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The Apolipoprotein E and -Fibrinogen G/A-455 Gene Polymorphisms Are Associated With Ischemic Stroke Involving Large-Vessel Disease
Abstract
The relationship between the apolipoprotein E (apoE) and beta-fibrinogen G/A-455 polymorphisms and cerebrovascular disease (CVD) was examined in the present study. We compared 227 patients with the subtypes of CVD (large-vessel disease, lacunar stroke, cardiac embolism, or undetermined pathomechanisms) with 225 control subjects. The occurrence of apoE isoforms (E2, E3, and E4) and the beta-fibrinogen G/A-455 genotype was determined in these individuals. No differences in apoE polymorphisms or allele frequencies between the CVD patients and control subjects were found. However, analysis of apoE genotypes as a function of stroke subtype revealed that the apoE4 allele was significantly more common in those patients with macroangiopathy-associated CVD. The only CVD risk factor that distinguished patients with the E4 allele from those with other apoE genotypes was elevated cholesterol. No association between the beta-fibrinogen G/A-455 polymorphism and CVD was found. However, homozygosity for the A allele was more common in patients with CVD resulting from large-vessel disease. These data demonstrate that the apoE4 allele and the AA genotype of the beta-fibrinogen G/A-455 polymorphism occur significantly more frequently in patients with CVD resulting from stenosis of large, brain-supplying vessels. Such genetic analyses may further our understanding of the etiology of cerebrovascular disease.
... gene (MTHFR) 15 , the β-fibrinogen gene (FGB) 16,17 , and the endothelial nitric oxide synthase gene (eNOS) 18,19 . However, whether IS-relevant genetic factors convey a risk for CES in AF patients with low CHA 2 DS 2 -VASc score remains unknown. ...
... We found that the FGB 455 G/A polymorphism was independently associated with increased risk of CES in AF patients with low CHA 2 DS 2 -VASc score. Our current study supports an important role of genetic predisposition in the pathogenesis of CES in AF patients.Earlier studies explored relationships between the FGB 455 G/A polymorphism and IS in different populations.Kessler et al. reported that the AA genotype of the FGB 455 G/A polymorphism occurred significantly more frequently in patients with large vessel infarcts16 . Nishiuma et al. found that the A allele of the 455 G/A polymorphism was an independent risk factor of IS in hypertensive patients in a Japanese population22 . ...
Previous work has suggested that ischemic stroke (IS) may be more likely to occur in individuals with a genetic predisposition. In this study, we investigated the potential association of IS-relevant genetic risk factors with cardioembolic stroke (CES) in atrial fibrillation (AF) patients with low CHA2DS2-VaSc score. Genotyping was performed using the GenomeLab SNPstream genotyping platform for five IS-relevant SNPs (MMP-9 C1562T, ALOX5AP SG13S114A/T, MTHFR 677 C/T, FGB 455 G/A, and eNOS G298A) in 479 AF patients with CES and 580 age and sex-matched AF patients without CES. The multivariate analysis adjusted for potential confounders and demonstrated that FGB 455 G/A was independently associated with increased risk of CES in AF patients and the significance remained after Bonferroni correction in the additive, dominant, and recessive models with ORs of 1.548 (95% CI: 1.251-1.915, P = 0.001), 1.588 (95% CI: (1.226-2.057, P = 0.003), and 2.394 (95% CI: 1.357-4.223, P = 0.015), respectively. Plasma fibrinogen levels were significantly higher in patients with the A allele compared with patients with genotype of GG (3.29 ± 0.38 mg/dl vs. 2.87 ± 0.18 mg/dl, P < 0.001). We found for the first time that the A allele of FGB 455 G/A was a risk factor for CES in AF patients, probably by elevating the level of plasma fibrinogen.
... In addition, clinical studies have shown that ApoE4 is overrepresented in both hyperlipidemic and heart disease populations [119][120][121][122]. For example, large vessel disease, myocardial infarction and stroke risks were shown to be higher in ε4 allele carriers than ε2 allele carriers [123,124]. Several studies estimated a 40% higher risk for CHD mortality in ε4 carriers compared with ε2 carriers or carriers of the ε3/ε3 genotype [125]. These facts sustain the nowadays increased need for personalized medicine and treatment, based not only on marker levels in plasma, but also on genetic characteristics of each individual. ...
In persons with dyslipidemia, a high residual risk of cardiovascular disease remains despite lipid lowering therapy. Current cardiovascular risk prediction mainly focuses on low-density lipoprotein cholesterol (LDL-c) levels, neglecting other contributing risk factors. Moreover, the efficacy of LDL-c lowering by statins resulting in reduced cardiovascular risk is only partially effective. Secondly, from a metrological viewpoint LDL-c falls short as a reliable measurand. Both direct and calculated LDL-c tests produce inaccurate test results at the low end under aggressive lipid lowering therapy. As LDL-c tests underperform both clinically and metrologically, there is an urging need for molecularly defined biomarkers. Over the years, apolipoproteins have emerged as promising biomarkers in the context of cardiovascular disease as they are the functional workhorses in lipid metabolism. Among these, apolipoprotein B (ApoB), present on all atherogenic lipoprotein particles, has demonstrated to clinically outperform LDL-c. Other apolipoproteins, such as Apo(a) - the characteristic apolipoprotein of the emerging risk factor lipoprotein(a) -, and ApoC-III - an inhibitor of triglyceride-rich lipoprotein clearance -, have attracted attention as well. To support personalized medicine, we need to move to molecularly defined risk markers, like the apolipoproteins. Molecularly defined diagnosis and molecularly targeted therapy require molecularly measured biomarkers. This review provides a summary of the scientific validity and (patho)physiological role of nine serum apolipoproteins, Apo(a), ApoB, ApoC-I, ApoC-II, ApoC-III, ApoE and its phenotypes, ApoA-I, ApoA-II, and ApoA-IV, in lipid metabolism, their association with cardiovascular disease, and their potential as cardiovascular risk markers when measured in a multiplex apolipoprotein panel.
... [14] They found that the E4 allele carrier had a 2.34-fold increase risk of ischemic stroke (OR = 2.34; 95% CI: 1.92-2.86). Our results are similar to the results in the ischemic stroke patients in Spanish, [15] Italian, [16] Chinese, [17] and German [18] studies. The E3/E4 genotype was found to be a risk for developing ischemic stroke, whereas the homozygote E3 was protective in our study cohort. ...
Context: Studies from the different ethnic regions of the world have reported variable results on association of APOE gene polymorphismin stroke. Aim: The aim of this study is to find out the possible association of APOE polymorphism in stroke patients in ethnic Bengalipopulation. Settings and Design: A prospective case–control study was undertaken in the Department of Neurology, Burdwan MedicalCollege, Burdwan, West Bengal, India, over a period of 3 years. Methods: We collected 10 ml venous blood samples from 148 clinicallyand radiologically diagnosed acute stroke patients (80 of ischemic stroke and 68 of intracerebral hemorrhage) and consecutive 108 ethnicage- and sex-matched controls, in ethylenediaminetetraacetic acid vials after informed written consent. Genomic DNA was prepared atS.N. Pradhan Centre of Neurosciences, University of Calcutta, Kolkata, India. Exotic single-nucleotide polymorphisms (rs429358, rs 7412)were analyzed by polymerase chain reaction-restriction fragment length polymorphism for genotype of APOE. Results: The frequencies ofdifferent APOE allele among 80 ischemic stroke patients were 5.6% (n = 9) for E2, 75.68% (n = 121) for E3, and 18.7% (n = 30) for E4.The E3 allele is significantly over-represented (P = 0.004) in controls compared to the patients (88% in controls vs 75.6% ischemic strokepatients and 80% hemorrhagic patients). A significantly high frequency of APOE4 allele was observed in ischemic (18.7%) and hemorrhagicpatients (11%) compared to controls (8%). The E4 allele plays a major risk for developing ischemic stroke [odds ratio (OR) = 2.744; 95%confidence interval (CI): 1.43–5.10] and E3 plays a protective role for hemorrhagic stroke (OR = 0.53; 95% CI: 0.29–0.96), while E4 alleleplays a nonsignificant (P = 0.31) increase in trend in hemorrhage stroke (OR = 1.4). Conclusions: There is significant association of APOEgene polymorphism in stroke patients of ethnic Bengali population. The E4 allele increases significant risk for development of ischemic strokes,and it also plays nonsignificant increase in trend in hemorrhagic strokes.Keywords: Apolipoprotein E, hemorrhage stroke, ischemic stroke, polymorphisms, stroke
(PDF) AnnIndianAcadNeurol234504-688707 190750 2. Available from: https://www.researchgate.net/publication/368357897_AnnIndianAcadNeurol234504-688707_190750_2 [accessed Feb 08 2023].
... Повышение частоты встречаемости гетерозигот-ного полиморфизма FGB:-455G/A при наличии комбинации «плоскостопие + II палец стопы длиннее I» характеризует повышенный риск тромбозов. Встречаемость 455АA-генотипа в популяции составляет 10-20 % [24,25] и ассоциируется с 10 % повышением уровня фибриногена в сыворотке крови по сравнению с таковым у носителей генотипа GG [26]. ...
... [1,3,4] Apolipoprotein E (ApoE) is an important component of all lipoproteins and its polymorphisms are associated with cardiovascular disorders and atherosclerosis, especially in allele e4 carriers. [5][6][7][8] ApoE is involved in modulation of inflammation and oxidation, [9,10] by influencing macrophage proliferation which also contributes to inflammation in emphysema. [11] However, there is no report about the association between ApoE polymorphism and COPD. ...
Chronic obstructive pulmonary disease (COPD) patients have increased cardiovascular morbidity and mortality. Apolipoprotein E (ApoE) is involved in chronic inflammation which is the common characteristic of emphysema and cardiovascular disease. ApoE polymorphisms are associated with cardiovascular disorders and atherosclerosis. There is no report about the association between ApoE polymorphism and COPD.
A total of 480 COPD patients and 322 controls who were unrelated Chinese Han individuals were enrolled. Rs429358 and rs7412 were genotyped and the associations between ApoE polymorphisms and COPD risk were analyzed by logistic regression analysis. Online software SHEsis were applied to perform linkage disequilibrium (LD) and haplotypes analysis. The interactions of ApoE and environmental factor on COPD susceptibility was analyzed by software MDR3.0.2.
No significant association was found between rs429358, rs7412 and COPD under different genetic models. Rs429358 and smoking formed the best model in the MDR analysis. The frequency of E2/E2 phenotype was the lowest in 2 groups. E3/E3 was the most common phenotype, accounting for 69.8% of COPD patients and 68.9% of controls. No statistically difference was identified between the cases and controls under different phenotypes.
This was the first genetic association study between ApoE and COPD. No positive association was found in the Chinese Han population. Rs429358 and smoking status existed significant interaction, indicating that both of ApoE and smoking may be involved in the development of COPD disease.
... Au cours des dernières années, de nombreuses études d'association de type cas-témoins ont été publiées, mais peu se sont avérées positives. On peut cependant retenir l'existence d'une relation probable entre le gène de l'apo E (allèle 4, 2) et les AVC hémorragiques (AVC H) et l'allèle 4 et les AVC ischémiques (AVC I), via son rôle dans la pathogenèse de l'angiopathie amyloïde et la maladie athéromateuse respectivement [4][5][6][7][8]. L'Apo E est l'une des principales composantes protéiques des complexes moléculaires de transport des lipides, les lipoprotéines. ...
Unlabelled:
Our study is the type case-control realized at the Hospital of Constantine, discusses the relationship between polymorphism of apolipoprotein E and stroke.
Methods:
The determination of the polymorphism of apolipoprotein E was carried out by PCR- digestion (polymerase chain reaction) using the enzyme of restriction HhaI. The study population consisted of 218 Algerian patients with stroke (divided into 63% ischemic and 37% hemorrhagic), and 509 control subjects.
Results:
Three isoforms of apolipoprotéin E have been identified. The allelic distribution of apo E in the general population showed a predominance of the allele ɛ3 (84.3%) followed distantly by allele ɛ4 (10.7%) and ɛ2 (5%) respectively. ɛ3/ɛ4 genotype was significantly more represented among subjects with ischemic stroke (29.5%) compared with control subjects (18.8%). The odds ratio is 1.72 compared to carriers of the genotype ɛ3/ɛ3 (CI is 95% and p <0.05).
Conclusions:
The distribution of allelic frequencies of apolipoprotein E in the population of Constantine is similar to that of Southern Europe. Our results imply a role of the genotype of apolipoprotein E (ɛ4 allele) in the pathogenesis of stroke and are limited to the accidents of the ischemic type. The ɛ2 allele does not appear to be implied in occurred of this affection; however, large additional studies are necessary to confirm this result.
... [14] They found that the E4 allele carrier had a 2.34-fold increase risk of ischemic stroke (OR = 2.34; 95% CI: 1.92-2.86). Our results are similar to the results in the ischemic stroke patients in Spanish, [15] Italian, [16] Chinese, [17] and German [18] studies. The E3/E4 genotype was found to be a risk for developing ischemic stroke, whereas the homozygote E3 was protective in our study cohort. ...
Context:
Studies from the different ethnic regions of the world have reported variable results on association of APOE gene polymorphism in stroke.
Aim:
The aim of this study is to find out the possible association of APOE polymorphism in stroke patients in ethnic Bengali population.
Settings and design:
A prospective case-control study was undertaken in the Department of Neurology, Burdwan Medical College, Burdwan, West Bengal, India, over a period of 3 years.
Methods:
We collected 10 ml venous blood samples from 148 clinically and radiologically diagnosed acute stroke patients (80 of ischemic stroke and 68 of intracerebral hemorrhage) and consecutive 108 ethnic age- and sex-matched controls, in ethylenediaminetetraacetic acid vials after informed written consent. Genomic DNA was prepared at S.N. Pradhan Centre of Neurosciences, University of Calcutta, Kolkata, India. Exotic single-nucleotide polymorphisms (rs429358, rs 7412) were analyzed by polymerase chain reaction-restriction fragment length polymorphism for genotype of APOE.
Results:
The frequencies of different APOE allele among 80 ischemic stroke patients were 5.6% (n = 9) for E2, 75.68% (n = 121) for E3, and 18.7% (n = 30) for E4. The E3 allele is significantly over-represented (P = 0.004) in controls compared to the patients (88% in controls vs 75.6% ischemic stroke patients and 80% hemorrhagic patients). A significantly high frequency of APOE4 allele was observed in ischemic (18.7%) and hemorrhagic patients (11%) compared to controls (8%). The E4 allele plays a major risk for developing ischemic stroke [odds ratio (OR) = 2.744; 95% confidence interval (CI): 1.43-5.10] and E3 plays a protective role for hemorrhagic stroke (OR = 0.53; 95% CI: 0.29-0.96), while E4 allele plays a nonsignificant (P = 0.31) increase in trend in hemorrhage stroke (OR = 1.4).
Conclusions:
There is significant association of APOE gene polymorphism in stroke patients of ethnic Bengali population. The E4 allele increases significant risk for development of ischemic strokes, and it also plays nonsignificant increase in trend in hemorrhagic strokes.
... 11) and stroke (Ref. 12). Cerebral autosomal dominant arteriopathy with subcortical infarcts and leuekoencephalopathy (CADASIL), arising from notch3 gene mutations, has increasingly been recognised as a cause of familial subcortical stroke (Ref. ...
Ischaemic heart disease and stroke are vascular events with serious health consequences worldwide. Recent genetic and epigenetic techniques have revealed many genetic determinants of these vascular events and simplified the approaches to research focused on ischaemic heart disease and stroke. The pathogenetic mechanisms of ischaemic heart disease and stroke are complex, with mitochondrial involvement (partially or entirely) recently gaining substantial support. Not only can mitochondrial reactive oxygen species give rise to ischaemic heart disease and stroke by production of oxidised low-density lipoprotein and induction of apoptosis, but the impact on pericytes contributes directly to the pathogenesis. Over the past two decades, publications implicate the causative role of nuclear genes in the development of ischaemic heart disease and stroke, in contrast to the potential role of mitochondrial DNA (mtDNA) in the pathophysiology of the disorders, which is much less understood, although recent studies do demonstrate that the involvement of mitochondria and mtDNA in the development of ischaemic heart disease and stroke is likely to be larger than originally thought, with the novel discovery of links among mitochondria, mtDNA and vascular events. Here we explore the molecular events and mtDNA alterations in relation to the role of mitochondria in ischaemic heart disease and stroke.
... These phenotypes are involved in cholesterol transport; the ε4 allele is associated with higher levels of total and low-density cholesterol [23] as well as CVD [24]. The association between the ε4 allele and CVD is believed to be mediated by the influence of APOE on lipid metabolism and large-vessel atherosclerosis (vessel hardening) [25][26][27][28]. ...
Objective:
This study investigated the retinal arteriolar central reflex (CR, the central reflection observed in photographs of retinal vessels), which may provide information about micro-vascular health in the retina and also the brain, due to the homology between these vascular networks. The study also describes a novel computer based semi-automated technique that accurately quantifies retinal arteriolar CR and vessel width, and calculates the CR to vessel width ratio (CRR) from digital retinal photographs.
Methods:
Digital retinal photographs were collected from participants in the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL), including 25 participants diagnosed with Alzheimer's disease (AD) (age 72.4 ± 7.5 yrs, 12 male, 13 female) and 123 elderly participants without dementia (cognitively normals: CN) (age 71.6 ± 5.6 yrs, 55 male, 68 female). Using a sub-cohort of 144 (22 AD, 122 CN) with the novel CRR measures, we identified significantly higher CRR levels in AD participants (mean CRR 0.253 (SD 0.04)) as compared with CN's (mean CRR 0.231 (SD 0.04), p = 0.025). Adjustment for APOE ε4 allele status however, reduced the significance (p = 0.081). CRR was significantly higher in APOE ε4 allele carriers (mean CRR 0.254 (SD 0.03) as compared with non-carriers (mean CRR 0.224 (SD 0.05), p < 0.0001).
Results:
These data indicate that CRR is strongly linked to APOE ε4 status and exhibits a weaker, independent trend with AD diagnosis. The retina may be useful as a novel model for non-invasive monitoring of the effects of APOE ε4 on the central nervous system, particularly in cerebrovascular disease.
... Наиболее изученным в гене Fb является полиморфизм, представляющий собой замену гуанина (G) на аденин (А) в 455 нуклеотиде промоторной области, обусловливающий повышенное содержание фибриногена в плазме [23]. Известна ассоциативная связь А аллеля с риском развития ИБС и ИМ [24]. ...
Aim. To study association between stroke and gene polymorphism of angeotensin converting enzyme (ACE), angeotensin II type 1 receptor (ATR1), apolipoprotein СIII (APO CIII), apoproteine Е (APO E), methylentetrahydrofolate reductase (MTHFR), fibrinogen (Fb), endothelial NO-synthase (NOS3) in arterial hypertension (HT).Material and methods. Molecular genetic analysis by polymerase chain reaction was done in 41 patients with HT, who experienced first episode of acute disturbances of cerebral blood circulation (ADCBC).Results. Stroke rate in patients with HT is associated with A1166C of ATR1 gene polymorphism, G-455A of Fb gene polymorphism and C677T of MTHFR gene polymorphism. The high risk markers are C-allele of ATR1 gene, -455А allele and AA genotype of Fb gene, 677T allele of MTHFR. The A-allele and genotype AA of ATR1 gene, G-445 allele of Fb gene, С677-allele and CC genotype of MTHFR gene play protective role against ADCBC in HT.Conclusion. It is established an association between gene polymorphism of some molecules and ADCBC in HT.
... These results are inconclusive and should be looked at carefully as no previous study in the literature (14), Dutch (29), Korean (30) and Polish (31) populations found no association between the A allele of the FGB -455 G>A polymorphism and ischemic stroke. In contrast, others studies found a higher frequency for the AA genotype of FGB -455 G>A polymorphism in patients with CVD (32). The A allele of the FGB -455 G>A polymorphism seems to be associated with an increased risk of developing recurrent lacunar stroke (12). ...
Introduction : Being a multifactorial disease, stroke is one of a major causes of death and disability worldwide. Several genetic polymorphisms have been associated with stroke etiophatology and FGB −455 G>A and GP IIIa PIA1/A2 are among them. In the present study, we investigated the association between FGB −455 G>A and GP IIIa PIA1A2 polymorphisms and the risk of ischemic stroke in a group of Romanian stroke patients.
Subjects and methods : This case-control study included 148 patients with ischemic stroke and 150 healthy age, sex and ethnically matched unrelated controls. FGB −455G>A and GP IIIa PIA1A2 genotyping was carried out using PCR-RFLP. The association of FGB −455G>A and GP IIIa PIA1A2 polymorphisms and cardiovascular risk factors with ischemic stroke was tested using logistic regression analysis.
Results : Molecular analysis did not reveal an increased frequency of the FGB -455 G>A variant allele and GP IIIa PIA1/A2 variant allele in the study group compared to the control group (p = 0.140, OR = 0.750, 95% CI = 0.522 - 1.077; p = 0.823, OR = 0.944, 95% CI = 0.558 - 1.599 respectively). Furthermore, after performing logistic regression analysis adjusted for the known risk factors, a positive association with stroke was found in smokers (p = 0.026, OR = 1.800, 95% CI = 1.071 - 3.024)
Conclusions : No association was found between FGB −455 G>A and GP IIIa PIA1/A2 polymorphisms and ischemic stroke in the studied population.
... In this study, the −455 G/A locus genotype showed a significant interaction of age with fibrinogen level at mRS day 0. In the literature, some results were consistent with this study, but others were different [20][21][22]. These may be explained by the fact that cerebral infarction is a polygenic disease, and many candidate genes are involved in the pathogenesis process. ...
... Although previous studies demonstrated that the β-fibrinogen-455 GA mutation increases ischemic stroke risk, the findings are controversial (54)(55)(56)(57). Although our results indicate that the β-fibrinogen -455 GA mutation is associated with ischemic stroke, this mutation did not pose significant risk in the presence of other risk factors. ...
OBJECTIVE: The present study aimed to investigate whether the frequency of factor V, methylenetetrahydrofolate reductase (MTHFR), prothrombin, β-fibrinogen gene mutations, and human platelet alloantigens (HPA), plasminogen activator inhibitor 1 (PAI1), apolipoprotein E (APOE), and angiotensin converting enzyme (ACE) gene polymorphisms in stroke patients is higher than that in normal individuals.
METHODS: Two hundred twelve patients with cerebral infarction and 238 individuals of similar age and gender with no history of stroke were included. Demographics and risk factors for cerebrovascular disease of all individuals were determined. Biochemical parameters were analyzed in serum, and electrocardiography was performed. Factor V, MTHFR, prothrombin, β-fibrinogen mutations and HPA, PAI, APOE, and ACE polymorphisms were investigated. Data were analyzed with SPSS 15.0 software using descriptive statistics, chi-square, independent two-group t-test, and logistic regression tests. Statistically significant differences in independent variables were further analyzed by logistic regression. p < 0.05 was considered statistically significant.
RESULTS: HPA, PAI, APO, and ACE polymorphism frequency was not significantly different between the stroke and control groups. Factor V H1299R, factor V Leiden, and β fibrinogen -455GA mutation frequency was significantly higher in the stroke than the control group by the chi-square test, but not by logistic regression analysis.
CONCLUSION: Stroke etiopathogenesis is multifactorial, and prothrombin gene mutations increase the impact of existing risk factors when other risk factors are considered.
... However, studies to date have produced conflicting results as to the importance of apolipoprotein E alleles in predisposition to ischaemic stroke (Table 5). In small case-control or cross-sectional studies, both the ε2/ε3 genotype (Couderc et al., 1993;de Andrade et al., 1995;Schmidt et al., 1997) and the ε4 allele (Pedro-Botet et al., 1992;Kessler et al., 1997;Margaglione et al., 1998) have been over-represented in patients with ischaemic stroke. Other groups have examined the role of the apolipoprotein E genotype in modulating the outcome of cerebral infarction as this lipoprotein appears to be an important regulator of lipid turnover within the brain and of neuronal membrane maintenance and repair. ...
Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.
... Stwierdzono między innymi rodzinne występowanie miażdżycy tętnic szyjnych u rodzeństwa z cukrzycą typu 2 [53]. Ponadto, podkreśla się rolę polimorfizmu genów dla apolipoproteiny E oraz b-fibrynogenu w progresji powikłań sercowo-naczyniowych, w tym udarów [54]. ...
... Currently, the relationship between the -455G/A and -148C/T polymorphisms of the β-Fg gene and arterial thrombosis is controversial. Kessler et al [6] proposed that the -455G/A polymorphism within the promoter of the β-Fg gene is closely related to the plasma Fg level. The higher the allele frequency, the higher the plasma Fg level; and this positively correlates with the incidence of ischemic cerebrovascular disease. ...
We sought to investigate the correlation between the -455G/A and -148C/T polymorphisms of the β-fibrinogen gene and plasma fibrinogen levels in patients with cerebral infarction and in healthy subjects among the Xinjiang Uygur and Han Chinese populations, by using polymerase chain reaction-restriction enzyme digestion analysis. Results showed that there were no statistically significant differences in the distributions of the -455G/A genotype and allele frequency between the Uygurs and the Han. Plasma fibrinogen levels in cerebral infarction patients among the Uygurs and the Han were higher than those among healthy subjects. In particular, the frequencies of the -455G/A AA and -148C/T TT genotypes were significantly higher than in healthy subjects. Individuals carrying the A or T allele had a higher incidence of cerebral infarction compared with those carrying the G or C allele. Our experimental findings indicate that the -148C/T and -455G/A polymorphisms are associated with cerebral infarction in Xinjiang Uygur and Han Chinese subjects. The susceptibility- conferring alleles are -148T and -455A, and the susceptibility-conferring genotype is -455G/A + AA.
... Three reports demonstrated a positive association between the apoE4 allele and ischemic CVD (two European (9,23), and one Japanese (19). Kessler et al (18) found that E4 allele is more common in CVD patients with large-vessel atherosclerosis than in those with other types of CVD. Eight studies were excluded for this analysis (some of which did not distinguish consistently ischemic stroke from hemorrhagic stroke) (13,14,40), and the study of Ferruci et al. (17) did not permit measurement of the apoE allelic frequencies. ...
The possible association of apolipoprotein E (apoE) DNA polymorphism with ischemic cerebrovascular disease was evaluated in 65 patients who had suffered completed stroke or transient ischemic attack and 330 healthy controls. ApoE genotypes were determined by restriction isotyping/MADGE analysis. Significant difference in apoE genotype frequencies between case and control group was observed (p<0.01). Patients affected by ischemic stroke had higher frequency of E4 allele and lower E2 allele than age-matched control subjects. Compared with persons without E4 allele, carriers of an E4 allele had 2.1 times higher risk of incident stroke. Our results indicate that the apoE gene polymorphism may be a risk factor for the development of ischemic cerebrovascular disease in Serbian population..
... Other studies have demonstrated that the apoE4 allele and the AA genotype of beta-fibrinogen G/A-455 polymorphism occurred more frequently in patients with stroke resulting from stenosis of large, brain-supplying vessels, while the apolipoprotein E epsilon 2 allele carriers had a lower risk of stroke. [88][89][90] Another genetically determined factor, the plasminogen activator inhibitor-1 (PAI-1), has been incriminated in the development of stroke. In a study of 558 patients with stroke and 172 controls, the PAI-1 activity was significantly higher in patients with stroke (n = 245) both at presentation (11.6 U/mL) and after 3 months (11.8 U/mL), in paired samples, than in control subjects ( These characteristics have been classified into those describing the overall distribution of grey tones (overall brightness) and those that describe the spatial variation of the grey tones of the plaque in the image.93 ...
The aim of this review is to present the current knowledge regarding stroke. It will appear in three parts (in part II the pathogenesis, investigations, and prognosis will be presented, while part III will consist of the management and rehabilitation). In the current part (I) the definitions of the clinical picture are presented. These include: amaurosis fugax, vertebrobasilar transient ischemic attack, and stroke (with good recovery, in evolution and complete). The role of the following risk factors is discussed in detail: age, gender, ethnicity, heredity, hypertension, cigarette smoking, hyperlipidemia, diabetes mellitus, obesity, fibrinogen and clotting factors, oral contraceptives, erythrocytosis and hematocrit level, prior cerebrovascular and other diseases, physical inactivity, diet and alcohol consumption, illicit drug use, and genetic predisposition. In particular, regarding the carotid arteries, the following characteristics are analyzed: atheroma, carotid plaque echomorphology, carotid stenosis, presence of ulcer, local variations in surface deforma bility, pathological characteristics, and dissection. Finally the significance of the cerebral collateral circulation and the conditions predisposing to cardioembolism and to cerebral hemorrhage are presented.
Introduction:
Rising studies indicate that the apolipoprotein E (APOE) gene is related to the susceptibility of ischemic stroke (IS). However, certain consensus is limited by the lack of a large sample size of researches. This meta-analysis was performed to explore the potential association between the APOE gene and IS.
Methods:
To identify relevant case control studies in English publications by October 2020, we searched PubMed, Embase, Web of Science, and the Cochrane Library. Pooled odds ratios (ORs) with fixed- or random-effect models and corresponding 95% confidence intervals (CIs) were calculated to analyze potential associations.
Results:
A total of 55 researches from 32 countries containing 12207 IS cases and 27742 controls were included. The association between APOE gene ε4 mutation and IS was confirmed (ε4 vs. ε3 allele: pooled OR = 1.374, 95% CI, 1.214-1.556; ε2/ε4 vs. ε3/ε3: pooled OR = 1.233, 95% CI, 1.056-1.440; ε3/ε4 vs. ε3/ε3: pooled OR = 1.340, 95% CI, 1.165-1.542; ε4/ε4 vs. ε3/ε3: pooled OR = 1.833, 95% CI, 1.542-2.179; and APOE ε4 carriers vs. non-ε4 carriers: pooled OR = 1.377; 95% CI, 1.203-1.576). Interestingly, APOE ε4 mutation showed a dose-response correlation with IS risk (ε4/ε4 vs. ε2/ε4: pooled OR = 1.625; 95% CI, 1.281-2.060; ε4/ε4 vs. ε3/ε4: pooled OR = 1.301; 95% CI, 1.077-1.571). Similar conclusions were drawn in the small artery disease (SAD) subtype, but not in large artery atherosclerosis (LAA) or in cardioaortic embolism (CE), by subgroup analysis.
Conclusions:
These observations reveal that specific APOE ε4 mutation was significantly associated with the risk of IS in a dose-dependent manner, while APOE ε4 mutation was related to SAD subtype onset without a cumulative effect.
Arterial thrombosis (AT) is a pivotal event in the natural history of coronary heart disease (CHD), stroke (cerebrovascular ischemic disease), and peripheral vascular disease. CHD represents a continuum of myocardial ischemia ranging from unstable angina to coronary artery disease (CAD), and to myocardial infarction (MI). Although a family history of CAD is a risk factor for cardiovascular ischemic episodes, the overall impact of family history is modest. Common forms of AT segregate in a non-Mendelian inheritance pattern. Over 95% of early CHD cases are not caused by monogenic defects such as familial hypercholesterolemia (FH), but rather by multiple genetic and environmental determinants. The pathogenesis of AT is probably different from that of venous thrombosis (VT). Most forms of AT are multifactorial disorders resulted from many different combinations of genetic prothrombotic polymorphisms and environmental atherogenic factors, even though some by themselves may not be sufficient to cause disease. Environmental risk factors for AT include high fat diets, cigarette smoking, increased salt consumption, and decreased intake of folate.
Bu çalışma, 2016-2017 yılları arasında Iğdır ili Çalpala Köyü’ndeki yonca tarlalarında önemli
derecede ekonomik zarara yol açan yonca hortumlu böceği (Hypera postica (Gyllenhal, 1813)
(Coleoptera: Curculionidae))'nın erginlerine karşı, Satureja hortensis L., S. montana L., S.
spicigera L. ve S. thymbra L. (Lamiaceae) bitkilerinden elde edilen uçucu yağların
insektisidal etkilerini belirlemek amacıyla laboratuvar şartlarında (25±1 °C, %60±5 orantılı
nem ve 14:10 aydınlık:karanlık) yürütülmüştür. Bu uçucu yağların toksisitelerini test etmek
için her bir petriye (9 × 1,5 cm) 15’er adet ergin birey konulmuş ve üzerlerine her bir dozda
(5, 10 ve 20 μL/petri) uçucu yağlar püskürtülmüştür. Daha sonra, her petri kabına erginlerin
beslenmesi için yeterli miktarda taze yonca (Medicago sativa L.) yaprağı ilave edilmiştir.
Petrilerin kapağı kapatılarak etrafı parafilm ile sarılmıştır. Kontrol olarak steril su+etanol ve
pozitif kontrol olarak ise ticari insektisit olan Malathion kullanılmıştır. Tüm testler 3’er kez
tekrarlanmıştır. Uygulamanın 24, 48, 72 ve 96 saatler sonrasında ergin ölümleri
kaydedilmiştir. Ölüm oranları %4.44 ile 100 arasında farklı oranlarda saptanmıştır. En yüksek
ölüm oranları (%48.8’den %100’e kadar) S. hortensis’in uçucu yağının 20 μL/petri dozunda,
en düşük ölüm oranları ise (%4.44’den %62.20’e kadar) S. spicera’nın 5 μL/petri dozunda
tespit edilmiştir. Bu sonuçlara göre, S. hortensis ve S. thymbra uçucu yağlarının H.
postica’nın erginlerine karşı daha etkili oldukları, S. montana ve S. spicigera’nın uçucu
yağlarının ise daha düşük etki gösterdiği belirlenmiştir. Test edilen uçucu yağların, yonca
hortumlu böceği erginleri üzerinde insektisidal etkiye sahip oldukları ve bu zararlının
mücadelesinde kullanılabilecekleri tespit edilmiştir.
ABSTRACT:
Background: Recurrent pregnancy loss (RPL) is caused by different factors, including genetics and thrombophilia. FV LEIDEN, FVR 2, FXIII, β-FIBRINOGEN , PROTROMBIN, PAI 1, HPA 1, MT 677, MT 1298, ACE, APO E, and APO B have been identified linking to hereditary thrombophilia.
Objective: In this study, the effect of 12 factors, FV LEIDEN, FVR 2, FXIII, β-FIBRINOGEN ,
PROTROMBIN, PAI 1, HPA 1, MT 677, MT 1298, ACE, APO E, and APO B are statistically
evaluated in RPL patients data from recent articles.
Materials and methods: In patients with recurrent miscarriage, the polymorphisms in which clotting factor genes were statistically analyzed. In addition, were discussed coagulation genes which relation to other diseases.
Results: According to the studies related to this subject, FV LEIDEN (45%), PROTROMBIN
(31%), FXIII (89%), β-FIBRINOGEN (29%), PAI 1 (75%), MT 677 (44%) and MT 1298 (33%)
were related to the abortions.
Conclusion: Most commonly encounter mutations FV LEIDEN, FVR 2, MT 677, FXIII and β-
FIBRINOGEN genes similarly between country of the world. In this context, it may be useful in patients with RPL to monitor the clotting factors in order to clarify the cause of RPL.
Abstract. The study was aimed at the determination of the role of quantitative ECG analysis with use of synergetics principles in the evaluation of the extent of coronary artery involvement in the patients with stable and unstable ischemic heart disease (IHD). Totally 159 patients were enrolled into the study. Among them, 78 patients had verifi ed stable form of IHD, while 56 patients had the signs of IHD destabilization and 25 healthy persons served as controls. The technique of ECG analysis with use of fractal and harmonic analysis offers the opportunity of the early determination of the coronary involvement. In the case of coronary emergency it is becoming possible to predict the probability of the hemodynamically signifi cant stenosis and to stratify the patients according to the presence of indications for high-tech treatment as well as to monitor its effect over time.
The presence of different APOE isoforms represents a well-known risk factor for cardiovascular diseases. Besides the pleiotropic effects of APOE polymorphism on heart and neurological diseases, this review summarizes the less-known functions of APOE and the possible implications for cardiovascular disorders. Beyond the role as lipid transporting protein, its involvement in lipid membrane homeostasis and signaling, as well as its nuclear transcriptional effects suggests a more complex role of APOE, receiving great interest from researchers and physicians from all medical fields. Due to the presence of different APOE isoforms in human population, understanding APOE's role in pathological processes represents not only a challenge, but a demand for further development of therapeutic strategies for cardiovascular diseases.
There is a association of polymorphism in the promoter region of the beta fibrinogen gene -455 G/A with enhancement plasma fibrinogen level. Diabetes mellitus is a risk factor for early neurologic deterioration in acute ischemic stroke. The prothrombotic fibrinogen protein is frequently elevated in patients with diabetes and may be association with poorer prognosis. This study evaluated the association of beta fibrinogen gene -455 G/A promoter polymorphism on modified Ranking Scale of Ischemic Stroke patients treated with diabetic and nondiabetic group. In a Cohort study design comprises 200 consecutive patients diabetic and a nondiabetic who, three months using completed a detailed outcome stroke. Of 200 samples genotype distribution were 27.1% for GG+GA and 0% for AA with diabetic and than 4.4% for GG+GA and 0.05% diabetic patients. Fibrinogen levels were higher in diabetic than nondiabetic group patients (307.7 + 106.3 vs 278 + 84 gr/dl, p=0.002). Fibrinogen level was found to be an independent predictor for diabetic patients. On Genotype GG+GA were associated wth diabetic and nondiabetic group patients. Modified Rankin Scale on day 90 were found associated with diabetic and nondiabetic patients.
Conclusion: Elevated fibrinogen level is dose-dependently associated with 90 days outcome severity stroke with diabetic following ischemic stroke
James Parkinson, a physician from London, described the «shaking palsy» now known as Parkinson’s disease (PD) in his classic essay in 1817. Parkinson noted
tremor, bradykinesia, rigidity and stooped posture as the key motor features of this condition but also drew attention to sleep dysfunction, delirium, dementia, and
dysautonomia, now known to be non-motor symptoms (NMS) of PD. Inspite of their importance, NMS in PD still remain under-recognised and poorly studied.
Description of neuropathological correlates of NMS, as well as the development of comprehensive tools for their assessment in the early 2000’s, such as the NMS
questionnaire (NMSQuest) and scale (NMSS), helped to establish the importance of NMS in PD and their crucial link with quality of life. In many countries,
NMS evaluation in PD is now a part of the good clinical practice standards. Studies of the integral role of NMS in PD clinical structure and natural history
of PD led to the concept of PD as a complex combination of motor and non-motor manifestations with a long prodromal phase dominated by a number of NMS.
The prodromal phase of PD is a major current research topic: NMS-associated biomarkers may help to identify subjects who are at risk of developing motor-phase
PD and, potentially, are candidates for neuroprotective therapies. NMS burden grading with cut off values, which can be used as outcome measure in clinical trials
in patients with PD, have been validated. The complex multi-neurotransmitter dysfunction of PD has been reported to manifest clinically as difeferent non-motor
subtypes. Recognition of such subtypes may lead to the emergence of personalized and precision medicine approaches in PD.
Translation of the explosion in knowledge of acute ischemic stroke into satisfactory treatment regimens has yet to happen. At present tPA, intra-arterial prourokinase and low-molecular-weight heparin form the vanguard for therapeutic intervention, yet these treatments have a limited therapeutic window. Part of this expansion in understanding has been driven by the contribution of stroke genetics and genomics. However, despite the enormous preclinical and clinical information of receptors, enzymes, second messenger systems, and so forth, that are implicated in stroke pathophysiology, delivery of novel drug treatment has been slow. This introductory chapter discusses the multiple sources of clinical and preclinical genetic information. It will describe the importance of integrating expression information into multiple preclinical models with temporal and spatial roles in lesion pathology and, furthermore developing an understanding of function in the clinic before claiming a role in ischemic stroke. The goal of such a holistic integration of information is to increase the yield from current datasets of gene expression and ultimately to help expand the choice of treatment available to the physician and patient.
Stroke is an important clinical problem because of its large contribution to mortality. The main causal and treatable risk factors for stroke include hypertension, diabetes mellitus, dyslipidemia, and smoking. In addition to these risk factors, recent studies have shown the importance of genetic factors and interactions between multiple genes and environmental factors. Genetic linkage analyses of families and sib-pairs as well as candidate gene association studies have implicated several loci and many candidate genes in predisposition to ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Recent genome-wide association studies identified various loci and genes that confer susceptibility to ischemic stroke or intracranial aneurysm. Such studies may provide insight into the function of implicated genes as well as into the role of genetic factors in the development of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage.
Table of Contents: Introduction / Genetics of Stroke / Single-Gene Disorders Associated with Stroke / Genetics of Common Forms of Stroke / Clinical Implications / Conclusion / References / Titles of Related Interest
Background:
Previous studies examining the association of apolipoprotein E (APOE) gene polymorphism with the risk of ischemic stroke (IS) have yielded conflicting results. Therefore, we performed a meta-analysis to investigate the association between APOE ?4 gene polymorphism and risk of IS.
Summary:
A literature search for genetic association studies published before May 30, 2015, was conducted in the PubMed, EMBASE and Google Scholar databases. The following search terms were used: (apolipoprotein E) or (APOE) and (?4) and (polymorphism) or (polymorphisms) and ('ischemic stroke' or 'IS') and ('cerebral infarction' or 'CI') and ('genetic polymorphism' or 'single nucleotide polymorphisms' or 'SNP'). ORs and 95% CIs were used to calculate the strength of association. Begg's funnel plot was used to assess the potential for publication bias. In our meta-analysis, 26 case-control studies involving 6,397 IS cases and 19,053 controls were included. Overall significant association between carrier of ?4 allele and risk of IS was observed (OR 1.43, 95% CI 1.10-1.85, p = 0.007). In the subgroup analysis based on ethnicity, a significant association between Apo ?4 carrier and risk of IS was observed in Asian studies (OR 1.53, 95% CI 1.04-2.25, p = 0.031) whereas borderline significant association between APO ?4 carrier and risk of IS was observed in Caucasian studies (OR 1.36, 95% CI 0.95-1.93, p = 0.093).
Key messages:
Our meta-analysis suggests that APOE ?4 allele is associated with higher risk of IS in Asian population as compared to Caucasian population.
Coronary heart disease is the leading cause of death worldwide affecting millions of people in both developed and developing countries. The dual aims of this book are to review the well-established and emerging risk factors in coronary heart disease (CHD) and to apply this knowledge to public health approaches to disease prevention. The book includes authoritative accounts of studies within a single population and international studies, important areas of methodological development, trials to test preventive strategies, and the application of epidemiological and other knowledge to the development of public health policy for the prevention of widespread disease. It is an all-encompassing work containing contributions from the world authorities in the field. The book is divided into four sections. The introduction reviews advances in the understanding of, and the current status, of risk factors for CHD. Section Two looks at recent global trends and emerging patterns of CHD morbidity and mortality in several countries, and includes chapters on work done under the auspices of the World Health Organisation (WHO) on the global burden of disease in relation to smoking and blood pressure. Section Three focuses on advances in understanding the aetiology of CHD with each chapter focused on a particular risk factor. Section Four explores measures of prevention and intervention in terms of public health policy with specific examples from around the world.
Various studies on the relationship between serum cholesterol level and the risk of stroke have been published recently. Subsequent reviews have extrapolated information on stroke from the clinical trials originally aimed at lowering cholesterol for the primary and secondary prevention of myocardial infarction (MI) in middle-aged patients. We have reviewed the epidemiological knowledge on the relationship between serum cholesterol levels and stroke, and also focused on possible reduction of the risk of stroke with hydroxymethyglutaryl coenzyme A (HMG-CoA) reductase inhibitor treatment. Possible benefits from such therapy are particularly relevant for the elderly population which is at particularly high risk for stroke.
The effects of serum cholesterol levels on the risk for haemorrhagic and ischaemic stroke have been evaluated. Indirect epidemiological evidence indicates that serum levels of total cholesterol and its subfractions are determinants of stroke, but their associations are relatively weak. When exploring the possible association of serum cholesterol levels with the increased risk of stroke with aging, we concluded that, as in younger adults, elevated total cholesterol and decreased high density lipoprotein-cholesterol levels predispose to ischaemic stroke in the elderly. The mechanism through which serum cholesterol levels increase stroke risk is based on its actions on the artery walls.
Indirect evidence suggests that the reduction in the stroke risk with HMG-CoA reductase inhibitors is larger than would be expected with reduction of elevated serum cholesterol level alone. Therefore, antioxidant and endothelium-stabilising properties of HMG-CoA reductase inhibitors may contribute in reducing the risk of stroke in recipients.
Lowering high serum cholesterol with HMG-CoA reductase inhibitors has been beneficial in the primary and secondary prevention of MI. No trials have specifically tested the effect of cholesterol lowering with HMG-CoA reductase inhibitors on stroke occurrence. High serum cholesterol levels are a risk factor for ischaemic stroke, although the risk imparted is lower than that for MI. Although the relative risk of stroke associated with elevated serum cholesterol levels is only moderate, its population attributable risk is high given the increase in the elderly population worldwide.
The effect of cholesterol reduction with HMG-CoA reductase inhibitors on prevention of ischaemic stroke should be evaluated in prospective, randomised, placebo-controlled trials in the elderly. The tolerability of lipid-lowering drugs in the elderly and the cost effectiveness of primary prevention of stroke using lipid-lowering drugs also needs to be assessed in the elderly.
Several investigations have been performed to examine the influence of the β-fibrinogen (FGβ) gene polymorphisms on the risk of ischemic stroke, but the results of these studies are controversial. Our study aimed at investigating whether the FGβ gene (-148C/T, 448G/A, and -854G/A) polymorphisms were associated with susceptibility to ischemic stroke by conducting meta-analysis.
Relevant studies were identified from 4 Chinese databases, PUBMED and EMBASE before May 30, 2014. The strength of association was evaluated by the odds ratio with 95% confidence interval. Inconsistency index and the Cochran's Q statistic were used to check heterogeneity. Publication bias was tested using funnel plots and Egger's regression test.
Thirty-two independent studies with 4311cases and 4124controls were included. Significant association between -148C/T polymorphism and the risk of ischemic stroke was found in overall analysis and middle-age, but not in young adults and elderly people. Similarly, association was also observed for -854G/A polymorphism, especially in cerebral arterial main trunk infarction (MCI) and cerebral penetrating arterial infarction (PCI). However, no significance was found between 448G/A polymorphism and ischemic stroke in Chinese people; likewise, no evidence of a significant association was observed when stratified according to the subtype of ischemic stroke (MCI and PCI).
These results suggest that -148C/T and -854G/A polymorphisms probably contribute to susceptibility of ischemic stroke.
Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Fibrinogen is a large complex glycoprotein that is aids in the formation of blood clots. As an acute phase protein, fibrinogen has clinical application as a biomarker in the management of patient with venous and arterial disease. High levels are associated with inflammation and the risk of cardiovascular disease. During venous and arterial thrombolysis therapy, fibrinogen levels have prognostic significance regarding risk of bleeding. In this review, the application of fibrinogen as a biomarker in care of the vascular surgery patient is detailed.
Background
Elevated plasma fibrinogen level has been shown to be an independent risk factor of ischemic heart disease, cerebrovascular disease, and peripheral vascular disease. The aim of this study is to determine the associations of plasma fibrinogen levels, coronary artery disease CAD, classical vascular risk factors, and genetic polymorphisms at position -455 and C448 of the -fibrinogen gene. Methods We measured the plasma fibrinogen levels and lipid levels in 374 patients with angiographically defined CAD and 290 control patients. The genotypes of -fibrinogen in randomly selected patients were determined by restriction fragment length polymorphism and allele-specific oligomer hybridization. Results 1 Higher plasma fibrinogen levels were observed in the patients with CAD, especially who had multiple coronary artery atherosclerosis. 2 The plasma fibrinogen levels were higher in smokers, and positively related with age and total cholesterol levels. 3 The two polymorphisms were in tight linkage disequilibrium and the genotype frequencies were similar in patients and control subjects. The significant association between -455G/A genotype and plasma fibrinogen was noted in females but not in males. 4 In logistic regression model, the elevated plasma fibrinogen was an independent risk factor of CAD. Conclusion The present study shows that the plasma fibrinogen level is an independent risk factor for coronary atherosclerosis, and the genetic variants of the fibrinogen gene are associated with an increased plasma fibrinogen in females. Korean Circulation J 2000 ; 30 8 : 947-957 KEY WORDSFibrinogen·Coronary artery disease·Genetics·Polymorphism.
Background/purpose:
Data on the role of the -455G > A polymorphism of the gene encoding β fibrinogen subunit (FGB) and the Thr312Ala polymorphism of the gene for the α fibrinogen subunit (FGA) in childhood ischemic stroke are insufficient. Therefore the aim of the study was to evaluate a possible association between these two polymorphisms and arterial ischemic stroke.
Methods:
The study group consisted of 85 children after ischemic stroke, 146 of their parents and 159 controls. Both polymorphisms were genotyped using the restriction fragment length polymorphism method. Two study designs were used: a case-control model and a family-based transmission-disequilibrium test. Statistica 7.1 and EpiInfo 6 softwares were used in all analyses.
Results:
In the TDT test, a tendency to a higher transmission of the 312Ala allele of the FGA gene and the -455A allele of the FGB gene was observed, however, it was statistically non-significant. The frequencies of alleles and genotypes of both FGA and FGB genes polymorphisms did not differentiate children from both groups also in the case-control model. Additive or synergistic effects between FGA and FGB genes polymorphisms were not observed.
Conclusion:
An analysis of the results obtained in this study and a critical review of previously published data indicate that examined gene polymorphisms are not related to ischemic stroke in children.
Stroke is a global health problem and a leading cause of disability worldwide. There have been numerable studies undertaking research on different aspects of ischaemic stroke employing various epidemiological, clinical and molecular parameters. Nevertheless ischaemic stroke being a complex disorder with different subtypes demands equal attention towards its subtypes too. Since there has been enough evidence that disposition to certain subtype is genetically determined and there is a distinct mechanism that influences its development, association studies should focus on subtypes simultaneously while studying specific genes. Data from such studies will thus provide better and intricate findings with regard to heterogenous ischaemic stroke. In the present review we discuss the genes studied by our group over a period of seven years in association with stroke subtypes in a South Indian population and correlate the findings with similar genetic studies from other populations so as to provide an overview of various genes involved in the pathogenesis of ischaemic stroke subtypes.
Copyright © 2014 Elsevier B.V. All rights reserved.
Background:
Previous studies have investigated the association between a polymorphism (-455 G>A) in the β-fibrinogen gene and the risk of cerebral infarction. However, these results are controversial. To shed light on these inconclusive findings, we performed a meta-analysis of studies relating the β-fibrinogen genetic polymorphism (-455 G>A) to the risk of cerebral infarction.
Methods:
We identified literature published before July 2013 by searching PubMed, EMBASE, ISI Web of Science, the Chinese National Knowledge Infrastructure database (CNKI) and the Wanfang database in China and by reviewing the references of retrieved articles. We included studies that reported odds ratio (OR) with 95% confidence interval (CI) for the association between the β-fibrinogen genetic polymorphism and cerebral infarction risk. Publication bias was tested by a funnel plot, and the OR of all studies were combined dependent on the results of the heterogeneity tests among the individual studies. The software Review Manager (Version 5.2) was used for meta-analysis.
Results:
Twenty independent case-control studies containing 9477 subjects were included. Our results showed that the -455 G>A polymorphism in the β-fibrinogen gene was associated with the increased risk of cerebral infarction [(AA+GA) vs. GG, OR=1.17, 95%CI: 1.04-1.31, p=0.008; A vs. G, OR=1.12, 95%CI: 1.01-1.23, p=0.03] in the Chinese population by a meta-analysis. However, we did not find this association in the Caucasian population [(AA+GA) vs. GG, OR=0.99, 95%CI: 0.87-1.11, p=0.84; A vs. G, OR=0.97, 95%CI: 0.84-1.13, p=0.73, respectively].
Conclusion:
The results of our meta-analysis indicate that the -455 G>A polymorphism in the β-fibrinogen gene is a susceptibility marker of ischemic cerebral infarction in the Chinese population.
A thesis submitted to the Faculty of Graduate Studies and Research in partial fblfilment of the requirernnts of the degree of the Master of Science.
The incidence of arterial ischemic stroke (AIS) in childhood (about 2-13 per 100,000 children a year) is much lower than the incidence in the adult population. Still, adverse outcomes of acute brain ischemia in childhood include death (10 % of AIS children), neurological sequel, epileptic seizures (over 50 %) and recurrence (over 20 %). The knowledge of childhood stroke etiopathogenesis is still insufficient and the diagnostic and therapeutic procedures-controversial. Risk factors for childhood stroke differ from those observed in adults due to differing exposure to external risk factors. The most frequently reported risk factors for pediatric ischemic stroke are cerebral arteriopathies and vascular malformations, cardiac diseases, infections, traumas and metabolic diseases. Because of its multifactorial etiology pediatric AIS probably has a multigenic inheritance pattern. The genetic susceptibility to AIS may be determined by specific polymorphic variants encoding markers of hemostasis regulation and they are some of the most important targets in searching for genetic determinants in pediatric AIS. The authors have reviewed the recent literature on risk factors of childhood ischemic stroke with the focus on genetic factors like polymorphisms of genes encoding coagulation factors II, V, VII and XIII, MTHFR, fibrinogen beta, and compared them with the results performed in adult patients.
Ischemic stroke (IS) and coronary heart disease (CHD) are two vascular disorders that are a common cause of death worldwide. Several studies have assessed the association of the β-fibrinogen-455G/A (FGB-455G/A) polymorphism and risk of IS and CHD, but the results are still inconsistent. Our study aimed to investigate whether the FGB-455G/A polymorphism was associated with susceptibility to IS and CHD by using meta-analysis.
Relevant studies were identified from PubMed, Embase and four Chinese database up to July 2013.Data were analyzed and processed by Stata 11.2. A pooled OR with 95% CI was calculated to estimate the strength of the genetic association. Cumulative meta-analysis was performed to assess the tendency of pooled OR over time.
45 studies based on a total of 7238 cases and 7395 controls were included in our meta-analysis. The results indicated that the FGB-455G/A polymorphism is associated with the risk of IS when compared with the dominant model (OR=1.518, 95%CI=1.279-1.802 for AA+GA vs. GG). In the subgroup analysis by ethnicity, significantly elevated risks were associated with the A allele in Asians (OR=1.700, 95%CI=1.417-2.040), but not in Caucasians (OR=0.942, 95%CI=0.813-1.091). Both the hypertension and non-hypertension subgroups reached significant results, but no significance was found when stratified according to sex or subtype of IS. Results indicate that the FGB-455G/A polymorphism is associated with CHD (OR=1.802, 95%CI=1.445-2.246).
Our meta-analysis suggests that the FGB-455G/A polymorphism contributes to susceptibility to IS and CHD.
This chapter presents the epidemiological studies and developments in the cellular and molecular mechanisms of stroke pathophysiology. Stroke is the result of irreversible neuronal injury resulting from interruption of blood flow to a part of the brain or spinal cord. Modifiable risk factors (e.g., hypertension, diabetes, and smoking) and nonmodifiable risk factors (e.g., age, race, and sex) for stroke have been identified. Accumulating evidence indicates that these traditional stroke risk factors have some genetic determinants. In addition, many genetic diseases may result in stroke in a subgroup of patients (e.g., hemoglobinopathies, coagulopathies, connective tissue disorders, and metabolic disorders). There are also several genetic diseases in which stroke is a key component of the clinical presentation such as cerebral autosomal dominant arteriopathy with subcortical and two distinct but similar forms of cerebral amyloid angiopathy. Identification of specific mechanisms involved in genetically determined stroke syndromes may help elucidate the pathogenesis of more common multifactorially determined stroke syndromes, and may also suggest new strategies for stroke prevention and treatment.
The apolipoprotein E (ApoE) plays an important role in lipid metabolism; This apoprotein presents three major isoforms (apoE2; apoE3 and apoE4) that modulate lipid levels; Carriers of the apoE4 allele have higher total and LDL-cholesterol plasma concentration and a greater coronary risk; particularly for myocardial infarction; Nevertheless; not all the people with this allele develop the disease; which suggests that other genetic or environmental factors are necessary for its total expression; In this review; we will analyze the importance of several polymorphisms in the apoE gene promoter region; as well as various environmental factors; including diet; in the association of this gene with lipid metabolism and cardiovascular risk
Aims/hypothesis. We investigated the relation between the G/A-455 (Hae III) β-fibrinogen gene polymorphism and plasma fibrinogen concentration and its role in ischaemic heart disease in 264 Chinese patients
with Type II (non-insulin-dependent) diabetes mellitus and 182 non-diabetic control subjects. Methods. The G/A-455 polymorphism was determined in genomic DNA using polymerase chain reaction and Hae III restriction enzyme digestion. Fibrinogen
was measured with the Claus method. Results. Fibrinogen concentrations were higher in diabetic patients (3.3 ± 0.5 vs 2.5 ± 0.9 g/l in controls, p p A allele was 27 % in both diabetic patients and control subjects' similar to findings in Caucasians. In control subjects, the
AA genotype was associated with higher fibrinogen concentrations (2.8 ± 0.38 g/l vs 2.5 ± 0.5 in GG or GA, p < 0.03), contributing to 4 % of the variance in plasma fibrinogen. The genotype effect was smaller and not significant among
non-smokers, women and diabetic patients. Higher fibrinogen concentrations and AA genotype frequency were found in diabetic patients with ischaemic heart disease (p p AA genotype, age and mean arterial pressure were associated with ischaemic heart disease, with odds ratios of 4.19 (p p p Conclusion/interpretation. The G/A-455 polymorphism is a genetic determinant of fibrinogen concentrations and ischaemic heart disease in this Chinese cohort. It
also interacts with environmental influences associated with smoking, the female sex and Type II diabetes in determining plasma
fibrinogen concentrations. [Diabetologia (1999) 42: 1250–1253]
Cerebral Vascular Accident (stroke), despite remarkable progress within recent years in the
field of its management and treatment, remains a major cause of mortality and morbidity in
many countries. Genetics of complex diseases has known a great progress in recent years ,
due to technology development, but also to two major international initiatives; the Human Genome
Project that has enabled the sequencing of the human genome in its entirety and the discovery
of SNP (Single nucleotide polymorphisms), which had a great success for association studies.
Genetic studies of stroke have shown that apart from rare forms with Mendelian transmission,
most strokes are considered as multi-factorial disease. The genetic study of stroke is being
more and more research-more than 2300 candidates for stroke polymorphisms are currently
listed. These factors have generally been short-listed based on their involvement in metabolic
pathways known or through studies pangenomics. The most of them have been association
studies by different teams and different populations. Although most of these studies seem to
focus more on myocardial infarction stroke is attracting increasing interest of researchers. The
genes studied are most typically those involved in the coagulation pathway, the metabolism of
homocysteine, and lipid metabolism namely FV, FII, fibrinogen, PAI1, MTHFR, ApoE and ACE.
Others have been explored without consensus (Enos, PON, LPL, FGA / FGB / FGG, F7, F13A1,
vWF, F12, SERPINE1, ITGB3, PLA2, ITGA2B, ITGA2, GP1BA, AGT, NOS3, LPL, PON1, PDE4D,
ALOX5AP, MTR, CBS, NINJ2). The results published today are often controversial depending
on the population studied, age of patients and subtypes of stroke. Some of these factors come
close to the consensus than others.
The relationship between apoE phenotype and plasma lipid levels was analyzed in the combined data of published studies. Accordingly, 45 population samples from 17 different countries were included in the analysis. The mean plasma values of cholesterol (CH), triglyceride (TG), and high density lipoprotein (HDL)-CH of the apoE 2/2, 3/2, 4/3, 4/4, and 4/2 groups were compared with the same parameters of the E 3/3 subset. The standardized difference between the plasma lipid concentrations of the apoE subgroups and of their respective apoE 3/3 control (Z-score), as well as their mean weighted value, were calculated for each study and in each subgroup. The analysis confirmed that subjects carrying the epsilon 2 and epsilon 4 alleles had, respectively, lower (Z2/2 = -0.39, Z3/2 = -0.34) and higher (Z4/3 = 0.15, Z4/4 = 0.29) plasma cholesterol values than subjects carrying the epsilon 3/epsilon 3 genotype. In addition, results indicated a consistent relationship between plasma TG levels and apoE phenotype among different populations. TG concentrations were significantly higher in apoE 2/2, 3/2, 4/3 and E 4/2 than in E 3/3 subsets (Z2/2 = 0.42, Z3/2 = 0.14, Z4/3 = 0.13, Z4/2 = 0.19). Further, this trend was found in samples of normolipidemic adults and children, in diabetic and obese individuals, as well as in hyperlipidemic subjects indicating an ubiquitous relationship. Concurrently, HDL-CH was significantly lower in the apoE 4/3 (Z4/3 = -0.09) than in the E 3/3 subset.(ABSTRACT TRUNCATED AT 250 WORDS)
The human apolipoprotein (apo) E gene is polymorphic, with three common alleles (epsilon 2, epsilon 3, epsilon 4) coding for three isoforms (E2, E3, E4). The isoforms differ from each other by a single amino acid substitution, and also differ in their binding affinity for the four apo E receptors. Apo E polymorphism is an important determinant of risk for the development of cardiovascular and Alzheimer diseases, the prevalence of the epsilon 4 allele being increased in both kinds of patients compared with control subjects. Furthermore, the prevalence of the epsilon 4 allele differs among populations (range 5-40%, respectively, for Taiwanese and Papua New Guineans). Genotyping or phenotyping needs to be introduced in clinical laboratories. The choice of the method should be based on the types of patients who are examined. The apo E genotype is also a determinant of apo E plasma concentration. Standardization of apo E measurement is an important prerequisite before investigating the clinical interest of plasma apo E concentration. Determination of apo E genotype/phenotype and later the plasma concentration are expected to yield useful clinical laboratory information.
We analyzed blood samples from 407 healthy Swedish individuals, 244 men and 163 women, ages 17 to 86 years, for apolipoprotein (apo) E isoforms and serum triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol. Parallel genotyping by means of polymerase chain reaction (PCR)-amplified DNA was performed in 200 subjects. Identical results were obtained by genotyping and phenotyping in 95% of all subjects analyzed. The apo E allelic frequencies were 7.8% for epsilon 2, 71.9% for epsilon 3, and 20.3% for epsilon 4. Compared with other Caucasian populations, the present population had a high relative allelic frequency of epsilon 4. The epsilon 4 frequency decreased with increasing age and was significantly lower in individuals > 60 years of age (14.7%). When controlling for age and sex, there were strong correlations between total serum and LDL cholesterol and the various epsilon alleles. The epsilon 4 and epsilon 3 alleles correlated positively with serum cholesterol and the epsilon 4 allele correlated positively with LDL cholesterol. In contrast, HDL cholesterol and serum triglycerides did not show any correlation to the allele types. Thus, the results demonstrate a considerable age variation of the epsilon allele frequency among healthy Swedes and an influence of apo E alleles on serum and LDL cholesterol concentrations.
We investigated the association between fibrinogen levels and a HaeIII restriction fragment length polymorphism located at -453 bp from the start of transcription of the beta fibrinogen gene. 292 healthy men aged 45 to 69 years, recruited from general practices throughout Britain, were studied. None had a history of ischaemic heart disease. 41.1% (120) were smokers and fibrinogen levels were higher in this group. The frequency of the non-cutting allele (designated H2) was 0.19 and was the same in smokers and non-smokers. The H2 allele was associated with elevated levels of fibrinogen in both smokers and non-smokers and the effect of genotype was similar in both groups. After smoking, HaeIII genotype was the strongest predictor of fibrinogen levels and explained 3.1% of the variance in fibrinogen levels. These results confirm earlier studies that variation at the fibrinogen locus contributes to the between-individual differences in plasma fibrinogen level.
Epidemiological observations indicate that high plasma fibrinogen levels are strongly correlated with the frequency of two major thrombotic complications of atherosclerosis, stroke and myocardial infarction. Thrombosis is increasingly recognized as a central mechanism in stroke and myocardial infarction, and fibrinogen is involved in events thought to play a major role in thrombosis. Therefore, elucidation of the relationship between fibrinogen and thrombosis may strengthen the predictive value of this protein and suggest new treatment to prevent stroke and myocardial infarction. The current data relating fibrinogen to thrombosis are not easy to reconcile with the available epidemiological observations. In addition, advances in understanding the atherogenic potential of several risk factors for coronary heart disease have used information on the measurement of the risk factors in population-based studies. Thus, measuring plasma fibrinogen to predict stroke and myocardial infarction may be important in gaining insight into the thrombogenic potential of this protein and in inspiring new strategies against the thrombotic complications of atherosclerosis.
We examined the relation between the serum total cholesterol level and the risk of death from stroke during six years of follow-up in 350,977 men, 35 to 57 years of age, who had no history of heart attack and were not currently being treated for diabetes mellitus. The diagnosis of stroke and the type of stroke were obtained from death certificates. Using proportional-hazards regression to control for age, cigarette smoking, diastolic blood pressure, and race or ethnic group, we found that the six-year risk of death from intracranial hemorrhage (International Classification of Diseases, ninth edition [ICD-9], categories 431 and 432) was three times higher in men with serum cholesterol levels under 4.14 mmol per liter (160 mg per deciliter) than in those with higher cholesterol levels (P = 0.05 by omnibus test across five cholesterol levels). On the other hand, a positive association was observed between the serum cholesterol level and death from nonhemorrhagic stroke (P = 0.007). The inverse association of the serum cholesterol level with the risk of death from intracranial hemorrhage was confined to men with diastolic blood pressure greater than or equal to 90 mm Hg, in whom death from intracranial hemorrhage is relatively common. We conclude that there is an inverse relation between the serum cholesterol level and the risk of death from hemorrhagic stroke in middle-aged American men, but that its public health impact is overwhelmed by the positive association of higher serum cholesterol levels with death from nonhemorrhagic stroke and total cardiovascular disease (ICD-9 categories 390 through 459).
The apo E locus contributes to determining the variation in plasma cholesterol levels of healthy and diseased populations. It also influences the expression of hyperlipidemia and appears to modulate the susceptibility to atherosclerosis in a complex multifactorial interaction. There is evidence that the presence of apo E2 is protective, whereas that of apo E4 predisposes to coronary artery disease. The burden of proof, however, lies on future, well-designed clinical trials and prospective studies. The study of the biological significance of the apo E polymorphism in humans has emphasized the importance of gene-gene and gene-environment interactions in the pathogenesis of hyperlipidemia and atherosclerosis. The apo E polymorphism involves the coding region of the apo E gene and results in alterations of the gene product which, in turn, either directly or secondarily affect the metabolic fate of the lipoprotein particles. Rapid advances in knowledge over the last decade have provided a metabolic explanation for the observation of the opposite effects of the epsilon 4 and the epsilon 2 alleles on lipoprotein levels. Apo E2 has lower receptor binding affinity which results in delayed clearance of apo E2-bearing lipoprotein particles from plasma. Apo E4 is distributed differently from apo E3 between VLDL and HDL, is degraded more rapidly than apo E3, and may enhance the catabolism of E4-bearing particles, leading to other alterations in lipoprotein metabolism which result in elevated levels of LDL. In view of the significant opposite impacts of the epsilon 4 and the epsilon 2 alleles on plasma LDL cholesterol concentrations, it is evident that determination of the apo E phenotype will become a useful adjunct to the assessment of the cardiovascular risk profile of an individual. In addition, the relationship between the epsilon 2 allele and type III hyperlipoproteinemia provides a valuable model for the study of complex genetic interactions in the pathogenesis of hyperlipidemia. The further study of apo E and its interactions shows great promise for a deeper comprehension of the pathogenesis of atherosclerosis.
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A significantly lower frequency of the epsilon 2 allele and a significantly higher frequency of the epsilon 3 allele were found in the normolipidemic Japanese population than those in the normolipidemic Caucasian populations. We have compared plasma lipid variables among the apolipoprotein (apo) E phenotype groups and estimated the average effects of the three common alleles (epsilon 2, epsilon 3 and epsilon 4) on plasma lipid levels in normolipidemic subjects. Plasma triglyceride (TG), very low density lipoprotein (VLDL)-TG, VLDL-cholesterol (C) and apo E levels were high in the apo E3/2 group, intermediate in the apo E3/3 group and low in the apo E4/3 group, whereas plasma total cholesterol (TC), low density lipoprotein (LDL)-C and high density lipoprotein (HDL)-C levels were low in the apo E3/2 group, intermediate in the apo E3/3 group and high in the apo E4/3 group. Furthermore, the epsilon 2 allele had an effect to increase the TG, VLDL-TG, VLDL-C and apo E levels and decrease the TC, LDL-C and HDL-C levels, whereas the epsilon 4 allele had an effect opposite to the epsilon 2 allele. These results indicate that the epsilon 2 and epsilon 4 alleles have the reciprocal effects on plasma lipid, lipoprotein and apo E levels.
During the tenth biennial examination of the Framingham Study, 1315 participants who were free of cardiovascular disease had fibrinogen levels measured. During the ensuing 12 years, cardiovascular disease developed in 165 men and 147 women. For both sexes, the risk of cardiovascular disease was correlated positively to antecedent fibrinogen values higher than the 1.3 to 7.0 g/L (126 to 696 mg/dL) range. The magnitude of the risk diminished with advancing age in women but not in men. Risk for coronary heart disease also was significantly related to fibrinogen level. Here, the magnitude of risk displayed diminishing impact with age, again only in women. Risk of stroke increased progressively with fibrinogen level in men but not in women. The impact of fibrinogen value, considered as a separate variable, on cardiovascular disease was comparable with the major risk factors, such as blood pressure, hematocrit, adiposity, cigarette smoking, and diabetes. Fibrinogen values were also significantly related to these risk factors. Taking all these into account in a multivariate analysis, fibrinogen level was still significantly related to the incidence of cardiovascular disease in men and marginally significant in women. For coronary heart disease, the fibrinogen level was significant for both men and women. Elevated fibrinogen level is a predictor of cardiovascular disease that should be added to the cardiovascular risk factor profile.
To study the possible risk factors for cardiovascular disease, we collected data on plasma levels of coagulation factors, blood pressure, serum cholesterol, and smoking in a random sample of 792 men 54 years of age. During 13.5 years of follow-up, myocardial infarction occurred in 92 men, stroke in 37, and death from causes other than myocardial infarction or stroke in 60. The blood pressure, degree of smoking, serum cholesterol, and fibrinogen level measured at the base-line examination proved to be significant risk factors for infarction by univariate analyses during follow-up, and blood pressure and fibrinogen were risk factors for stroke. Fibrinogen and smoking were strongly related to each other. The relation between fibrinogen and infarction, and between fibrinogen and stroke, became weaker when blood pressure, serum cholesterol, and smoking habits were taken into account, but was still significant for stroke. Although causality cannot be inferred from these data, it is possible that the fibrinogen level plays an important part in the development of stroke and myocardial infarction.
We studied the influence of selected genetic markers on the intra-individual long-term variability in serum lipid levels. The study cohort consisted of a sub-sample from a large follow-up study of atherosclerosis precursors in children and young adults. A total of 320 subjects had determinations of apo B XbaI RFLP genotypes, 305 subjects had apo AI/CIII SstI RFLP genotype determinations and 1581 subjects had their apo E phenotypes determined. Complete data on serum lipids were available at 3-year intervals over a 6-year follow-up period. The subjects were healthy and aged 3-18 years at baseline. Intra-individual variability was assessed with a nested analysis of variance procedure. Each of the genetic markers studied here significantly affected intra-individual variability of serum lipid levels. No clear sex influence was observed, although the differences in variability tended to be more significant in males. Apo B XbaI genotypes significantly influenced intra-individual variability of total and LDL-cholesterol levels in both sexes. A marked effect of the XbaI genotype was also found on triglyceride variability. In males the standardized intra-individual triglyceride variances were 0.71 and 0.34 in genotypes X1X1 and X2X2, respectively (p < 0.001), with a clear gene dosage effect. The apo AI/CIII genotype had an influence only on the variability of total cholesterol and LDL-cholesterol levels and only in males. The apo E phenotypes were associated with intra-individual variability in total and LDL-cholesterol levels but again, only in males.(ABSTRACT TRUNCATED AT 250 WORDS)
Beta-fibrinogen G/A-455 polymorphism genotype was determined in 123 young survivors of myocardial infarction and 86 healthy controls from Sweden. Frequency of the A-455 allele was 0.25 (95% Confidence Interval 0.21-0.29) in both patients and controls, significantly higher than that reported previously (0.19, 95% CI 0.16-0.22) in 292 men from the UK. Mean plasma fibrinogen level was significantly higher in patients (3.6 g/l) than in controls (3.1 g/l), with p < 0.001. Genotype was significantly associated with (adjusted) plasma fibrinogen level in controls (p = 0.003). This effect was confined to the smokers (n = 50) where mean fibrinogen level was significantly (p = 0.001) higher in G/A-455 and A/A-455 individuals (3.5 g/l) compared with G/G-455 homozygotes (2.9 g/l). There was a significant interaction between smoking status and genotype in determining plasma fibrinogen levels in the controls. These data provide independent confirmation of the association between beta-fibrinogen G/A-455 genotype and plasma fibrinogen levels previously observed in healthy men from the UK.
Numerous epidemiologic studies have clearly shown that high plasma fibrinogen levels are strongly correlated with the frequency of myocardial infarction, stroke, and peripheral atherosclerosis. These data indicate that measurements of fibrinogen should be included in cardiovascular risk factor profiles. Since thrombosis is recognized as the central mechanism of these atherosclerotic complications, it seems advisable to accept the predictive value of this protein. Fibrinogen is involved in platelet aggregation, blood rheology, and endothelial cell injury, which are thought to play a key role in thrombogenesis. Fibrinogen may predict bypass occlusion but appears to have no significant influence on restenosis following successful coronary angioplasty. Furthermore, fibrinogen represents an acute-phase protein, being of no specificity. Its level varies genetically, as well as circadian and seasonal variations, and is influenced by a number of circumstances and drugs. Plasma levels of fibrinogen decrease by life-style changes, smoking cessation, and different medications such as fibrates, but the risk-lowering effect is not proven yet.
The limited effectiveness of any therapy for acute stroke dictates that emphasis be placed on strategies for preventing stroke. The identification and management of risk factors is paramount. Modifiable risk factors include hypertension, smoking, hyperlipidemia, and diabetes. Patients with transient ischemic attacks or stroke are at risk for recurrent stroke and should be considered for antithrombotic therapy and carotid endarterectomy. Patients with nonvalvular atrial fibrillation should also be treated with antithrombotic therapy. The proper management of other cardiac, malignant, and hematologic disorders is important in preventing stroke in these high-risk patients.
Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.