osteoprotegerin and Brain-Ischemia

Stroke is a major cause of mortality and morbidity around the world. Microembolic signals (MES), as the markers of unstable atherosclerotic plaque, can predict the occurrence and prognosis of ischemic stroke (IS). MES can also assess the efficacy of antithrombotic agents and predict the recurrence probability of IS. Unstable plaques are the main source of MES; thus, numerous biomarkers of atherosclerotic plaque instability are highly likely to predict the presence of MES. This study aims to review recent biomarker candidates for MES or microembolism. Current research indicates that the following are independent markers for positive MES: high level of serum soluble P-selectin, chemokine (C-X-C motif) ligand 16 (CXCL16) and fibrinogen, high neutrophil count, reduced ratio of CD4+CD25

Topics: Biomarkers; Brain Ischemia; Chemokine CXCL16; Fibrinogen; Fibrinolytic Agents; Humans; Intracranial Embolism; Neutrophils; Osteoprotegerin; P-Selectin; Plaque, Atherosclerotic; Prognosis; Recurrence; Stroke; T-Lymphocytes, Regulatory

The major cause of ischemic stroke is unstable or thrombogenic atherosclerotic plaques. Vascular calcification, a process that appears crucial for plaque stability, shares common features with bone formation. Many bone turnover proteins exhibit metabolic properties, but the evidence is conflicting regarding their possible involvement in vascular disease. Antibodies against sclerostin and dickkopf-1 are currently being evaluated as potential therapy for treating bone disorders. It is important to carefully assess the cardiovascular and metabolic effects of these proteins. The aim of the present study was to explore serum levels of bone turnover markers in patients with acute noncardio-embolic ischemic stroke in comparison with healthy controls.. In a cross-sectional study, we compared 48 patients aged ≥75 years with noncardio-embolic ischemic stroke and 46 healthy controls. Serum levels of dickkopf-1, sclerostin, osteoprotegerin, osteopontin and osteocalcin were determined by Luminex technique.. We found clearly increased serum levels of osteoprotegerin, sclerostin, dickkopf-1 and osteopontin in patients with stroke compared with healthy controls. No difference was seen in serum levels of osteocalcin between the two groups.. Our findings strengthen the hypothesis of bone turnover markers being involved in vascular disease. Whether these proteins can be used as candidate markers for increased stroke risk or prognostic biomarkers remains to be further elucidated.

Topics: Adaptor Proteins, Signal Transducing; Aged; Aged, 80 and over; Biomarkers; Bone Morphogenetic Proteins; Bone Remodeling; Brain Ischemia; Female; Genetic Markers; Humans; Intercellular Signaling Peptides and Proteins; Male; Osteocalcin; Osteopontin; Osteoprotegerin; Plaque, Atherosclerotic; Stroke

High circulating levels of osteoprotegerin (OPG) carry prognostic impact in cohorts with various cardiovascular diagnoses. With the present study, we aim to investigate the role of OPG within the scale of myocardial damage.. This study includes 219 consecutive patients with acute ST-elevation myocardial infarction randomized to primary percutaneous coronary intervention (pPCI) or pPCI and remote ischemic per-conditioning. Salvage index via myocardial single-photon emission CT assessment (data available in 61% of the patients) was performed, and derived from Day 1 (myocardial area at risk) and Day 30 (final infarct size). Plasma OPG levels were measured using an in-house immunoassay. A combined end-point of all-mortality, myocardial infarction, stroke, readmission for heart failure and ischemic stroke/transient ischemic attack (Major Adverse Cardiac and Cerebrovascular Events [MACCE]) was used for follow-up; 45 (38-48 months).. High OPG levels were associated with the severity of cardiovascular disease. During follow-up, OPG was a predictor of MACCE (unadjusted, HR: 2.1, 95% CI: 1.14-3.85, P = 0.017). Adjustments for age, gender, and body mass index preserved the independent predictive power of OPG. However, OPG levels were neither associated with salvage index nor with the final infarct size. Remote ischemic per-conditioning had no effect on OPG levels.. Despite absent association between OPG levels and the scale of myocardial damage, high OPG levels predict a significantly increased risk of MACCE.

Topics: Aged; Biomarkers; Brain Ischemia; Denmark; Female; Heart Failure; Humans; Immunoassay; Ischemic Attack, Transient; Ischemic Preconditioning; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Osteoprotegerin; Patient Readmission; Percutaneous Coronary Intervention; Predictive Value of Tests; Proportional Hazards Models; Recurrence; Risk Factors; Stroke; Time Factors; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Up-Regulation; Upper Extremity

Osteoprotegerin was implicated in vascular injury and inflammatory responses, but its prognostic value in ischemic stroke remained unclear. We aimed to prospectively investigate the association between plasma osteoprotegerin and ischemic stroke prognosis combined with a Mendelian randomization analysis.. Our prospective study follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guideline. We measured baseline plasma osteoprotegerin levels for 3490 ischemic stroke patients recruited between August 2009 and May 2013 in 26 hospitals across China. The primary outcome was a composite outcome of death and major disability at 3 months after ischemic stroke.. Elevated plasma osteoprotegerin was associated with poor prognosis of ischemic stroke, and genetically determined high plasma osteoprotegerin was associated with an increased risk of primary outcome in Mendelian randomization analysis.. URL: https://www.. gov; Unique identifier: NCT01840072.

Topics: Biomarkers; Brain Ischemia; Humans; Ischemic Stroke; Mendelian Randomization Analysis; Osteoprotegerin; Prognosis; Prospective Studies; Risk Factors; Stroke

Osteoprotegerin (OPG) is a component of the tumor necrosis factor receptor superfamily. Several studies have shown a relationship between OPG and cardiovascular disease. We investigated the association between plasma OPG levels and hemorrhagic transformation in stroke patients who received endovascular thrombectomy (EVT).. We prospectively enrolled 360 patients diagnosed with acute ischemic stroke and performed EVT from April 2014 to December 2020. Blood sampling for plasma OPG was performed after fasting for 12 h after EVT. Hemorrhagic transformation was defined using the definition and classification of the European Cooperative Acute Stroke Study-3 trial.. Of all the included patients, 130 (36.1%) experienced hemorrhagic transformation. The mean ± standard deviation of the plasma OPG concentrations was 200.2 ± 74.4 pg/mL. In multivariable analysis, after adjusting for age, sex, body mass index (BMI), and variables with p < 0.1 in univariable analysis (diabetes mellitus, atrial fibrillation, coronary artery disease, alcohol intake, current smoking, NIHSS, ASPECT score, mass effect, hemoglobin, vitamin D 25(OH)D), increased plasma OPG concentration was independently related to any hemorrhagic transformation (highest tertile vs. lowest tertile of OPG; odds ratio [OR] 2.31, 95% confidence interval [CI] (1.29-4.14), p = 0.005) and severity of hemorrhagic transformation (OR 2.92, 95% CI (1.66-5.12), p = 0.001).. Our results demonstrate that increased plasma OPG level is related to the occurrence and severity of hemorrhagic transformation in patients with cerebral infarction who receive EVT.

Topics: Brain Ischemia; Endovascular Procedures; Humans; Ischemic Stroke; Odds Ratio; Osteoprotegerin; Stroke; Thrombectomy; Treatment Outcome

Osteoprotegerin (OPG) is a component of the tumor necrosis factor receptor superfamily. Several studies have shown a relationship between OPG and cardiovascular diseases. We hypothesized that there is a relationship between plasma OPG levels and cerebral small vessel disease (SVD).. Patients diagnosed with their first cerebral ischemic infarction between April 2014 and March 2017 were enrolled. All the enrolled patients were evaluated through the hospital stroke protocol, including routine blood tests, brain imaging, and measuring the plasma OPG levels. The presence and burden of cerebral SVD [cerebral microbleeds (CMBs), asymptomatic lacunar infarction (ALI), high-grade perivascular space (HPVS), high-grade white matter hyperintensity (HWMH)], and total SVD score were assessed through brain magnetic resonance imaging.. Of the 270 patients included in our study, 158 (58.5%) were men. The mean age of the patients was 63.8 ± 11.6 years. In multivariable analysis, plasma OPG levels were positively associated with the presence and burden of each cerebral SVD. The odds ratios (OR) of CMBs, ALI, HPVS, and HWMH for the association of OPG per standard deviation (SD) increase were 1.58 [95% confidence interval (CI), 1.09-2.27], 1.40 (95% CI, 1.04-1.88), 1.88 (95% CI, 1.27-2.78), and 1.47 (95% CI, 1.04-2.08), respectively. Plasma OPG levels were positively correlated with total SVD score (beta = 0.211, standard error = 0.061, p-value = 0.009, R. Plasma OPG levels correlate with the presence and burden of cerebral SVD in patients with acute ischemic stroke.

Topics: Acute Disease; Aged; Biomarkers; Brain Ischemia; Cerebral Small Vessel Diseases; Cost of Illness; Female; Humans; Ischemic Stroke; Male; Middle Aged; Osteoprotegerin; Retrospective Studies

Instability of atherosclerotic plaques is associated with the occurrence of stroke. Microembolic signals (MESs) are an indicator of unstable plaque. A relationship between plasma osteoprotegerin (OPG) and ischemic stroke has already been identified. The aim of this study was to investigate whether plasma OPG levels have a relationship with MESs and to evaluate the feasibility of OPG as a biomarker of stroke severity and occurrence of MESs.. Our study consisted of 127 patients with large artery atherosclerosis stroke and 56 controls. Patients were classified into subgroups based on stroke severity and the occurrence of MESs. MES-monitoring was performed for 60 min using transcranial Doppler within 72 h of stroke onset. Stroke severity at admission was assessed by the National Institutes of Health Stroke Scale.. Plasma OPG levels correlate with stroke severity and the occurrence of MESs.

Topics: Aged; Biomarkers; Brain Ischemia; Female; Humans; Intracranial Embolism; Male; Middle Aged; Osteoprotegerin; Stroke

The serum level of osteoprotegerin (encoded by OPG or TNFRSF11B) was previously shown to be increased in patients with ischemic stroke. A single nucleotide polymorphism rs3134069 in the TNFRSF11B gene was previously associated with ischemic stroke in a population of diabetic patients in Italy. It remains to be determined whether rs3134069 is associated with ischemic stroke in the general population or populations without diabetes.. We genotyped rs3134069 and performed a case-control association study to test whether rs3134069 is associated with ischemic stroke in 2 independent Chinese Han populations, including a China-Central population with 1629 cases and 1504 controls and a China-Northern population with 1206 cases and 720 controls.. This study demonstrates that rs3134069 in TNFRSF11B increases risk of ischemic stroke by decreasing TNFRSF11B expression.

Topics: Adult; Aged; Asian People; Brain Ischemia; Case-Control Studies; Chi-Square Distribution; China; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Odds Ratio; Osteoprotegerin; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Risk Assessment; Risk Factors; Stroke

Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor superfamily and is involved in the progress of atherosclerosis. We chose a gene polymorphism locus, OPG rs3102735, to explore how OPG gene polymorphisms relate to the occurrence of ischemic stroke and microembolic signals and to evaluate their relationship with the severity of neurologic deficits at admission and the degree of vascular stenosis.. We studied 251 patients diagnosed with large artery atherosclerosis (LAA) stroke and 121 controls. The LAA stroke patients were divided into clinical subgroups according to the presence of microembolic signals, severity of neurologic deficits at admission, and the degree of vascular stenosis. The OPG rs3102735 gene polymorphism was examined by polymerase chain reaction and restriction fragment length polymorphism. The microembolic signals (MES) were monitored by transcranial Doppler (TCD) for 60min within 72h of stroke onset. The severity of neurologic deficits at admission was evaluated by the National Institutes of Health Stroke Scale (NIHSS).. The CC+CT genotypes and allele C frequencies of the rs3102735 gene polymorphism were significantly higher in the LAA group than in the control group (39% vs. 25.6%, P=0.026; 21.7% vs.13.2%, P=0.006), higher in MES-positive compared to MES-negative patients (58.7% vs. 32.4%, P<0.01; 34.1% vs.17.6%, P<0.01), and higher in patients with an NIHSS Score (≥6) than in those with an NIHSS Score (<6) (46.9% vs.33.3%, P=0.031; 43.4% vs.18.3%, P=0.04). However, the genotypes and allele frequencies of SNPs in rs3102735 did not show significant differences in the degree of vascular stenosis (P>0.05).. Our findings suggest that the OPG rs3102735 gene polymorphism might be related to the occurrence of LAA ischemic stroke, microembolic signals and stroke severity and not the degree of vascular stenosis.

Topics: Acute Disease; Aged; Brain Ischemia; Carotid Stenosis; Female; Humans; Male; Middle Aged; Osteoprotegerin; Polymorphism, Single Nucleotide; Stroke

After an acute ischaemic stroke (AIS), several inflammatory biomarkers have been investigated, but their predictive role on functional recovery remains to be validated. Here, we investigated the prognostic relevance of biomarkers related to atherosclerotic plaque calcification, such as osteopontin (OPN), osteoprotegerin (OPG) and the receptor activator of nuclear factor kappa-B ligand (RANKL) in a cohort of patients with AIS (n = 90) during 90-day follow-up.. Radiological and clinical examinations as well as blood sampling were performed at admission and at days 1, 7 and 90 from the event. Validated scores [such as modified Rankin scale (mRS) and the National Institutes of Health Stroke Scale (NIHSS)] were used to assess poststroke outcome. Serum levels of OPN, OPG and RANKL were measured by colorimetric enzyme-linked immunosorbent assay (ELISA).. When compared to the admission, OPN serum levels increased at day 7. Serum OPN levels at this time point were positively correlated with both ischaemic lesion volume and NIHSS at days 7 and 90. A cut-off of 30.53 ng/mL was identified for serum OPN by receiver operating characteristic (ROC) curve analysis. Adjusted logistic regression showed that serum OPN levels at day 7 predicted worse mRS at day 90 [OR 4.13 (95% CI 1.64-10.36); P = 0.002] and NIHSS [1.49 (95% CI 1.16-1.99); P = 0.007], independently of age, gender, hypertension and thrombolysis.. Serum levels of OPN, but not OPG and RANKL, peaked at day 7 after AIS and predicted worse neurological scores. Therefore, OPN might have a pathophysiological and clinical relevance after AIS.

Topics: Aged; Biomarkers; Brain Ischemia; Disabled Persons; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Osteopontin; Osteoprotegerin; Prognosis; Prospective Studies; RANK Ligand; Stroke; Up-Regulation

Osteoprotegerin (OPG) is a soluble secreted protein and a decoy receptor, which inhibits a receptor activator of nuclear factor κB (NF-κB) ligand (RANKL)/the receptor activator of NF-κB (RANK) signaling. Recent clinical studies have shown that a high-serum-OPG level is associated with unfavorable outcome in ischemic stroke, but it is unclear whether OPG is a culprit or an innocent bystander. Here we demonstrate that enhanced RANKL/RANK signaling in OPG(-/-) mice or recombinant RANKL-treated mice contributed to the reduction of infarct volume and brain edema via reduced postischemic inflammation. On the contrary, infarct volume was increased by reduced RANKL/RANK signaling in OPG(-/-) mice and WT mice treated with anti-RANKL neutralizing antibody. OPG, RANKL, and RANK mRNA were increased in the acute stage and were expressed in activated microglia and macrophages. Although enhanced RANKL/RANK signaling had no effects in glutamate, CoCl2, or H2O2-stimulated neuronal culture, enhanced RANKL/RANK signaling showed neuroprotective effects with reduced expression in inflammatory cytokines in LPS-stimulated neuron-glia mixed culture, suggesting that RANKL/RANK signaling can attenuate inflammation through a Toll-like receptor signaling pathway in microglia. Our findings propose that increased OPG could be a causal factor of reducing RANKL/RANK signaling and increasing postischemic inflammation. Thus, the OPG/RANKL/RANK axis plays critical roles in controlling inflammation in ischemic brains.

Topics: Animals; Brain; Brain Edema; Brain Ischemia; Cell Death; Cells, Cultured; Coculture Techniques; Cytokines; Encephalitis; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neurons; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; RNA, Messenger; Signal Transduction

This study investigated correlations between mortality, stroke subtype and stroke severity with serum osteoprotegerin (OPG) and S-100 protein levels prior to the treatment of patients admitted to the emergency department and diagnosed with ischaemic stroke. Pretreatment serum samples were collected from patients (n = 90) to determine OPG and S-100 protein levels. Age- and sex-matched healthy individuals (n = 16) served as controls. Compared with controls, OPG and S-100 protein levels were significantly higher in the cardioembolic and atherothrombotic stroke groups. Within the stroke group, OPG levels were significantly higher in the cardioembolic and atherothrombotic stroke groups compared with the transient ischaemic attack (TIA) group. S-100 protein levels were significantly higher in the atherothrombotic stroke group than in the lacunar stroke and TIA groups, and in the cardioembolic stroke group compared with the lacunar stroke group. Serum OPG and S-100 protein levels were significantly higher in patients who died compared with survivors. In predicting stroke subtype and severity, although both OPG and S-100 protein levels were indicators, S-100 protein was more valuable for mortality prediction.

Topics: Brain Ischemia; Case-Control Studies; Humans; Osteoprotegerin; Prospective Studies; S100 Proteins; Severity of Illness Index; Stroke

Concentrations of osteoprotegerin (OPG) have been associated with the presence of vascular and cardiovascular diseases, but the knowledge of this marker in the setting of ischaemic stroke is limited.. In 244 patients with acute ischaemic stroke (age: 69 +/- 13 years), samples of OPG were obtained serially from presentation to day 5. Patients with overt ischaemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all-cause mortality as the sole end-point. Multivariable predictors of OPG values at presentation included haemoglobin (T = -2.82; P = 0.005), creatinine (T = 4.56; P < 0.001), age (T = 9.66; P < 0.001), active smoking (T = 2.25; P = 0.025) and pulse rate (T = 3.23; P = 0.001). At follow-up 72 patients (29%) had died. Patients with OPG < or =2945 pg mL(-1) at baseline had a significantly improved survival rate on univariate analysis (P < 0.0001); other time-points did not add further prognostic information. In multivariate analysis, after adjustment for age, stroke severity, C-reactive protein levels, troponin T levels, heart and renal failure concentrations of OPG independently predicted long-term mortality after stroke (adjusted hazard ratio, 2.3; 95% CI: 1.1 to 4.9; P = 0.024).. Osteoprotegerin concentrations measured at admission of acute ischaemic stroke are associated with long-term mortality.

Topics: Acute Disease; Aged; Aged, 80 and over; Biomarkers; Brain Ischemia; Cause of Death; Female; Humans; Linear Models; Male; Middle Aged; Osteoprotegerin; Prognosis; Stroke

Topics: Acute Disease; Brain Ischemia; Humans; Osteoprotegerin; Stroke

Topics: Biomarkers; Brain Ischemia; Case-Control Studies; Humans; Osteoprotegerin; Predictive Value of Tests; Prospective Studies; Stroke

Several studies suggest that osteoprotegerin (OPG) concentrations may be associated with the risk of ischemic stroke, but no large prospective studies have been conducted. We conducted a nested case-control study within a large cohort to elucidate a possible relation.. The study was done within a follow-up study including 57 053 men and women. Baseline data included OPG concentrations, lifestyle factors, and medical history. Median length of follow-up was 3.1 years. We assessed the relationship between OPG and stroke risk using conditional logistic regression to adjust for known risk factors (smoking, blood pressure, cholesterol, diabetes, body mass index, alcohol use, polyunsaturated fatty acids, and education).. We identified 254 cases with verified incident acute ischemic stroke and 254 age- and sex-matched controls. Median plasma OPG concentration among cases was 1.84 microg/L (25th-75th percentile 1.45-2.30 microg/L) compared with 1.87 microg/L (1.49-2.27 microg/L) in the control group. The adjusted odds ratio was 0.87 (95% CI 0.46-1.63) comparing participants in the highest quartile of OPG concentrations with those in the lowest quartile.. These findings provide no support for the hypothesis that plasma OPG concentrations are associated with an increased risk of ischemic stroke. This result could indicate a different pathogenic process in stroke development from that in ischemic heart disease, where OPG is a strong predictor.

Topics: Acute Disease; Aged; Brain Ischemia; Case-Control Studies; Female; Humans; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Prospective Studies; Risk Assessment; Stroke

Arterial calcification is associated with increased risk of cardiovascular events. Osteoprotegerin (OPG) is a cytokine involved in the bone metabolism and vascular calcification. Recent data support a relationship between high serum levels of OPG and increased risk for cardiovascular disease in human. The aim of this study was to evaluate the OPG serum levels in acute ischemic stroke. Our study was further designed to detect differences in serum OPG levels between subtypes of ischemic stroke.. The study consisted of 51 patients with acute ischemic stroke and 28 control subjects. Stroke subtypes were defined by the TOAST classifications. Serum OPG levels were measured with the ELISA method.. OPG serum levels were significantly higher in patients with ischemic stroke than in control subjects (p<0.001). OPG serum levels were significantly higher in large-vessel disease (LVD) subtype compared with small-vessel disease (SVD) subtype and controls (p<0.001, p<0.001). There was no significant difference in OPG serum levels between SVD group and control subjects. Serum OPG levels were correlated with age (r=0.407, p=0.005) and fasting glucose levels (r=0.542, p=0.001) in ischemic stroke group. Logistic regression analysis showed that plasma OPG levels (OR 2.1, 95% CI, 1.16 to 3.4, p=0.01) associated with presence of stroke independently of the other risk factors.. High serum OPG levels were associated with the LVD stroke subtype, suggesting that OPG levels may play role in pathogenesis of atherothrombotic stroke. The precise mechanism for the role of OPG in atherosclerosis needs to be investigated further.

Topics: Aged; Arteriolosclerosis; Atherosclerosis; Brain Infarction; Brain Ischemia; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Osteoprotegerin; Risk Factors; Stroke; Thrombosis

Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]).. MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFalpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures.. In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFalpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals.. Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.

Topics: Adult; Age Distribution; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Brain; Brain Ischemia; Cardiovascular Diseases; Cross-Sectional Studies; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Magnetic Resonance Imaging; Male; Middle Aged; Osteoprotegerin; Sex Distribution; Tumor Necrosis Factor-alpha

Arterial calcification and osteoporosis often coexist, especially in postmenopausal women. Osteoporosis associates with a substantially increased risk of stroke in elderly women, suggesting that impaired estrogen signaling may link stroke and osteoporosis. Osteoprotegerin (OPG, TNFRSF11B) and interleukin-6 (IL-6, IL6) are putative target genes for estrogen signaling and have been implicated in both cardiovascular diseases and osteoporosis. We hypothesized that specific polymorphisms in these genes may be associated with increased risk of ischemic stroke or intracerebral hemorrhage (ICH).. We performed a population-based prospective nested case-control study, in which the relationships between polymorphisms (OPG-1181G/C, OPG-950T/C and IL6-174G/C) and ischemic stroke and ICH were examined. Definitive first-ever stroke events (n = 388), i.e. ischemic stroke (n = 320), ICH (n = 61) and unspecified stroke (n = 7) cases, and controls without cardiovascular disease (n = 773), matched for age, sex and geographical region were studied. Univariate and multivariate models using conditional logistic regression, which included traditional risk factors, were used to test for association.. Carriers of the OPG-1181C/C genotype had a significantly (p = 0.018) increased risk of ICH (OR, 2.69; 95% CI, 1.19-6.12) in the univariate analysis. After adjustments (hypertension, diabetes, BMI and triglycerides), this genotype remained significantly (p = 0.005) associated with ICH (OR, 6.04; 95% CI, 1.71-21.29). By contrast, no correlations were found between this genotype and ischemic stroke, nor between the OPG-950T/C or IL6-174G/C polymorphisms and stroke subtypes.. In this population, the OPG-1181C/C genotype associates with first-ever ICH, implying that alterations in OPG-mediated signaling in the vasculature may be involved in the pathophysiology of this disease.

Topics: Adult; Aged; Brain Ischemia; Case-Control Studies; Cerebral Hemorrhage; Female; Gene Frequency; Genetic Predisposition to Disease; Health Surveys; Humans; Interleukin-6; Logistic Models; Male; Middle Aged; Odds Ratio; Osteoprotegerin; Polymorphism, Single Nucleotide; Prospective Studies; Risk Assessment; Risk Factors; Stroke; Sweden