Role of Uncoupling Protein 2 Gene Polymorphisms on the Risk of Ischemic Stroke in a Sardinian Population.

The mitochondrial uncoupling protein 2 (UCP2) acts as an anion transporter and as an antioxidant factor able to reduce the reactive oxygen species level. Based on its effects, UCP2 prevents the membrane lipids, proteins, and DNA damage while preserving normal cellular functions. Many variants have been identified within the human UCP2. Some of them were associated with a higher risk of obesity, diabetes and cardiovascular diseases in different populations. UCP2 appears a suitable candidate also for the risk of ischemic stroke. In the current study, we investigated the possible association between few variants of UCP2 (rs659366, rs660339, rs1554995310) and the risk of ischemic stroke in a genetically homogenous cohort of cases and controls selected in Sardinia Island. This population has been previously analysed for other candidate genes. A total of 250 cases of ischemic stroke and 241 controls were enrolled in the study. The allelic/genotypic distribution of the 3 UCP2 variants was characterized and compared among cases and controls. The results of our study confirmed known risk factors for ischemic stroke: age, history of smoking, hypertension, hypercholesterolemia, and atrial fibrillation. No association was found between the 3 UCP2 variants and the risk of ischemic stroke in our Sardinian cohort.

Thrombolysis in Acute Ischemic Stroke after Idarucizumab for Dabigatran Etexilate Reversal in Elderly: A Case Report.

INTRODUCTION: Dabigatran is one of the nonvitamin K antagonist oral anticoagulants. Thrombolytic treatment with intravenous recombinant tissue plasminogen activator is contraindicated in patients taking a DOAC. Idarucizumab was recently approved for dabigatran-activity reversing in severe bleeding, emergency surgery, or urgent procedures, but many attempts have been made to use idarucizumab in patients presenting with acute ischemic stroke in order to be eligible for thrombolysis. CASE: Our patient was an 89-year-old woman with severe aphasia who was treated with dabigatran for nonvalvular atrial fibrillation. She received an infusion of idarucizumab followed by thrombolytic therapy, with complete remission of symptoms after 24 hours. DISCUSSION: Idarucizumab is a safe option for patients with acute ischemic stroke treated with dabigatran; otherwise eligibles for thrombolysis, even in very old people like our patient.

Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians.

Genetic factors contribute to the risk of ischemic stroke (IS). The phosphodiesterase-4D (PDE4D) and the 5-lipoxygenase activating protein (ALOX5AP) genes were identified as contributors to stroke in an Icelandic population. In an attempt to better define the contributory role of PDE4D and ALOX5AP genes to the risk of IS in humans, we carried out the present association study in a well-characterized, earlier published, genetically homogenous population from the island of Sardinia, Italy. In this cohort, including 294 cases and 235 controls, age, hypertension, hypercholesterolemia, and atrial fibrillation represent risk factors for IS. The PDE4D gene was evaluated by four single nucleotide polymorphisms (SNP32, SNP45, SNP83, SNP87) and by the microsatellite AC008818-1; the ALOX5AP gene was characterized by three SNPs (SG13S32, SG13S89, ALO2A). The results of our study provide no evidence of association between any single PDE4D and ALOX5AP gene variant with the risk of IS in the Sardinian cohort. Haplotype analysis, including that constructed with allele 0 of microsatellite AC008818-1 and SNP45 of the PDE4D gene, was also negative. In conclusion, we found no evidence of association between PDE4D and ALOX5AP genes and the risk of IS in a genetically homogenous population from Sardinia.

Beta2-adrenergic receptor gene polymorphisms and risk of ischemic stroke.

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

The Pl(A1/A2) polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: increased risk of ischemic stroke in high-risk patients.

OBJECTIVE: The platelet GPIIIa plays a pivotal role in platelet aggregation. Previous studies showed an association between the GPIIIa Pl(A1/A2) polymorphism and coronary thrombosis, while there is only contrasting evidence about its role in stroke. We explored the possibility that this polymorphism represents a risk factor for stroke in hypertensive patients. METHODS: We studied two populations. In loco, we genotyped 140 hypertensive control individuals and 28 hypertensive patients with ischemic stroke. Furthermore, we performed an analysis of previously published data of 451 Sardinian hypertensive patients, already characterized and genotyped. RESULTS: Association analysis revealed that the Pl(A2) distribution was similar between hypertensive patients with and without stroke, but when considering a more homogeneous population of high-risk hypertensive patients, defined according to ESH/ESC 2003 guidelines, we observed that the frequency of the Pl(A2) allele was higher among stroke versus nonstroke patients (stroke, 46.4%; nonstroke, 22.6%; P = 0.01). The multiple regression analysis taking into account this polymorphism among other factors known to contribute to ischemic stroke confirmed the Pl(A2) allele as an additive risk factor for stroke (B = 0.986, Wald = 4.943, P < 0.03), increasing the risk of stroke by 2.9 (95% confidence interval = 1.23-6.85, P < 0.02). Similar results were obtained in the Sardinian population: in hypertensive patients with three or more risk factors, Pl(A2) increases the risk (odds ratio = 2.8, 95% confidence interval = 1.3-6.0, P < 0.001) and is an additive risk factor for stroke (B = 1.073, Wald = 6.920, P < 0.01). CONCLUSIONS: Our data suggest that the Pl(A2) polymorphism is a genetic determinant of ischemic stroke in a selected high-risk hypertensive population.

Chitotriosidase in patients with acute ischemic stroke.

BACKGROUND: Following an acute brain ischemia, local endothelia allow monocyte chemoattraction into the lesion site which contributes to brain damage through a group of neurotoxic factors. A relationship exists between the extent of brain damage and the plasma level of monocyte products, including chitotriosidase, though usually strictly related to preexisting infectious-inflammatory diseases. PURPOSE: Since chitotriosidase activity is also elevated in pathogen-free conditions, we tested whether chitotriosidase upregulation might be specifically related to stroke and unrelated to clinically relevant infectious diseases. METHODS: We studied the plasma level of chitotriosidase activity, TNF-alpha and IL-6 in 44 consecutive patients with acute brain ischemia without concomitant symptoms or signs of inflammatory-infectious diseases. Results were compared with stroke severity and outcome as detected by brain CT and NIH scale. Blood samples were collected, on average, 11 h after stroke onset. RESULTS: Chitotriosidase activity positively correlates with stroke severity, as measured by NIH scale (r = 0.69, p < 0.01), to the extent of brain damage as documented by CT (r = 0.75, p < or = 0.001) and the TNF-alpha level (r = 0.76, p < 0.001); it also inversely correlates with the IL-6 level (r = -0.43, p < or = 0.05). CONCLUSION: Our results indicate that chitotriosidase is a specific marker of macrophage activation occurring in stroke which directly correlates with stroke severity independently of preexisting inflammatory or infectious conditions.

Polymorphisms in prothrombotic genes and their impact on ischemic stroke in a Sardinian population.

Genetic factors are involved in the individual predisposition to develop ischemic stroke (IS). In the present study we tested the role of the Factor VII G10976A and -C122T polymorphisms on the susceptibility to develop IS in a genetically homogenous and clinically well ascertained case-control study including 294 cases (median age 75 years; 176 males/118 females) and 286 controls (median age 73 years; 163 males/123 females) in Sardinia, Italy. In addition, we carried out an exploratory analysis with respect to other frequently studied polymorphisms of haemostatic factor genes:Factor II G20210A, Factor V G1691A,,Fibrinogen alpha-chain Thr312Ala, Fibrinogen beta-chain -C148T, Factor XIII G185T, GPIIb/IIIa T1565C. Among all the genes tested, FVII -C122T showed a significant, independent contribution to IS predisposition both in crude and adjusted analyses (crude OR 1.52, 95% CI 1.09-2.10, P=0.013; adjusted OR 1.48, 95% CI 1.04-2.09, P=0.028, respectively). Haplotype analyses revealed a conserved population structure with high linkage disequilibrium between both FVII mutations tested. Blood levels of FVII had an inverse relationship with the polymorphism involved. Apart from genetic influence, there was a significant role for hypertension (OR=1.7, 95% CI 1.19-2.43, P=0.003), hypercholesterolemia (OR=2.21, 95% CI 1.38-3.54, P=0.001) and atrial fibrillation (OR=1.66, 95% CI 1.06-2.58, P=0.026) on IS occurrence. In summary, we describe evidence for a possible direct association of FVII gene molecular variants with the occurrence of IS in a genetically homogenous human sample.

Gene polymorphisms of the renin-angiotensin-aldosterone system and the risk of ischemic stroke: a role of the A1166C/AT1 gene variant.

OBJECTIVE: The role of the renin-angiotensin-aldosterone system (RAAS) genes on predisposition to develop stroke, a multifactorial and polygenic cardiovascular trait, is still under investigation. In the present study we characterized the contributory role of RAAS genes in the susceptibility to develop ischemic stroke in humans. METHODS: Allele and genotype frequencies of RAAS genes were characterized in a population of 215 cases (including only atherothrombotic and lacunar forms) and 236 controls selected in Sardinia, a large Mediterranean island with a well-known segregated population. Statistical analysis was performed in the whole population and, based on a significant interaction between angiotensin II receptor (AT1) genotype and hypertension, was also repeated in the hypertensive subgroup. RESULTS: A significant association of the C1166/AT1 gene allelic variant with stroke was found when assuming a dominant model of transmission [unadjusted odds ratio (OR)=1.5, 95% confidence interval (CI) 1.1-2.2, P=0.024]. The strength of the association became more evident in the subgroup of hypertensive individuals (135 cases and 110 controls). In fact, in this cohort the independent OR for the AT1 gene was 2.1, 95% CI 1.2-3.7, P=0.006 in the dominant model and 2.0, 95% CI 1.3-3.2, P=0.002 in the additive model. No other RAAS gene was identified as a contributor to stroke. CONCLUSIONS: Our findings support a predisposing role of an AT1 gene variant in the development of ischemic stroke. In particular, the AT1 gene variant exerted a major impact on ischemic stroke occurrence in the presence of hypertension.

Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in humans.

BACKGROUND AND PURPOSE: A precise definition of genetic factors responsible for common forms of stroke is still lacking. The purpose of the present study was to investigate the contributory role of the genes encoding atrial natriuretic peptide (ANP) and type A natriuretic peptide receptor (NPRA) in humans' susceptibility to develop ischemic stroke. METHODS: Allele and genotype frequencies of ANP and NPRA were characterized in an Italian case-control study with patients affected by vascular disease or risk factors. Subjects were recruited from the island of Sardinia (206 cases, 236 controls). RESULTS: A significant association between the ANP/TC2238 polymorphic site and stroke occurrence was found when a recessive model of inheritance was assumed. The risk conferred by this mutant genotype, when estimated by multivariate logistic regression analysis, was 3.8 (95% confidence interval, 1.4 to 10.9). A significantly increased risk of stroke recurrence was observed among cases carrying the ANP/CC2238 genotype compared with cases carrying the ANP/TT2238 genotype (P=0.04). No direct association of NPRA with stroke occurrence was detected. However, a significant epistatic interaction between the ANP/CC2238 genotype and an allelic variant of NPRA led to a 5.5-fold increased risk of stroke (95% confidence interval, 1.5 to 19.4). CONCLUSIONS: Our findings support a direct contributory role of ANP to stroke in humans. A significant interaction between ANP and NPRA on stroke occurrence was found.