急性髓系白血病(AML)易感性的关系。方法:用1∶1配对病例-对照方法,LDR-PCR分型法,对78例AML患者和100例对照组进行GSTP1基因A81G突变分析。结果:AML病例组GSTP1基因G等位基因频率(26.9%)和突变基因型(Ile/Val和Val/Val)频率(41%)均高于对照组(11.5%和19%)。携带Ile/Val和Val/Val基因型的个体发生AML的相对风险度为其(Ile/Ile)基因型个体的2.981倍(95%CI=1.35～4.68)。结论:本研究人群NQO1基因多态性与AML遗传易感性相关,等位基因A对AML易感性有保护作用。     

RXRα基因遗传变异与2型糖尿病易感性的关系

目的 探讨江苏汉族人群视黄醛X受体α(RXRα)基因遗传变异与2型糖尿病( Type 2 diabetes Mellitus,T2 DM)易感性的关系.方法 采用病例对照研究,选取新诊断的T2DM患者1 105例,与患者年龄、性别频数匹配的健康对照1 107例,用Real-time PCR联合Taqman-MGB探针方法进行基因型检测.结果 在调整性别、年龄和体重指数等因素后,4个多态位点均未发现与T2DM易感性存在统计学关联(均P＞0.05).然而,RXRα基因4个潜在功能性位点构成的主要单倍型中,与最常见的单倍型GTAT相比,TTAT单倍型(含变异等位基因rs1045570T)可显著降低T2DM的患病风险[调整0R(95％CI)=0.868(0.801 ～0.940)].结论 RXRα基因遗传变异可能与江苏汉族人群T2DM遗传易感性有关.     

FGFR2基因多态性与乳腺癌易感性的Meta分析

目的综合分析中国汉族女性成纤维细胞生长因子受体2(fibroblast growth factor receptors2,FGFR2)基因rs2981582C/T、rs2981579C/T多态性与乳腺癌易感的相关性。方法电子检索Pubmed、CNKI等数据库中FGFR2基因多态性与乳腺癌易感性相关所有病例对照研究,进行meta分析,并对各研究数据进行统计处理及异质性检验,发表偏倚评估,合并OR值及95%置信区间。结果本文检索到符合要求的文献共12篇,10篇全文和2篇会议摘要,包括6126例病例和5329例正常对照,meta分析的结果表明rs2981582单核苷酸多态性中携带TT基因型的人群乳腺癌的患病风险增加30%(OR=1.30,95%Cl:1.14-1.48),携带CT基因型的人群乳腺癌的患病风险增加16%(OR=1.16,95%Cl:1.07-1.26),而携带CC基因型的人群患乳腺癌的风险却降低23%(OR=0.77,95%Cl:0.71-0.83);rs2981579单核苷酸多态性中携带TT基因型的人群乳腺癌的患病风险增加20%(OR=1.20,95%Cl:0.95-1.51),携带CT基因型的人群乳腺癌的患病风险降低7%(OR=0.93,95%Cl:0.77-1.13),而携带CC基因型的人群患乳腺癌的风险却降低13%(OR=0.87,95%Cl:0.71-1.08)。结论 FGFR2基因多态性中TT基因突变型可能是中国女性患乳腺癌的危险风险因子。     

KDR基因多态性与中国人群冠心病风险相关

目的 在前面研究的基础上进一步研究KDR基因启动子区多态-604功能性机理和这3个功能性多态-604、1192和1719构建的单体型与冠心病风险的关系.方法 凝胶电泳迁移的方法研究-604位多态是否确实与核蛋白结合.利用EH软件构建单体型研究与冠心病风险的关系,比较单体型与单个多态所致的风险.结果 凝胶电泳迁移表明-604位多态所在区域能与核蛋白结合,单体型分析表明危险等位基因组合增加了冠心病风险.结论 KDR基因的3个多态与中国人群冠心病相关.     

TIM-3-574G>T基因多态性与中国汉族人群支气管哮喘的相关性分析

目的采用Meta分析评价T细胞免疫球蛋白黏蛋白域蛋白-3(TIM-3)-574 G>T(rs10515746)基因多态性与中国汉族人群支气管哮喘易感性的关系。 方法检索中外文献数据库中TIM-3-574 G>T基因多态性与中国汉族人群支气管哮喘易感性关系的病例对照研究，末次检索时间为2017年12月20日。采用RevMan 5.0对TIM-3-574 G>T基因多态性与哮喘易感的显性模型OR值进行合并、敏感性分析和亚组分析，以及采用Stata对纳入文献的发表偏倚情况进行评估。 结果共纳入5篇文献，其中病例组患者1 241例，对照组患者1 005例。Meta分析显示中国汉族人中TIM-3-574 G>T基因上突变型GT者的支气管哮喘发病风险较野生型纯合子GG者增加3.06倍(OR＝4.06，95%CI：2.34，7.05)，携带突变基因T者患支气管哮喘的风险比携带野生型G基因者增加3.31倍(OR＝4.31，95%CI：2.50，7.43)。亚组分析显示携带GT基因型的成人和儿童患病风险均较纯合子GG高(儿童组：OR＝4.07，95%CI：1.62，10.20；成人组：OR＝3.09，95%CI：1.40，6.85)。 结论T细胞免疫球蛋白黏蛋白域蛋白-3-574 G>T基因多态性与中国汉族人群支气管哮喘易感性有密切相关，突变T基因携带者患支气管哮喘的风险更高。     

Is there a role of the Thr164Ile-β2-adrenoceptor polymorphism for the outcome of chronic heart failure?

OBJECTIVE: The Thr164Ile-beta(2)-adrenoceptor (AR) polymorphism exhibits lower affinities for catecholamines and reduced basal and agonist-stimulated adenylyl cyclase activity in vitro. It has been suggested that patients with chronic heart failure (CHF) due to ischemic or dilated cardiomyopathy carrying the Thr164Ile-beta(2)AR polymorphism exhibit much more rapid progression to death or heart transplantation (HTX) than CHF-patients carrying the homozygous Thr164-beta(2)AR. This study aimed to further evaluate the role of the Thr164Ile-beta(2)AR in CHF. For this we hypothesized that the Thr164Ile-beta(2)AR variant should be more abundant in HTX-patients than in patients with stable CHF or healthy controls. METHODS AND RESULTS: We genotyped 309 HTX-patients, 520 stable CHF-patients and 328 healthy controls for the three beta(2)AR variants Arg16Gly, Gln27Glu and Thr164Ile. The prevalence of the Thr164Ile-beta(2)AR variant was not considerably different in HTX-patients (2.3%) from that in CHF-patients (1.9%) or healthy controls (2.1%). Similarly, the frequency of the minor Ile164-allele was f(-)=0.0106 in HTX-patients, f(-)=0.0096 in CHF-patients and f(-)=0.0113 in healthy controls. CONCLUSIONS: The prevalence of the hypofunctional Thr164Ile-beta(2)AR variant and the frequency of the Ile164-allele were almost identical in CHF-patients, who had undergone HTX, with those in patients with stable CHF or in healthy controls. Thus, the role of the Thr164Ile-beta(2)AR in CHF remains questionable.     

Association of toll-like receptor 4 variants and ankylosing spondylitis: a case-control study

OBJECTIVE: Functional single nucleotide polymorphisms within the ectoplasmic domain of the Toll-like receptor 4 (TLR4) gene have been shown to result in an endotoxin-hyporesponsive phenotype and aberrant signal transduction for bacterial agonists. TLR4 is in proximity to a genome-wide linkage peak in 9q32-33. Given the proposed function and location of TLR4, we examined the association of 2 functional variants of TLR4 in patients with ankylosing spondylitis (AS) in Newfoundland. METHODS: In total, 101 AS patients and 100 ethnically matched controls were genotyped, using the Sequenom MassArray platform, for 2 functional variants in the TLR4 gene: Asp299Gly (A/G polymorphism) and Thr399Ile (C/T polymorphism). RESULTS: The minor allele frequency for the Asp299Gly variant (G) was significantly higher in AS cases compared to controls (7.5% vs 2.6%, respectively; OR 3.10, p = 0.037). The minor allele frequency for the Thr399Ile variant (T) for cases and controls was 7.4% vs 3.0% (OR 2.59, p = 0.071). Haplotype analysis using Haploview noted a higher proportion of GT in the cases (for GT, chi-squared p = 0.023). CONCLUSION: Given the functional role of TLR4 variants in the innate immune system, larger studies are now warranted to elucidate the association of TLR4 variants in AS.     

Frequency of the calcium-sensing receptor variant A986S in patients with primary hyperparathyroidism

OBJECTIVE: Recent studies have shown an influence of the calcium-sensing receptor variant A986S on the serum calcium concentration, suggesting that this genetic variant could be a candidate for various bone and mineral disorders. The intention of this study was therefore to investigate the frequency of the described calcium-sensing receptor variants A986S, R990G and Q1011E in patients with primary hyperparathyroidism to test the hypothesis as to whether these variants represent risk factors for the development of primary hyperparathyroidism. DESIGN: Fifty patients with primary hyperparathyroidism were included in the study. One hundred and two healthy blood donors served as controls. METHODS: Detection of the genetic variants A986S, R990G and Q1011E was done by direct sequencing of exon 7 of the calcium-sensing receptor in leucocyte DNA. RESULTS: The heterozygous variant A986S was found in 34% (17 of 50) of the healthy age- and sex-matched controls and 40% (20 of 50) of the patients with primary hyperparathyroidism. This difference was not statistically significant (P=0.68). However, in male patients the heterozygous variant A986S was found more frequently (67%, 6 of 9) than in male controls (20%, 2 of 10, P=0.07). The variants R990G and Q1011E were found less frequently (8-20%) in patients and controls without significant differences between the groups. Patients with the heterozygous variant Q1011E had significantly higher serum calcium and parathyroid hormone levels than patients with the wild-type variant (P<0.01). There was no correlation of serum calcium (total and corrected for albumin) with the calcium sensing receptor variant A986S in 102 healthy blood donors (P=0.45). CONCLUSIONS: The calcium-sensing receptor variants do not, therefore, seem to be major genetic determinants for the development of primary hyperparathyroidism. The variant A986S may possibly represent a risk factor for the development of parathyroid neoplasia in men. Moreover, the presence of the genotype Q1011E might influence the clinical course of the disease. The previously reported significant correlation of serum calcium levels with the genetic variant A986S in healthy subjects could not be confirmed.     

Coagulation factor XIII gene variation, oral contraceptives, and risk of ischemic stroke

Prothrombotic conditions are associated with ischemic stroke in young women. In particular, the combination of oral contraceptive use and prothrombotic genetic variants appears to increase the risk of ischemic stroke. We performed a population-based case-control study in 190 women aged 20 to 49 years with ischemic stroke and 767 women without cardiovascular disease stratified for age, calendar year of the index event, and residence. A total of 4 variants of coagulation factor XIII subunit A and B genes (F13A1 and F13B) were investigated. The Phe allele of the F13A1 Tyr204Phe variant was present in 59 (31%) patients and 43 (6%) controls; the odds ratio for ischemic stroke was 9.1 for Phe/Phe and Phe/Tyr versus Tyr/Tyr genotype; the 95% confidence interval was 5.5 to 15. Homozygous genotypes (Phe/Phe) conferred a higher risk (odds ratio, 77; 95% confidence interval, 7.0-848) than heterozygous (Tyr/Phe) genotypes (odds ratio, 8.2; 95% confidence interval, 4.9-14). The risk of ischemic stroke was further increased in carriers of the 204Phe allele using oral contraceptives (odds ratio, 20; 95% confidence interval, 9-46) compared with nonusers with Tyr/Tyr genotype. In conclusion, the F13A1 204Phe allele was strongly associated with ischemic stroke in young women. Oral contraceptive use further increased the risk of ischemic stroke.     

Apolipoprotein A5 gene IVS3+G476A allelic variant confers susceptibility for development of ischemic stroke

BACKGROUND: T-1131C, T1259C and IVS3+G476A are naturally occurring variants of the apolipoprotein A5 (APOA5) gene and their possible impact on the development of ischemic stroke was investigated in the present study. METHODS AND RESULTS: PCR-RFLP assays were used to determine the distributions of the APOA5 alleles in small-vessel, large-vessel and mixed subgroups of 378 patients and in 131 stroke-free control subjects. Increased triglyceride levels were found in subjects carrying -1131C, 1259C, IVS3+476A alleles in all stroke groups and in the controls. The -1131C and IVS3+476A alleles, but not the T1259C variant, showed significant accumulation in all stroke subgroups. Logistic regression analysis adjusted for age, gender, body mass index, total cholesterol level, ischemic heart disease, hypertension, diabetes mellitus, smoking-and drinking habits revealed that the IVS3+476A allele represents independent susceptibility factor for stroke (odds ratio for small-vessel: 4.748; large-vessel: 3.905; mixed: 2.926; overall: 3.644 at 95% confidence interval; p<0.05), we could also confirm the previously verified pathogenic role of the -1131C variant. CONCLUSIONS: All of the 3 APOA5 variants are associated with elevated triglycerides, but only the -1131C and the IVS3+476A alleles confer risk for all types of ischemic stroke; such an association could not be detected for the 1259C allele.     

Apolipoprotein A5 IVS3+476A allelic variant associates with increased trigliceride levels and confers risk for development of metabolic syndrome in Hungarians.

BACKGROUND: Metabolic syndrome consists of multiple risk factors that are increasing the cardiovascular mortality. The T-1131C variant of the apolipoprotein A5 gene, associated with increased triglycerides, has been found to confer risk for cardiovascular diseases and metabolic syndrome. Because other naturally occurring variants of the gene also correlate with elevated triglycerides, the possible role of 2 common variants, the IVS3+G476A and T1259C, with metabolic syndrome was investigated. METHODS AND RESULTS: A total of 213 metabolic syndrome patients and 142 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Serum triglycerides were increased in carriers compared with non-carriers in both groups (p<0.001); serum cholesterol levels were similar in all genotypes. The IVS3+476A allele frequency was increased in metabolic syndrome patients compared with controls (8.05 vs 2.47%; p<0.05), whereas the 1259C allele frequency did not differ between the groups. Multiple logistic regression analyses adjusted for age, gender, serum total cholesterol, acute myocardial infarction and stroke revealed that the IVS3+476A variant confers risk for development of metabolic syndrome (odds ratio =3.529, 95% confidence interval 1.308-9.029, p=0.009), but the 1259C allele had no such an effect. CONCLUSIONS: Carrying the IVS3+473A allele is associated with elevated triglycerides and confers risk for development of metabolic syndrome, a combination that represents increased risk for development of atherogenic vascular diseases.     

Beta2-adrenergic receptor gene polymorphisms and risk of ischemic stroke

BACKGROUND: Beta2-adrenergic receptors (beta2-AR) mediate vasorelaxation in response to adrenergic agents. Genetic polymorphisms of beta2-AR were implicated in various cardiovascular and noncardiovascular traits. METHODS: We tested the role of the beta2AR-16 and beta2AR-27 gene variants in the susceptibility to the development of ischemic stroke in a genetically homogenous and clinically well-characterized case-control sample that included 294 cases and 286 controls from Sardinia, Italy. This population was shown to be an optimal study sample for carrying out genetic analyses. RESULTS: Age, hypertension, dyslipidemia, and atrial fibrillation were independent risk factors for stroke in this cohort. We found that the presence of the Glu27 allelic variant was associated with a significantly increased risk of stroke when assuming a recessive mode of inheritance (odds ratio [OR], 1.68; 95% confidence interval [CI], 1.17-2.41; P = .005). The same results were obtained for the subgroup of ischemic strokes of arterial origin (n = 215): OR, 1.71; 95% CI, 1.14-2.57; P = .009. Furthermore, haplotype analysis confirmed that the presence of the Glu27 allele increased the risk of cerebrovascular accidents. CONCLUSIONS: Our data suggest that the Glu27 allelic variant of the beta2-AR gene may be a determinant of ischemic stroke.