云南汉族心肌梗死相关基因的多态性研究

目的 探索凝血因子Ⅶ(coagulation factor Ⅶ,FⅦ)、凝血因子Ⅻ(coagulation factor Ⅻ,FⅫ)、人血纤蛋白原( fibrinogen,FBG)及9p21的基因多态在云南汉族人群中的分布及其与心肌梗死的相关性.方法 应用聚合酶链反应-限制性片段长度多态和焦磷酸测序分型技术对142例心肌梗死患者和192名对照者的FⅦ、FⅫ、FBG、9p21多个位点的基因进行检测分析.结果 R353Q、5′F7、C46T、-148C/T、rs1333049、rs4977574位点的多态性在心肌梗死组与对照组之间差异无统计学意义(P＞0.05),-455G/A的AA基因型、rs1333040的T等位基因和TT基因型、rs10116277的T等位基因和TT基因型、rs2383207的G等位基因和GG基因型频率均显著高于对照组(P＜0.05),而rs1333040的CT和rs10116277的GT基因型频率均显著低于对照组(P＜0.05).结论 FⅦ、FⅫ、FBG基因的-148C/T、9p21的rs1333049位点的多态性与云南汉族心肌梗死无显著关联,FBG基因的-455G/A和9p21的rs1333040、rs10116277、rs2383207位点的多态性可能与云南汉族心肌梗死有一定的相关性.     

Lack of association of genetic variants in the LRP8 gene with familial and sporadic myocardial infarction

Coronary artery disease (CAD) and myocardial infarction (MI) have a genetic basis, but the precise genetic underpinning remains controversial. Recently, an association of the LRP8 R952Q polymorphism (rs5174) with familial premature CAD/MI was reported. We analysed rs5174 (or the perfect proxy rs5177) in 1,210 patients with familial MI and 1,015 controls from the German MI Family study, in 1,926 familial CAD (1,377 with MI) patients and 2,938 controls from the Wellcome Trust Case Control Consortium (WTCCC) MI/CAD cohort, in 346 CAD patients and 351 controls from the AtheroGene study and in 295 men with incident CAD and 301 controls from the Prospective Epidemiological Study of MI study and found no evidence for association in any of the populations studied. In the WTCCC and the German MI Family studies, additional single-nucleotide polymorphisms in the LRP8 gene were analysed and displayed no evidence for association either. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Wolfgang Lieb, Tanja Zeller, Massimo Mangino, Jeanette Erdmann, and Laurence Tiret contributed equally.     

CYP2C19、CYP3A5基因多态性与心肌梗死的相关性研究

目的探讨CYP2C19、CYP3A5基因的多态性与心肌梗死发病风险的相关性。方法随机选取心肌梗死患者及健康对照各500例,采用荧光PCR法和Sanger测序分别检测其CYP2C19、CYP3A5基因的多态性,用Logistic回归分析其与心肌梗死的相关性,用Quanto软件评估统计学效能。结果CYP2C19基因rs4986893位点的AG、GG基因型和A等位基因的频率以及CYP3A5基因rs776746位点的AA、AG、GG基因型和G等位基因频率在两组之间的差异具有统计学意义(P<0.05),CYP2C19基因rs4244285、rs12248560位点的基因型和等位基因以及rs4986893位点的AA基因型的频率在两组之间差异无统计学意义(P>0.05)。在校正年龄、性别、体质指数后,Logistic回归分析显示CYP2C19基因rs4986893的AG基因型和A等位基因以及CYP3A5基因rs776746的GG基因型和G等位基因可能是心肌梗死发病的风险因素,而rs4986893的GG基因型以及rs776746的AA、AG基因型可能是心肌梗死的保护因素。依据样本量、样本结构和等位基因频率以及Quanto分析,本研究的结果具有理想的统计学效能(99%)。结论CYP2C19、CYP3A5基因的多态性可能增加心肌梗死的发病风险。     

Genetic polymorphisms of inflammatory cytokines and myocardial infarction in the elderly

Cardiovascular diseases (CVD), such as myocardial infarction (MI), are major causes of disability and mortality in the elderly. The increasing burden of CVD in ageing industrialized populations requires intensive research in order to improve preventive and therapeutic strategies especially in old people and if possible slow the processes of cardiovascular disease generation and progression. Ageing is accompanied by an age-dependent up-regulation of the inflammatory response, due to chronic antigenic stress stimulation, which potentially triggers the onset of inflammatory diseases, especially CVD. However, the exact mechanisms are still poorly understood. Since CVD are caused by interactions between genetic and environmental factors, a possible approach to their prevention is to identify the potential genetic component of inflammatory cardiovascular risk factors, providing the basis for personalized lifestyle modification and improved pharmacological therapy. Some common gene polymorphisms associated with high production of inflammatory molecules have been associated with atherosclerosis. Therefore, controlling inflammation might play a protective role against CVD, especially in ageing. Although a large number of studies of pro- and anti-inflammatory gene variants in association with CVD and MI exists, the emerging data are quite conflicting and do not provide definitive evidence for a role of these polymorphisms in the pathogenesis of MI. In this paper we review the evidence for a possible role of genetic polymorphisms of the most important inflammatory cytokines (IL-6, TNF-alpha, IL-10) and immune receptors (CD14 receptor and TLR-4) in modulating the incidence or the prognosis of MI, with a special focus in ageing population.     

Lack of association between LTA and LGALS2 polymorphisms and myocardial infarction in Japanese and Korean populations

To investigate the recently reported associations of polymorphisms in lymphotoxin-alpha (LTA) and galectin-2 (LGALS2) with myocardial infarction (MI), we analyzed a single nucleotide polymorphism of LTA (LTA 252A>G in LTA intron 1) and that of LGALS2 (LGALS2 3279C>T in LGALS2 intron 1) in Japanese and Korean populations. Although significant associations with MI were not observed in either population, we found that LTA 252GG was significantly associated with the severity of the disease for both the Japanese and Korean populations (P=0.017 and P=0.001, respectively). On the other hand, the polymorphism of LGALS2 was not associated with the severity of coronary atherosclerosis. These observations showed that, while the LTA 252GG genotype might modify the development of coronary atherosclerosis, the relation of LTA and LGALS2 to MI itself remained much less certain.     

Resolving inflammatory links between myocardial infarction and vascular dementia

Myocardial infarction is associated with increased risk for vascular dementia. In both myocardial infarction and vascular dementia, there is evidence that elevated inflammatory biomarkers are associated with worsened clinical outcomes. Myocardial infarction leads to a systemic inflammatory response, which may contribute to recruitment or activation of myeloid cells, including monocytes, microglia, and perivascular macrophages, within the central nervous system. However, our understanding of the causative roles for these cells linking cardiac injury to the development and progression of dementia is incomplete. Herein, we provide an overview of inflammatory cellular and molecular links between myocardial infarction and vascular dementia and discuss strategies to resolve inflammation after myocardial infarction to limit neurovascular injury.     

Genetics of C‐reactive protein and complement factor H have an epistatic effect on carotid artery compliance: The Cardiovascular Risk in Young Finns Study

Atherosclerosis is characterized by a prominent inflammatory component and C‐reactive protein (CRP) has been implicated to modulate the complement activity in atherosclerotic arteries via complement factor H (CFH) binding. In this study, we examined whether the gene‐gene interactions between CRP haplotypes and CFH Tyr402His functional polymorphism exerted an effect on early atherosclerosis. Single nucleotide polymorphisms (SNPs) in CFH (Tyr402His) and CRP (?717A > G, ?286C > T > A, +1059G > C, +1444C > T and +1846G > A) were genotyped in the participants of the Cardiovascular Risk in Young Finns Study (n = 1698, aged 24–39 years). The CRP SNPs were further constructed into haplotypes and their interactive effects with the CFH Tyr402His polymorphism on the early atherogenic vascular changes [i.e. carotid artery compliance (CAC) and intima‐media thickness (IMT)] were examined. After risk factor adjustment, a significant gene‐gene interaction (P = 0·007) on CAC was observed between CRP haplotype ATGTG and CFH Tyr402His polymorphism in males. Furthermore, logistic regression analysis verified the risk‐modifying interactive effect on CAC between these loci (OR 3·70, 95% CI 1·37–10·02, P = 0·010). No effects on CAC were observed in females and no effects on IMT were detected in either sex. We conclude that the combined presence of CRP haplotype ATGTG and CFH 402His allele may be disadvantageous to carotid artery elasticity in males.     

MTHFR Gene polymorphisms, B-vitamins and hyperhomocystinemia in young and middle-aged acute myocardial infarction patients

We have examined the prevalence of the C677T and A1298C single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in healthy Tamilians and in patients with acute myocardial infarction and related this polymorphism to plasma homocysteine concentrations, serum folate, serum cobalamin and riboflavin status. The SNPs in the MTHFR gene were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Plasma homocysteine, serum folate and serum cobalamin concentrations were analyzed using an automated chemiluminescence method and riboflavin status was assessed by measuring the erythrocyte glutathione reductase activity using spectrophotometric method. Out of the 200 young and middle-aged (<48 years) individuals included in the study, 100 were acute myocardial infarction (AMI) patients and 100 were healthy individuals with no documented history of heart diseases. There was a significant increase in homocysteine levels among the AMI patients as compared to the healthy controls (p<0.001). The results of this study indicate that hyperhomocystinemia is more prevalent in Tamilian AMI patients and that the MTHFR C677T and A1298C SNPs are not associated with hyperhomocystinemia. Folate status was found to be within normal range in all the study subjects. There was no correlation between homocysteine and different biochemical variables including cobalamin, folate and riboflavin. However, serum cobalamin was found to be significantly decreased in AMI patients when compared to controls (p<0.001). The simultaneous presence of decreased serum cobalamin status, hyperhomocystinemia and mutant genotype for both the SNPs might lead to an increased risk for the occurrence of AMI. Further intervention trials including the supplementation of cobalamin may prove whether homocysteine level decrease in response to the supplementation of cobalamin in individuals with hyperhomocystinemia and mutant genotype for both the above mentioned SNPs.     

血小板膜糖蛋白Ia基因807nt多态性与急性心肌梗死的关系研究

目的通过检测急性心肌梗死患者及对照人员的血小板膜糖蛋白（GP Ia）基因807nt多态性,探讨该多态性与急性心肌梗死发病的关系。方法血小板膜糖蛋白Ia基因807nt多态性分析：（1）碘化钾法提取人基因组DNA。（2）多聚酶链反应（PCR）扩增目的基因片段。（3）酶切产物经2%琼脂糖凝胶电泳分离后,紫外灯下检测酶切结果。（4）SPSS11.5软件分析数据。结果（1）急性心肌梗死组血小板膜糖蛋白Ia基因807nt处T等位基因频率显著高于对照组。（2）急性心肌梗死组血小板膜糖蛋白Ia基因807ntTT＋TC基因型频率显著高于对照组。（3）在血小板膜糖蛋白Ia基因807ntTT＋TC和CC基因型之间,高血压病和糠尿病的发病率无显著性差异。（4）在血小板膜糖蛋白Ia基因807nt TT＋TC和CC基因型之间,空腹血糖、血清甘油三脂浓度无显著性差异。（5）急性心肌梗死患者平均甘油三脂水平显著高于对照组。结论（1）血小板膜糖蛋白Ia基因807nt处T等位基因可能是急性心肌梗死发病的独立遗传性危险因素。（2）血小板膜糖蛋白Ia基因807nt多态性可能与高血压病、糖尿病的发病及糖代谢等无关。     

Acute myocardial infarction caused by coronary tumor thromboembolism: a rare primary manifestation of malignant tumor disease

Myocardial infarction in the context of malignant tumor disease is rare but well documented and can occur through various pathophysiological mechanisms. We report an unusual case of a patient with recurrent myocardial infarction due to coronary tumor thromboembolism as the first clinical manifestation of a previously unknown squamous cell carcinoma of the lung. The possible pitfalls leading to a wrong preliminary diagnosis in our case as well as the literature on myocardial infarction in patients with cancer were discussed.     

Membrane attack complex of complement and 20 kDa homologous restriction factor (CD59) in myocardial infarction

In order to investigate the mechanism of deposition of the complement membrane attack complex (MAC) in cardiomyocytes in areas of human myocardial infarction, the 20 kDA homologous restriction factor of complement (HRF20; CD59) and complement components (C1q, C3d and MAC) were analysed immunohistochemically using specific antibodies. Myocardial tissues obtained at autopsy from nine patients who died of acute myocardial infarction were fixed in acetone and embedded in paraffin. The ages of the infarcts ranged from about 3.5 h to 12 days. In cases of myocardial infarction of 20 h or less, MAC deposition was shown in the infarcted cardiomyocytes without loss of HRF20. Where the duration was 4 days or more, the cardiomyocytes with MAC deposition in the infarcted areas also showed complete loss of HRF20. Outside the infarcts, HRF20 in the cardiomyocytes was well preserved without MAC deposition. The present study suggests that the initial MAC deposition in dead cardiomyocytes can occur as a result of degradation of plasma-membrane by a mechanism independent of complement-mediated injury to the membrane. Loss of HRF20 from dead cardiomyocytes may not be the initial cause of MAC deposition, but may accelerate the deposition process of MAC in later stages of infarction.     

Lack of association between IL-1 and IL-6 gene polymorphisms and myocardial infarction in Turkish population

Inflammation and genetics play a key role in the pathogenesis of atherosclerosis and its clinical result myocardial infarction (MI). Proinflammatory cytokines, IL-1 and IL-6, have been shown to play essential roles in developmental stages of coronary artery plaque formation. The aim of this study was to determine the association between IL-1 [IL-1RN, IL-1β (-511, +3953)], IL-6 [-174, -572, -597] gene polymorphisms and MI in Turkish population. A total of 402 people were participated; 235 healthy control subjects and 167 MI patients (MI<40, n: 72; MI>40, n: 95). Polymerase chain reaction (PCR) was used to determine the genotype of IL-1RN, whereas the genotypes of IL-1β (-511, +3953) and IL-6 (-174, -572, -597) were determined using PCR followed with restriction digestion analysis. There was no significant difference between MI and controls for IL-1RN, IL-1β-511, +3953 (P: 0.875, 0.608, 0.442) and IL-6 -174, -572, -597 (P: 0.977, 0.632, 0.584) gene polymorphisms. Lack of association was observed between MI at younger age (MI<40) and either IL-1RN VNTR, IL-1β-511, +3953 (P: 0.878, 0.732, 0.978) or IL-6 -174, -572, -597 (P: 0.313, 0.654, 0.552) gene polymorphisms. This study demonstrated that there was not any association between IL-1, IL-6 gene variants and MI in Turkish population. In addition, IL-1 and IL-6 gene polymorphisms did not affect MI at younger age (MI<40) or older age (MI>40). Thus, IL-1 and IL-6 single nucleotide polymorphisms may not be a risk factor for susceptibility to MI in Turkish population.     

Decay-accelerating factor in the cardiomyocytes of normal individuals and patients with myocardial infarction

Summary The presence of decay-accelerating factor (DAF) was clearly demonstrated on the surface of normal cardiomyocytes. In patients who had died of myocardial infarction (MI) cardiomyocytes displayed different appearances: outside the ischaemically damaged region the myocytes showed no significant variations in DAF expression when compared with controls without MI. Within myocardial zones damaged by ischaemia, however, apparently normal myocytes showed large gaps in surface staining of DAF or formed clusters which were entirely devoid of reactivity with anti-DAF antibodies. The number of DAF-deficient myocytes increased with the extent of necrosis and also with the number of days between onset of MI and death. Even though injury to myocytes is to a large extent related to anoxia and to the presence of free oxygen radicals, the complement system also appears to be involved; DAF may have protective functions against complement-mediated injury. We speculate that phospholipase may be involved in the removal of DAF from the cardiomyocyte surface.This work was supported in part by grant no. 3.157.88 from the Swiss National Foundation for Scientific Research and a contribution from Sandoz Ltd. Pharma Division, Basel     

Lack of association between factor V Leiden and prothrombin G20210A polymorphisms in Tunisian subjects with a history of myocardial infarction

BackgroundMyocardial infarction is a multifactorial disease. It is provoked by occlusions in the coronary arteries resulting from exposure to multiple risk factors.ObjectiveTo study the risk of myocardial infarction associated with the gene polymorphisms of factor V Leiden and factor II (G20210A).Materials and methodsCases consisted of 100 myocardial infarction patients who were hospitalized in the Principal Military Hospital of Tunis and 200 control subjects with no history of myocardial infarction.ResultsThe prevalence of the factor V Leiden was higher in myocardial infarction patients (9%) than in control subjects (6%) with an OR=1.55 (95% CI=0.58–4.12), whereas the prevalence of prothrombin G20210A mutation was 3% and 2.5% in the patient and control groups, respectively [OR=1.21 (95% CI=0.22–5.94)].ConclusionOur results indicate that neither factor V Leiden nor the prothrombin G20210A contributed to the risk factors for myocardial infarction.     

参术冠心颗粒对心肌梗死大鼠冠脉微循环的影响*

 目的：探讨参术冠心颗粒（SSGX）对大鼠心肌梗死(MI)模型冠脉微循环作用。方法：健康SPF级SD大鼠50只,随机分成假手术(sham)组、MI组、SSGX高剂量、中剂量和低剂量治疗组,每组10只。后4组结扎冠状动脉建立MI大鼠模型,假手术组只穿线不进行结扎。造模3 d后超声检查淘汰不合格大鼠,药物干预4周,测定4周后各组大鼠血清心肌损伤标志物、梗死区中小血管平均血管面密度（MVC值）、梗死边缘区血小板内皮细胞黏附分子1(PECAM-1)和血管内皮生长因子(VEGF)表达。结果：MI组与sham组比较,光学显微镜见MI组死亡的心肌纤维间空隙变宽,密集的中型多形核白细胞浸润,肉芽组织增生,坏死心肌纤维被致密的胶原纤维取代。超声可见MI组左室室璧活动异常,射血分数减低。心肌钙蛋白T（cTnT）、MVC、PECAM-1和VEGF各指标与sham组比较均有显著差异（P<0.01）,证明造模成功。大鼠心肌梗死区中小血管的MVC、梗死边缘区PECAM-1及VEGF的表达,SSGX各剂量组与MI组相比表达明显增加,差异有统计学意义（P<0.01）,呈量效关系。但各SSGX组大鼠和MI组大鼠之间,心肌标志物差异无统计学意义（P>0.05）。结论:参术冠心颗粒能改善心肌梗死大鼠冠脉微循环状态,其机制可能与增加PECAM-1和VEGF表达、促进中小血管新生有关。     

Novel sequence elements define ancestral haplotypes of the region encompassing complement factor H

The genomic region encompassing complement factor H (CFH) is thought to be important in determining susceptibility to inflammatory diseases such as age-related macular degeneration, but only limited polymorphism has been described. After applying the genomic matching technique to three-generation families and an ethnically diverse reference panel we have demonstrated that the polymorphism resembles that found in the major histocompatibility complex. The different ancestral haplotypes carry either T or C at T1277C but also other more polymorphic alleles over a region of 2 Mb. Thus the association between age-related macular degeneration and T1277 or Y402 actually reflects multiple linked polymorphisms including an indel that cannot be dissected from any direct effect of Y402 and may be more important. We show for the first time that simple algorithms can identify genomic sequence elements that appear to be more useful haplospecific markers than single nucleotide polymorphism or microsatellites.