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Stroke is a common multifactorial disease, and the third leading cause of death worldwide, which results in serious long-term mental and physical disability among survivors. The role of affected triglyceride metabolism in the development of ischemic stroke is under extensive investigations. Here, we examined three SNPs, rs12130333 located within the ANGPTL3 locus; rs16996148 residing at the CILP2 gene locus; and rs17321515 at the TRIB1 locus, which were originally reported in association with decreased triglyceride levels; therefore, we investigated their possible protective effect against the development of ischemic stroke. A total of 459 Caucasian stroke patients, stratified as large-vessel, small-vessel, and mixed stroke groups, and 168 control subjects were genotyped using PCR-RFLP methods. As a result, we could not detect any differences in triglyceride or total cholesterol levels in relation to any allelic variants of rs16996148, rs17321515, or rs12130333 SNPs. No correlation was found between the minor alleles rs16996148-T (P = 0.881), rs17321515-G (P = 0.070), or rs12130333-T allele (P = 0.757) and the risk for development of stroke. The data presented here suggest different scale of effect of triglyceride modifier alleles and also their variable susceptibility or protective nature.

As stroke is the third leading cause of death after heart failure and tumors worldwide, cerebrovascular diseases reached substantial attention. In the past few years, significant progression has been seen in identification of genetic variants in the background of stroke and other cerebrovascular and cardiovascular events. Examination of these variants is a new approach to recognize pathogenesis of disorders that hopefully helps in future prevention and prospects of screening and, optimistically, it contributes to special care of patients susceptible for stroke. In the background of ischemic stroke several genetic variants have been identified, which localize in genes encoding proteins involved in hemostasis, renin-angiotensin system and lipid metabolism. The number of these variants exponentially increases permanently due to rapid spreading of genome wide association studies. The goal of this review is to summarize the results of genetic studies on ischemic stroke. Here the authors focus on genetic variants which can have major role in personalized medicine and prevention of stroke.

Both the natural variants of the apolipoprotein A5 (APOA5) and the glucokinase regulatory protein gene (GCKR) have been shown to associate with increased fasting triglyceride levels. Here, we investigated the possible association of the functional variants of these two genes with non-fasting triglyceride levels and their susceptibility nature in ischemic stroke. A total of 513 stroke patients and 172 healthy controls were genotyped. All the APOA5 variants (T-1131C, IVS3 + G476A, C56G, and T1259C) were associated with increased triglyceride levels in all stroke patients and controls; except for T1259C, they all conferred risk for the disease. No such association was found for the examined GCKR rs1260326 (C1337T) variant. Furthermore, we examined the effects of specific combinations of the GCKR rs1260326 and APOA5 polymorphisms. Our findings confirmed the previous results regarding the association of APOA5 variants with triglyceride-level increase and stroke susceptibility of these alleles. By contrast, we could not detect any association of the studied GCKR allele with triglyceride levels or with the susceptibility of stroke in the same cohort of patients. In addition, the effect of APOA5 did not change significantly when specific combinations of the two genes were present.

Objectives: Ischemic stroke is a suddenly developing temporary or often permanent damage of the brain. Several candidate genes have been shown to have an impact in the pathogenesis of stroke. The aim of our study was to investigate the possible association between the C56G variant of the apolipoprotein A5 (APOA5) gene and ischemic stroke., Methods: PCR-RFLP assays were performed to detect the C56G alleles in 403 patients with classified stroke types and 171 controls., Results: Triglyceride levels of subjects carrying 56G allele were elevated compared to the subjects with 56C allele in all stroke subgroups and in the controls. The serum total cholesterol levels did not differ between subjects with C or G alleles in each group. An accumulation of APOA5 56G allele was observed in the large-vessel associated stroke group compared to the healthy controls (10.9 vs. 5.6 %; p < 0.05), while its prevalence did not increase in any other stroke subgroups. Multivariate logistic regression analysis adjusted for differences in age, gender, BMI, serum total cholesterol levels, ischemic heart disease, hypertension, diabetes mellitus, smoking and drinking habits revealed that the APOA5 56G allele represents a susceptibility factor for large-vessel associated stroke (OR = 2.132 at 95 % CI; p < 0.05)., Conclusion: The data presented here suggest that the 56G allele can confer risk exclusively for development of large-vessel associated stroke. Thereby, the 56G allele differs from the APOA5 T-1131C allelic variant, which has been previously identified as a risk factor for all subgroups of the stroke disease.

Introduction: Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C mutations, being considered unfavourable genetic factors by causing elevated serum homocysteine levels, may be risk factors for cardiovascular disorders, including ischaemic stroke. In this study, the role of these two mutations in ischaemic stroke was examined:, Patients and Methods: Genetic and clinical data were analysed of 122 ischaemic stroke patients and 102 control subjects with no lesions by neuroimaging., Results: Neither of the two MTHFR mutations alone was found to be a significant genetic risk factor for ischaemic stroke. However, at least one MTHFR 677T allele combined with at least one MTHFR 1298C allele significantly increased the risk of ischaemic stroke (adjusted odds ratio: 3.39; p < 0.001)., Conclusion: The synergistic effect between the two MTHFR mutations may represent a new genetic stoke risk factor.

Recent observations revealed a novel role of angiotensin-converting enzyme 2 and the angiotensin II type-1 receptor (AT1R) in lung injury, thereby extending knowledge about the functions of the angiotensin system. Angiotensin II, whose target is the AT1R, is a potent vasoconstrictor. Accordingly, an imbalance leading to enhanced activity of the angiotensin II-AT1R axis is postulated to contribute to both circulatory disturbances and lung injury. In this context, a functional single-nucleotide polymorphism, AT1R A1166C, which leads to enhanced responsiveness of the AT1R, has been postulated as a candidate susceptibility factor for ischemic stroke. The aim of our study was to investigate its occurrence in ischemic stroke and to analyze its possible synergistic associations with clinical risk factors. Genetic and clinical data on 308 consecutive patients with acutely developing ischemic stroke were analyzed. A total of 272 stroke and neuroimaging alteration-free subjects served as a control group. Univariate and logistic regression statistical approaches were used. Alone, the AT1R 1166C allele did not pose a risk of stroke. In hypertensive smokers, however, it was associated with an increased risk of ischemic stroke (OR 22.3, 95% CI 5.8-110.2, p<0.001). Further subgroup analysis revealed the same association for both small-vessel (OR 24.3, 95% CI 6.1-121.1, p<0.001) and large-vessel (OR 21.3, 95% CI 4.6-81.1, p<0.001) infarction. On a pathophysiological basis, our results suggest the possibility that the AT1R A1166C polymorphism might give rise to ischemic stroke indirectly via an unfavorable effect on the cardiorespiratory function.

The possible pathogenic role of triglycerides (TG) in the development of ischemic stroke is still under extensive investigation. Recently, apolipoprotein (apo)A5 gene promoter region T-1131C polymorphism has been shown to associate with elevated serum TG levels. In the current work, a total of 302 subjects were classified as being large vessel-associated, small vessel-associated, or belonging to a mixed group of ischemic stroke-affected patients. The level of TG was increased in all groups (p < 0.01). The apoA5-1131C allele frequency was approximately twofold in all groups of stroke patients compared with the controls (5 vs 10-12%; p < 0.05); and the apoA5-1131C allele itself was also found to associate with increased TG levels in all groups. In a multivariate logistic regression analysis model adjusted for differences in age, gender, serum cholesterol, hypertension, presence of diabetes mellitus, smoking and drinking habits, and ischemic heart disease, a significantly increased risk of developing stroke disease was found in patients carrying the apoA5-1131C allele (p < 0.05; odds ratio OR = 2.1 [1.3-4.7]); this association was also proven for all subtypes of the stroke. The results presented here suggest that the apoA5-1131C allele is an independent risk factor for the development of stroke. Being that apoA5 gene is under the control of the peroxisome proliferator-activated receptor alpha, theoretically, the current observations also can have long-term therapeutic consequences.

The renin-angiotensin system plays an important role in the maintenance of blood pressure homeostasis. The angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II, which binds the angiotensin II type-1 receptor (AT1R), is a potent vasoconstrictor. On a pathophysiological basis, both ACE I/D and AT1R A1166C polymorphism lead to an enhanced activity of the angiotensin II-AT1R axis, thereby possibly contributing to circulatory disturbances. A mutually facilitatory effect may be presumed between the two polymorphisms. We examined whether this synergistic effect is involved in the evolution of different types of ischemic stroke. Genetic and clinical data on 308 consecutive patients with acutely developing ischemic stroke were analyzed. Atotal of 272 stroke and neuroimaging alteration-free subjects served as a control group. Univariate and logistic regression statistical approaches were used. The ACE D allele combined with the AT1R 1166C allele did not yield a risk of ischemic stroke. However, the co-occurrence of the homozygous ACE D/D and at least one AT1R 1166C allele was more frequent in the ischemic stroke group than in the control group (22.4 vs 11%, p < 0.005, OR, 2.33; 95% CI, 1.46-3.7). After specific subgroup analysis, this synergistic association was even stronger for small-vessel ischemic stroke (OR, 3.44; 95% CI, 1.9-6.24; p < 0.0005). Multivariate logistic regression analysis of the data confirmed this association (adjusted OR, 3.54, 95% CI, 1.88-7.16; p < 0.0005). Our results demonstrate that ACE D/D and AT1R 1166C polymorphism were associated with the development of small-vessel ischemic stroke through a mutually facilitatory interplay between them. Genetic interactions might contribute to the altered functional network in renin-angiotensin system in vascular disorders.

A direct role of lymphotoxin-alpha (LTA) in promoting atherosclerotic plaque growth has been demonstrated recently. The different protein transcripts of the naturally occurring genetic variants of the LTA gene have been demonstrated to exhibit affected functions, and an allelic difference in binding to transcription factor(s) has also been suggested. The homozygous variant of LTA characterized by the intron 1 252A-->G (252G) transition, which naturally coexists with an exon 3 804C-->A (804A) single-nucleotide polymorphism (SNP), has been reported as a susceptibility gene for myocardial infarction. Because the atherosclerotic process is also an integral component in the pathogenesis of certain types of vascular stroke, we investigated the possible significance of the above SNPs in 353 ischemic stroke patients and 180 healthy controls. The homozygous LTA allele with the 252G and 804C SNPs occurred more frequently in stroke patients (13.9%) than in controls (7.20%, p<0.025). Specific subclassification of the patients revealed an accumulation of these SNPs in large-vessel, pathology-associated cerebral infarction (18.2%); multivariate logistic regression analysis of the data confirmed this association, with an odds ratio of 2.1 (95% confidence interval, 1.3-6.2; p<0.005). Elimination of all subjects with a history or evidence of ischemic heart disease, including myocardial infarction, did not affect this association. These data show that besides the role in the development of myocardial infarction, the homozygous carriage of the LTA allele with 252G and 804A SNPs is a novel susceptibility factor for largevesselassociated ischemic stroke.

Introduction: Platelet glycoprotein IIb/IIIa is a membrane receptor with a central function in the platelet adhesion and ultimately in the thrombus formation. Two major variants of the gene encoding the IIIa subunit, called PLA1 (A1) and PLA2 (A2), have been identified in the general population. There are indications that the A2 allele can also be associated with acute thrombosis or stroke. The purpose of this study was to study the distribution of the A2 allele in different vascular subtypes of stroke disease., Materials and Methods: A total of 638 consecutive patients were analyzed and classified as having large vessel pathology (n=168) or a small vessel infarct (n=210). Localization of the vascular occlusions was deducted from analysis of the magnetic resonance imaging (MRI) scan results in stroke patients. The remainder patients were listed into a mixed vascular pathology group (n=167). Patients with other or poorly characterized stroke etiology were excluded from the study (n=93)., Results: In the small vessel and mixed vascular pathology groups, the PLA2 allele frequency was similar to that in the controls. By contrast, PLA2 allele frequency was approximately two-fold higher in patients with large vessel pathology (23.3%) than in the stroke-free control subjects (11.7%, p<0.0005). Multivariate logistic regression analysis of data confirmed this association with an odds ratio (OR) of 2.9 (95% confidence interval [CI]: 1.6-4.9, p<0.0005)., Conclusions: These data suggest that the PLA2 allele is more frequent in brain infarcts associated with large-vessel occlusion.

Objective: Ischemic stroke is a frequent heterogeneous multifactorial disease that is affected by several genetic mutations and environmental factors. We hypothesised the clinical importance of the co-occurrence of common, unfavorable genetic mutations in the development of different stroke subtypes., Method and Material: The Factor V Leiden G1691A (Leiden V), the prothrombin G20210A and the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutations and the angiotensin-converting enzyme I/D (ACE I/D) and apolipoprotein E (APOE) genotypes were examined by the PCR technique in 689 ischemic stroke patients and 652 stroke-free controls. Logistic regression models were used to estimate the relative risks of different stroke subtypes for different genotype combination patterns., Results: The ACE D/D genotype alone or in combination with the MTHFR 677T or the APOE 4 allele or with both was highly specific for small-vessel infarction. The Leiden V mutation alone or in different combination patterns with the ACE D, APOE 4 and MTHFR 677T alleles was specifically predisposed to large-vessel infarction. The APOE 4 allele alone was calculated to be a general, minor genetic risk factor for ischemic stroke. The MTHFR 677T allele alone was not a risk factor for any stroke subtype. In the different specific predisposition gene combinations, however, both the APOE 4 and MTHFR 677T alleles could increase the relative risk of the given stroke subgroup., Conclusions: Common mutations which alone are minor or non-significant risk factors for ischemic stroke can yield, in specific combination patterns, a highly significant, moderate genetic risk of specific stroke subtypes.