Platelet glycoprotein GP VI 13254C allele is an independent risk factor of premature myocardial infarction

Aim

The purpose of this study was to asses the impact of haemostatic and platelet receptor gene polymorphisms as an inherited risk factor for premature onset of myocardial infarction (MI).

Methods

Polymorphisms of platelet receptors - GP Ia (807C>T, rs1126643), GP VI (13254T>C, rs1613662), GP IIIa (HPA-1, rs5918), PAR -1 (IVS -14A>T; rs168753), P2Y₁₂ (34C>T, rs6785930 and H1/H2 haplotype, rs2046934), and genetic variations of the gene coding for cyclooxygenase-1 (COX-1) ( -842A>G, rs10306114 and 50C>T, rs3842787) were investigated. Mutations in the genes coding for coagulation factor V (Q506R (Leiden) mutation, rs6025) and factor II (prothrombin G20210A, rs1799963) were also determined. The prevalence of gene polymorphisms was investigated in 105 consecutive patients with premature MI. This was compared with the same gene polymorphism prevalence in a group of 132 patients in which coronary artery disease had been excluded. Genotyping was done using PCR, followed by melting curve analysis with specific fluorescent hybridization probes.

Results

A significant association between GP VI 13254C allele carriers and premature MI was found (p = 0.025). No other differences in prevalence of the investigated polymorphisms between the compared patient populations reached statistical significance. In a logistic regression, which took other cardiovascular risk factors into account, the significance of the GP VI 13254C allele and vascular risk was suggested (OR 1.888, 95% C.I. 1.029 to 3.464, p = 0.040). In a binary logistic regression the positive relationship between the GP VI genotype and female gender was observed (0R 3.676; 95% C.I. 1.159 to 11.628; p = 0.027). The frequencies of GP VI and GP Ia gene polymorphisms were independent of one another (p = 0.836).

Conclusion

The presence of the GP VI 13254C allele is an independent predictor of premature MI.     

Gene polymorphisms in the TNF locus and the risk of myocardial infarction

We investigated two genetic polymorphisms in the tumor necrosis factor locus (TNF-alpha -308 G-->A and LT-alpha +252 A-->G) as risk factors for coronary atherothrombotic disease (CAD) by determining its prevalence in 148 survivors of myocardial infarction (MI) with angiographically-proven severe CAD, and in 148 age-, gender- and race-matched controls. The odds ratio (OR) for MI related to the mutant TNF-alpha and LT-alpha alleles was 0.8 (CI95: 0.4-1.3) and 1. 3 (CI95: 0.8-2.0), respectively. We also sought interaction of smoking and metabolic risk factors for MI with each mutant genotype. Smokers not carrying the LT-alpha +252 A-->G mutation had a risk of MI of 2.7 (CI95: 1.4-5.4) whereas in smoking carriers the risk was 6. 9 (CI95: 3.4-14.1). An interactive effect of the LT-alpha mutation may also exist with dyslipidemia (OR for MI in non-carriers was 12 [CI95: 3.2-41.3] and in carriers the OR was 39, [CI95: 5.1-301] and with obesity (OR for MI was 2.7, [CI95: 1-7.2] in non-carriers and in carriers the OR was 6 [CI95: 2.1-16.8]). Lastly, the OR for MI in obese non-carriers of TNF-alpha -308 G-->A was 2.8 (CI95: 1.3-6) and in obese carriers the OR was 14.5 (CI95: 1.8-113). Although significant interactive effects could not be detected, the findings suggest that interaction of polymorphisms in the TNF locus with major risk factors for CAD may exist, and should be explored in larger studies.     

Assessment of genetic risk for myocardial infarction

Although lifestyle and environmental factors influence the prevalence of myocardial infarction, genetic epidemiological studies have suggested that several genetic variants increase the risk for this condition. We have performed a large-scale association study to identify gene polymorphisms for reliable assessment of the genetic risk of myocardial infarction. The study population comprised 3,483 unrelated Japanese individuals (1,913 men; 1,570 women), including 1,192 subjects with myocardial infarction and 2,291 controls. The genotypes for 164 polymorphisms of 137 candidate genes were determined with an oligonucleotide ligation assay based on analysis of fluorescent microspheres with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hypercholesterolemia revealed that the 677C-->T (Ala222Val) polymorphism of MTHFR, the 1595C-->G (Ser447Stop) polymorphism of LPL, and the -108/3G-->4G polymorphism of IPF1 were significantly associated with the prevalence of myocardial infarction. A stepwise forward selection procedure demonstrated that IPF1, MTHFR, and LPL genotypes significantly affected the prevalence of myocardial infarction. Combined genotype analysis of these polymorphisms yielded a maximum odds ratio of 2.54 for the combined genotype of TT for MTHFR, CC for LPL, and 3G3G for IPF1. The genotypes for MTHFR, LPL, and IPF1 may prove reliable for assessment of genetic risk for myocardial infarction. Determination of the combined genotype for these genes may contribute to primary, personalized prevention of this condition.     

Platelet production in myocardial infarction and sudden cardiac death

Megakaryocyte cytoplasmic volumes were studied in 13 subjects 18 +/- 2 days after admittance to the coronary care unit. Seven had suffered a myocardial infarction (MI group) while six had chest pain but no recent infarction. Megakaryocytes were also studied in 10 subjects suffering coronary sudden unexpected death (CSD group) and 11 subjects suffering sudden unexpected un-natural death. There was no significant difference between the megakaryocyte cytoplasmic volume distributions of the MI and CSD groups, although they had a significantly greater mean (p less than 0.01) and range (p less than 0.001) than their respective control groups. There was no significant difference in platelet volumes observed within 24 hr of the infarct and 18 +/- 2 days later. Mean platelet volume was significantly correlated (r = 0.89, p less than 0.006) to mean megakaryocyte cytoplasmic volume in the MI group. A computer simulation of platelet production showed no significant difference between platelet volumes observed in the MI group and those estimated to be circulating before death in the CSD group.     

Platelet membrane glycoprotein polymorphisms do not influence the clinical expressivity of von Willebrand disease type 1

Von Willebrand disease (VWD) is characterized by a significant variation in bleeding symptoms among patients with similar laboratory profiles and equivalent plasma levels of von Willebrand factor (VWF) activities. Considering the recent suggestion that platelet membrane glycoprotein polymorphisms (PltGPs) may play a role as modulators of thromboembolic or haemorrhagic diseases, we investigated the role of different PltGPs and GPVI content in the clinical expression of patients with VWD type 1.The diagnosis of VWD (n = 76) was based on laboratory findings (VWF:Ag, VWF:RCo, VWF:CB, FVIII:C, and multimer analysis), family and personal history of bleeding. All patients were interviewed using a standardized questionnaire, and classified into two categories: bleeders (unequivocal bleeding tendency, n = 53) and non bleeders (absence of bleeding symptoms, n = 23). PltGPs, HPA-1, 2 and 5 and C807T of GPIa were determined by fluorophore-labelled hybridization probes on a LightCycler. GPVI content was measured by western blotting. VWF:Ag,VWF:RCo,VWF:CB and FVIII:C levels were not significantly different between symptomatic and asymptomatic patients. There were no differences in the genotype distribution and allele frequencies between bleeders and non bleeders for the platelet alloantigen systems HPA-1, 2, 5 and the GPIa C807T polymorphism. The levels of platelet GPVI were similar in symptomatic and asymptomatic VWD patients (109.6 +/- 58.4 vs 114.1 +/- 52.5, respectively; p: 0.77). These results show that PltGPs HPA-1, 2 and 5 or the C807T dimorphism of GPIa do not influence the clinical expressivity of VWD type 1. The wide variation in GPVI content was not associated with the severity of bleeding in the patients. Other genetic factors that may contribute to the variable expressivity of VWD type 1 should be investigated.     

Platelet glycoprotein IIb/IIIa receptor blockade: lessening the risk of coronary interventions

For the patient undergoing percutaneous coronary intervention, the administration of a platelet glycoprotein IIb/IIIa receptor blocker reduces the incidence of a periprocedural nonfatal myocardial infarction and the need for unplanned emergency stenting. In the diabetic patient undergoing intracoronary stenting, the use of a platelet glycoprotein IIb/IIIa receptor blocker appears to decrease the need for subsequent target vessel revascularization. There is considerable evidence in support of the use of glycoprotein IIb/IIIa receptor inhibitors in all categories of patients--"high-risk" patients, "low-risk" patients, and those undergoing primary angioplasty for acute myocardial infarction--and for the full armamentarium of percutaneous procedures (angioplasty, directional atherectomy, rotational atherectomy, and intracoronary stenting).     

Vital exhaustion as risk indicator for myocardial infarction in women

To test the hypothesis that ‘vital exhaustion’ (VE), a state characterized by unusual fatigue, increased irritability, and feelings of demoralization, precedes the onset of myocardial infarction (MI) in females, 79 females hospitalized with a first MI (mean age: 59.3; =9.3) and 90 females hospitalized in the departments of general and orthopaedic surgery (mean age: 57.4; =9.1), were compared on the retrospective form of the Maastricht Questionnaire (MQ).

Defining ‘exhaustion’ as a score above the median of the MQ, 63% of the cases and 39% of the controls were exhausted before hospitalization (x²=10.02; p<0.00). The relative risk associated with exhaustion, after controlling for age, smoking, coffee consumption, diabetes, hypertension, non-anginal pain, and menopausal status, was estimated as 2.75 (95% CI:I.28-5.81; p<0.01), thus corroborating the hypothesis. Exploratory analyses of the origins of exhaustion in these females showed that of all biographical characteristics, holding a job and simultaneously taking care of the household was most strongly associated with elevated exhaustion scores.     

Platelet membrane glycoprotein V: characterization of the thrombin-sensitive glycoprotein from human platelets

Human platelets contain a single membrane glycoprotein which is susceptible to thrombin proteolysis, glycoprotein V. We have purified 1 mg of glycoprotein V from 10(13) platelets using a combination of gel filtration, hydroxylapatite and ion-exchange chromatographies. Glycoprotein V has a blocked amino-terminus. Following proteolysis by human alpha-thrombin, a major fragment, termed glycoprotein Vf1, had the sequence Gly-Pro-Phe-X-Arg-Pro-Ala-Ala-Asp-Glu-Ser-Val-Glu-Ala-Pro-Val-Asn-Gln-Al a-Glu- Ala-Pro-. The purified glycoprotein was not a substrate for human gamma-thrombin. Glycoprotein V contained 17.5% carbohydrate, with the majority of the carbohydrate consisting of neutral hexoses. Deglycosylated glycoprotein V had a molecular weight of 57.5 kDa compared to the glycosylated protein's 82 kDa and the deglycosylated protein was recognized by polyclonal antibodies raised against glycoprotein V. Immunoelectrophoresis of human and rat platelets and megakaryocytes gave a single immunoreactive band, with the rat glycoprotein having a slightly larger molecular mass. Glycoprotein V is most likely an integral membrane protein.     

TIMI危险评分对脑血管病合并急性心肌梗死患者预后的评估作用

目的 研究TIMI危险评分对脑血管病合并急性ST段抬高型心肌梗死PCI术后患者预后的评估作用.方法 回顾性分析河南省人民医院2018-09—2019-02经急诊收住院并诊断为脑血管病合并急性ST段抬高型心肌梗死(STEMI)患者222例,按照TIMI危险评分分为低危组(0～3分)71例(32.0％)、中危组(4～6分)...     

血小板膜糖蛋白CD41/CD61基因多态性及表达率与脑梗死的关系

目的探讨血小板膜糖蛋白CD41/CD61与脑梗死的关系。方法应用聚合酶链反应-限制性片断长度多态性分析技术(PCR-RFLP)和同步流式细胞术,分别检测CD41/CD61的基因多态性和表达率,并进行脑梗死组和对照组比较,其中脑梗死组115例:男64例,女51例,年龄36~77岁;对照组103例:男59例,女44例,年龄33~79岁。结果 (1)脑梗死组CD41 aa、ab和bb基因分布频率分别为20.0%、38.3%和41.7%,对照组分别为28.2%、48.5%和23.3%;两组间比较bb基因型有统计学意义(P<0.05);脑梗死组b等位基因频率(60.4%)高于对照组(47.6%),P<0.05。(2)CD61基因型均为aa型(未切开型)。(3)脑梗死组CD41/CD61表达率为96.0%±8%,对照组为85.5%±13%,差异有统计学意义(P<0.05)。(4)脑梗死组CD41 bb、aa基因型表达率分别为98.5%±13%、91.3%±8%,差异显著(P<0.05)。结论脑梗死与血小板膜糖蛋白CD41/CD61密切相关,CD41 bb基因影响CD41/CD61表达率;分析CD41基因多态性结合检测CD...