D-Dimer Is Associated With First-Ever Intracerebral Hemorrhage.

Background and Purpose- Hypertension is the most important risk factor for intracerebral hemorrhage (ICH), but further characterization is needed for groups at high risk of ICH. One way to predict the risk of developing a disease is with plasma biomarkers. This study aimed to investigate the association between the biomarker, D-dimer, and ICH risk. Methods- This population-based, nested case-control study was conducted using data from 2 population-based surveys; the Västerbotten Intervention Programme and MONICA Northern Sweden (Monitoring Trends and Determinants in Cardiovascular Disease). All participants underwent a health examination and blood sampling at baseline before the event. Cases (n=141) were diagnosed with a first-ever ICH between 1985 and March 2007. One or 2 controls (n=255) were matched to each case. Results- The median age was 60 years; 39% of participants were women; and the median time from blood sampling to ICH was 5.2 years. When D-dimer was evaluated as a continuous variable, it was significantly associated with ICH. After multivariable adjustment (for hypertension, body mass index, cholesterol levels, diabetes mellitus, and smoking), the odds ratio was 1.36 per SD of D-dimer (95% CI, 1.05-1.77). When participants were stratified in 3 groups according to time from blood sampling at health examination to ICH, we found that the association between D-dimer levels and ICH was most pronounced in individuals with the shortest time from blood sampling to ICH event (<3.5 years; odds ratio, 1.78; 95% CI, 1.05-3.05). Conclusions- High plasma concentrations of D-dimer were associated with increased risk of a future ICH, after adjusting for cardiovascular risk factors. This association was predominantly driven by the cases with the shortest time from blood sampling to ICH event.

Optimal Timing of Anticoagulant Treatment After Intracerebral Hemorrhage in Patients With Atrial Fibrillation.

BACKGROUND AND PURPOSE: This study aims to provide observational data on the relationship between the timing of antithrombotic treatment and the competing risks of severe thrombotic and hemorrhagic events in a cohort of Swedish patients with atrial fibrillation and intracerebral hemorrhage (ICH). METHODS: Patients with atrial fibrillation and a first-ever ICH were identified in the Swedish Stroke Register, Riksstroke, 2005 to 2012. Riksstroke was linked with other national registers to find information on treatment, comorbidity, and outcome. The optimal timing of treatment in patients with low and high thromboembolic risk was described through cumulative incidence functions separately for thrombotic and hemorrhagic events and for the combined end point vascular death or nonfatal stroke. RESULTS: The study included 2619 ICH survivors with atrial fibrillation with 5759 person-years of follow-up. Anticoagulant treatment was associated with a reduced risk of vascular death and nonfatal stroke in high-risk patients with no significantly increased risk of severe hemorrhage. The benefit seemed to be greatest when treatment was started 7 to 8 weeks after ICH. For high-risk women, the total risk of vascular death or stroke recurrence within 3 years was 17.0% when anticoagulant treatment was initiated 8 weeks after ICH and 28.6% without any antithrombotic treatment (95% confidence interval for difference, 1.4%-21.8%). For high-risk men, the corresponding risks were 14.3% versus 23.6% (95% confidence interval for difference, 0.4%-18.2%). CONCLUSIONS: This nationwide observational study suggests that anticoagulant treatment may be initiated 7 to 8 weeks after ICH in patients with atrial fibrillation to optimize the benefit from treatment and minimize risk.

Fish consumption and risk of stroke: a second prospective case-control study from northern Sweden.

BACKGROUND: Fish consumption has been concluded to be associated with decreased risk of stroke in several reviews. However, among men, but not women, an increased risk of stroke was previously found at high fish consumption (>3 meals/week) in northern Sweden. This study investigates if previous results on elevated stroke risk with high fish consumption in men in northern Sweden can be confirmed in a larger study with new cases in the same population. METHODS: A prospective nested case-control study was performed within the population-based Northern Sweden Health and Disease Study cohort. Information on fish consumption, other lifestyle and medical data was collected at baseline. Incident stroke cases (1987-2007, n = 735) were identified and 2698 controls matched for gender, age, year of baseline and geographical region. RESULTS: There were no associations between total fish or fatty fish consumption and stroke risk; thus the previous finding of increased risk of stroke with high fish consumption in men could not be repeated. High intake of lean fish (>twice/week compared to < once/month) was associated with increased stroke risk in men [OR 1.80 (95% CI 1.00, 3.21), but not in women [OR 0.50 (95% CI 0.24, 1.10)]. The association was driven by men living alone. CONCLUSIONS: The previous association between high total fish consumption and risk of stroke in men could not be repeated. The increased risk found in men with high intake of lean fish may be due to chance or confounding specific for this group.

Antithrombotic Treatment Following Intracerebral Hemorrhage in Patients With and Without Atrial Fibrillation.

BACKGROUND AND PURPOSE: Patients who survive intracerebral hemorrhage (ICH) often have compelling indications for anticoagulant and antiplatelet medication. This nationwide observational study aimed to determine the extent and predictors of antithrombotic treatment after ICH in Sweden. METHODS: Patients with a first-ever ICH in the Swedish Stroke Register (Riksstroke) 2005 to 2012 who survived hospital discharge were included. Riksstroke data were individually linked with other national registers to determine comorbid conditions and dispensed prescriptions of antithrombotic agents. RESULTS: Among the 2777 patients with atrial fibrillation (AF), the proportion with a dispensed prescription of antithrombotic agents was 8.5% (anticoagulants) and 36.6% (antiplatelet agents) within 6 months and 11.1% (anticoagulants) and 43.6% (antiplatelet agents) within 1 year. Among the 11 268 patients without AF, the corresponding figures were 1.6% (anticoagulants) and 13.8% (antiplatelet agents) within 6 months and 2.0% (anticoagulants) and 17.5% (antiplatelet agents) within 1 year. In patients with AF, predictors of anticoagulant treatment were less severe ICH, younger age, previous anticoagulation, valvular disease, and previous ischemic stroke. High CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes mellitus, stroke [doubled], vascular disease, age, and sex category [female]) scores did not correlate with anticoagulant treatment. There was a positive correlation between high CHA2DS2-VASc and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol) scores (rs=0.590, P<0.001). CONCLUSIONS: In majority of patients who receive antithrombotic agents, treatment is initiated within 6 months of ICH. Still, many patients with compelling indications for antithrombotic treatment are not prescribed antithrombotic agents. Factors other than high risk of embolic stroke by CHA2DS2-VASc in ICH survivors with concurrent AF are used to guide the anticoagulant treatment decision in Swedish clinical practice.

Long-term risk and predictors of recurrent stroke beyond the acute phase.

BACKGROUND AND PURPOSE: Previous studies have shown heterogeneous results on predictors and rates of stroke recurrence. This study set out to investigate the long-term risk and predictors of recurrent stroke in Northern Sweden 1995 to 2008. METHODS: In the population-based Monitoring Trends and Determinants of Cardiovascular Disease (MONICA) stroke incidence registry, stroke survivors of either ischemic stroke or intracerebral hemorrhage were followed for recurrent stroke or death. Cox regression was used to identify predictors of stroke recurrence. RESULTS: The study comprised 6700 patients and 26 597 person-years. During follow-up, 928 (13.9%) patients had a recurrent stroke. Comparison between the first time period (1995-1998) and the last (2004-2008) showed declined risk of stroke recurrence (hazard ratio, 0.64 [95% confidence interval, 0.52-0.78]). Previous myocardial infarction was less prevalent in the most recent cohort (P<0.001). Predictors of stroke recurrence were age (hazard ratio, 1.03 [95% confidence interval, 1.02-1.04]) and diabetes mellitus (hazard ratio, 1.34 [95% confidence interval, 1.15-1.57]). After an index intracerebral hemorrhage (n=815), a major part of recurrent events were ischemic (63%), and compared with the ischemic stroke group (n=5885), a tendency toward lower risk of recurrence was observed. CONCLUSIONS: Despite declining recurrence rates in this relatively young stroke population, almost one third are either dead or have experienced a second stroke in 5 years.

Ischemic stroke is associated with the ABO locus: the EuroCLOT study.

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

The impact of newly identified loci on coronary heart disease, stroke and total mortality in the MORGAM prospective cohorts.

Recently, genome wide association studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs) as being associated with coronary heart disease (CHD). We estimated the effect of these SNPs on incident CHD, stroke and total mortality in the prospective cohorts of the MORGAM Project. We studied cohorts from Finland, Sweden, France and Northern Ireland (total N=33,282, including 1,436 incident CHD events and 571 incident stroke events). The lead SNPs at seven loci identified thus far and additional SNPs (in total 42) were genotyped using a case-cohort design. We estimated the effect of the SNPs on disease history at baseline, disease events during follow-up and classic risk factors. Multiple testing was taken into account using false discovery rate (FDR) analysis. SNP rs1333049 on chromosome 9p21.3 was associated with both CHD and stroke (HR=1.20, 95% CI 1.08-1.34 for incident CHD events and 1.15, 0.99-1.34 for incident stroke). SNP rs11670734 (19q12) was associated with total mortality and stroke. SNP rs2146807 (10q11.21) showed some association with the fatality of acute coronary event. SNP rs2943634 (2q36.3) was associated with high density lipoprotein (HDL) cholesterol and SNPs rs599839, rs4970834 (1p13.3) and rs17228212 (15q22.23) were associated with non-HDL cholesterol. SNPs rs2943634 (2q36.3) and rs12525353 (6q25.1) were associated with blood pressure. These findings underline the need for replication studies in prospective settings and confirm the candidacy of several SNPs that may play a role in the etiology of cardiovascular disease.

Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting.

BACKGROUND: Bilirubin, an antioxidant, has been associated with reduced cardiovascular disease risk. A major cause of elevated plasma bilirubin is the common UGT1A1*28 promoter polymorphism in the gene of the bilirubin-conjugating enzyme UDP-glucuronosyltransferase 1A1, which reduces transcription by 70%. Earlier studies reporting a protective effect of bilirubin on stroke have not included analysis of UGT1A1*28. The purpose of this study is to investigate if bilirubin and UGT1A1*28 are protective against ischemic stroke in a prospective case-referent setting. METHODS: Cases with first-ever ischemic stroke (n = 231; median lag time 4.9 years) and 462 matched referents from the Northern Sweden Health and Disease Study Cohort were included. Plasma bilirubin was measured and UGT1A1*28 was analyzed by fragment analysis. RESULTS: Plasma bilirubin was lower in cases than in referents, but the difference reached significance only for women. The UGT1A1*28 polymorphism (allele frequency 30%) showed a strong gene-dose relationship with bilirubin levels both among cases and referents, but was not associated with risk for stroke. Among multiple other variables analyzed, the strongest correlation with bilirubin was found for plasma iron. CONCLUSIONS: There was no evidence for a protective effect of the UGT1A1*28 polymorphism against stroke and consequently neither for bilirubin. The findings suggest that other factors influencing the risk for stroke might also affect bilirubin levels.

Relative risks for stroke by age, sex, and population based on follow-up of 18 European populations in the MORGAM Project.

BACKGROUND AND PURPOSE: Within the framework of the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project, the variations in impact of classical risk factors of stroke by population, sex, and age were analyzed. METHODS: Follow-up data were collected in 43 cohorts in 18 populations in 8 European countries surveyed for cardiovascular risk factors. In 93 695 persons aged 19 to 77 years and free of major cardiovascular disease at baseline, total observation years were 1 234 252 and the number of stroke events analyzed was 3142. Hazard ratios were calculated by Cox regression analyses. RESULTS: Each year of age increased the risk of stroke (fatal and nonfatal together) by 9% (95% CI, 9% to 10%) in men and by 10% (9% to 10%) in women. A 10-mm Hg increase in systolic blood pressure involved a similar increase in risk in men (28%; 24% to 32%) and women (25%; 20% to 29%). Smoking conferred a similar excess risk in women (104%; 78% to 133%) and in men (82%; 66% to 100%). The effect of increasing body mass index was very modest. Higher high-density lipoprotein cholesterol levels decreased the risk of stroke more in women (hazard ratio per mmol/L 0.58; 0.49 to 0.68) than in men (0.80; 0.69 to 0.92). The impact of the individual risk factors differed somewhat between countries/regions with high blood pressure being particularly important in central Europe (Poland and Lithuania). CONCLUSIONS: Age, sex, and region-specific estimates of relative risks for stroke conferred by classical risk factors in various regions of Europe are provided. From a public health perspective, an important lesson is that smoking confers a high risk for stroke across Europe.

Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project.

BACKGROUND: Interleukin-18 is a pro-inflammatory cytokine suspected to be associated with atherosclerosis and its complications. We had previously shown that one single nucleotide polymorphism (SNP) of the IL18 gene was associated with cardiovascular disease (CVD) through an interaction with smoking. As a further step for elucidating the contribution of the IL-18 pathway to the etiology of CVD, we here investigated the association between the genetic variability of two IL-18 receptor genes, IL18R1 and IL18RAP, with the risk of developing CVD. METHODS: Eleven tagging SNPs, 5 in IL18R1 and 6 in IL18RAP, characterizing the haplotypic variability of the corresponding genes; were genotyped in 5 European prospective CVD cohorts including 1416 cases and 1772 non-cases, as part of the MORGAM project. Both single-locus and haplotypes analyses were carried out to investigate the association of these SNPs with CVD. RESULTS: We did not find any significant differences in allele, genotype and haplotype frequencies between cases and non-cases for either of the two genes. Moreover, the search for interactions between SNPs located in different genes, including 5 IL18 SNPs previously studied in the MORGAM project, and between SNPs and environmental factors remained unfruitful. CONCLUSION: Our analysis suggests that the variability of IL18R1 and IL18RAP genes are unlikely to contribute to modulate the risk of CVD.

C-reactive protein is a determinant of first-ever stroke: prospective nested case-referent study.

BACKGROUND AND PURPOSE: C-reactive protein (CRP) is a determinant of stroke, but there are no prospective studies on CRP and first ischemic stroke divided into etiologic subtypes. Our primary aim was to study CRP as a determinant of ischemic stroke, classified according to Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria, and intracerebral hemorrhage (ICH) in a prospective study. A secondary aim was to study the relationship between the 1444C>T polymorphism, plasma levels of CRP and stroke. METHODS: The study was a prospective population-based case-referent study nested within the Northern Sweden Cohorts. We defined 308 cases of ischemic stroke and 61 ICH. Two controls for each case were defined from the same cohort. RESULTS: The OR for the highest (>3 mg/l) versus lowest group (<1 mg/l) of CRP was 2.58 (95% CI 1.74-3.84) for ischemic stroke and 1.63 (95% CI 0.67-3.93) for ICH. In a multivariate model including traditional risk factors, CRP remained associated with ischemic stroke (OR 2.06; 95% CI 1.29-3.29). Small-vessel disease was associated with CRP in the multivariate model (OR 3.88; 95% CI 1.10-13.7). The CRP 1444 (CC/CT vs. TT) polymorphism was associated with plasma levels of CRP but neither with ischemic stroke nor with ICH. CONCLUSIONS: This prospective population-based study shows that CRP is significantly associated with the risk of having a first ischemic stroke, especially for small-vessel disease. No significant associations were found between the CRP 1444C>T polymorphism and any stroke subtype.

Genetic polymorphisms in the renin-angiotensin system confer increased risk of stroke independently of blood pressure: a nested case-control study.

OBJECTIVE: The renin-angiotensin system has a pathophysiological role in cardiovascular disease through a variety of processes. Polymorphisms in involved genes have been described and implicated in stroke. The aim of this study was to investigate two polymorphisms in two genes in the renin-angiotensin system and the risk of stroke. DESIGN: A nested case-control study using baseline data obtained from population-based surveys in northern Sweden was performed. There were 275 individuals without major concomitant disease who suffered a first ever stroke during follow-up and 549 controls matched for age, sex and domicile. METHODS: Blood samples obtained at baseline were analyzed for potential risk factors including the A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene and the functional insertion/deletion polymorphism of the angiotensin-converting enzyme gene. RESULTS: Individuals with the AA genotype of the AT1R gene were at increased risk of ischemic stroke (odds ratio = 1.60; P = 0.005) compared with those with the AC and CC genotypes. The D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with a higher risk of stroke (odds ratio = 1.58; P = 0.014). CONCLUSION: In this prospective study, there was an association between A1166C polymorphism in the angiotensin II receptor gene and ischemic stroke. We also replicated previous observations that the D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with increased risk of stroke. The observed elevated stroke risks conferred by these two polymorphisms are independent of each other and common risk factors such as blood pressure, diabetes, smoking and high cholesterol levels.

Genome-wide linkage scan of common stroke in families from northern Sweden.

BACKGROUND AND PURPOSE: Taking advantage of low genetic variations in northern Sweden, we performed a genome-wide linkage scan to investigate the susceptibility loci for common forms of stroke. METHODS: Fifty-six families, containing multiple cases of stroke and whose data had been previously used to replicate linkage to the phosphodiesterase 4D locus on chromosome 5q, were genotyped in a genome-wide scan. Fine mapping was performed, and subsequently 53 additional families from the same region were genotyped over the candidate regions. RESULTS: Linkage calculations were performed by using 3 different disease models, from a very broad (all stroke cases defined by World Health Organization MONICA criteria) to a narrower (ischemic stroke only) stroke phenotype. With all models, nonparametric multipoint linkage analysis yielded allele-sharing log of the odds (LOD) scores >1.2 at 9 locations: 1p34, 5q13, 7q35, 9q22, 9q34, 13q32, 14q32, 18p11, and 20q13. The highest allele-sharing LOD scores were obtained on chromosomes 5q (previously reported), 1p (LOD=2.09), and 18p (LOD=2.14). Fine mapping resulted in increased allele-sharing LOD scores for chromosome 5q (previously reported) and 9q22 (LOD=1.56), but all others decreased. Combining these initial results with a subsequent analysis of 53 additional families, we obtained the highest allele-sharing LOD scores on chromosomes 5q, 13q, and 18p, although none reached the initial genome-wide allele-sharing LOD scores. CONCLUSIONS: Genetic analysis of stroke in families from northern Sweden did not identify any new major stroke loci. This indicates that multiple minor susceptibility loci in addition to the previously known locus on chromosome 5 could contribute to the disease.

Estrogen receptor alpha gene polymorphisms and first-ever intracerebral hemorrhage.

BACKGROUND: Signaling through estrogen receptor alpha (ER alpha) regulates vasodilatation and atherogenesis. Since hypertension and atherosclerosis are major mechanisms in stroke development, we hypothesized that genetic variants of the ER alpha gene (ESR1) are determinants of future ischemic stroke or intracerebral hemorrhage (ICH). METHODS: In a population-based prospective nested case-control study, the relationships between ESR1 polymorphisms (c.454-397T>C and c.454-351A>G) and ischemic stroke and ICH were examined in univariate and multivariate models using conditional logistic regression, which included established risk factors.Definitive first-ever stroke events (n = 388), including 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 included. RESULTS: Carriers of the c.454-397T/T genotype had a significantly (p = 0.017) increased risk of ICH (OR 2.31, 95% CI 1.16-4.60) in a univariate analysis. This association persisted (OR 3.94, 95% CI 1.54-10.03), after adjustment for stroke risk determinants. Carriers of c.454-397T/T or c.454-397T/C genotypes had significantly (p = 0.002 and p = 0.004, respectively) higher mean systolic blood pressure (SBP), than carriers of c.454-397C/C, and a similar relationship was observed for diastolic blood pressure (DBP). The combinations of c.454-397T/T genotype and hypertension (OR 21.46, 95% CI 5.20-88.51), or high SBP (OR 18.17, 95% CI 4.91-67.31) or DBP (OR 11.94, 95% CI 3.75-38.03), were strongly associated with increased risk of ICH. CONCLUSIONS: In this population,the c.454-397T/T genotype associates with first-ever ICH, particularly in combination with hypertension. This implies that alterations in ER alpha-mediated signaling may be involved in the pathophysiology of this disease, with a putative impact on primary prevention.

Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3). CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population.

BACKGROUND AND PURPOSE: Recent Icelandic studies have demonstrated linkage for common forms of stroke to chromosome 5q12 and association between phosphodiesterase4D (PDE4D) and ischemic stroke. Using a candidate region approach, we wanted to test the validity of these findings in a different population from northern Sweden. METHODS: A total of 56 families with 117 affected individuals were included in the linkage study. Genotyping was performed with polymorphic microsatellite markers with an average distance of 4.5 cM on chromosome 5. In the association study, 275 cases of first-ever stroke were included together with 550 matched community controls. Polymorphisms were tested individually for association of PDE4D to stroke. RESULTS: Maximum allele-sharing lod score in favor of linkage was observed at marker locus D5S424 (lod score=2.06; P=0.0010). Conditional logistic regression calculations revealed no significant association of ischemic stroke to the defined at-risk allele in PDE4D (odds ratio, 1.1; 95% confidence interval, 0.84 to 1.45). A protective effect may though be implied for 2 of the polymorphisms analyzed in PDE4D. CONCLUSIONS: Using a candidate region approach in a set of stroke families from northern Sweden, we have replicated linkage of stroke susceptibility to the PDE4D gene region on chromosome 5q. Association studies in an independent nested case-control sample from the same geographically located population suggested that different alleles confer susceptibility/protection to stroke in the Icelandic and the northern Swedish populations.

Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of stroke: replicated findings in two nested case-control studies based on independent cohorts.

BACKGROUND AND PURPOSE: Impaired fibrinolytic function secondary to elevated plasminogen activator inhibitor-1 (PAI-1) levels has been implicated in ischemic stroke. PAI-1 levels are determined by genetic factors and environmental factors, triglyceride levels in particular. The aim of this study was to investigate the common functional 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene and the risk of stroke. METHODS: A nested case-control study design was applied, using baseline data for 2 independent cohorts obtained at population-based surveys in northern Sweden. In study A, there were 113, and in study B, there were 275 individuals without major concomitant disease at baseline who later experienced a first-ever stroke. Blood samples obtained at baseline were analyzed for potential risk factors, including the 4G/5G polymorphism of the PAI-1 gene. RESULTS: The 4G allele of the PAI-1 polymorphism was associated with an increased risk of future ischemic stroke in both studies (odds ratio [OR] of 4G homozygosity, 1.87; 95% CI, 1.12 to 3.15 in study A; OR of 4G homozygosity, 1.56; 95% CI, 1.12 to 2.16 in study B). Individuals with the combination of hypertriglyceridemia and 4G homozygosity were at the greatest risk of developing stroke. Multiple logistic regression analysis identified 4G homozygosity, systolic blood pressure, and diabetes as independent predictors of ischemic stroke. CONCLUSIONS: Identical findings in 2 independent studies strongly suggest a true and clinically important association between PAI-1 4G/5G genotype and risk of future ischemic stroke. The observed modification of the genotype effect by triglycerides may be interpreted as a gene-environment interaction.

Polymorphisms of IL-1beta, IL-1Ra, and TNF-alpha genes: a nested case-control study of their association with risk for stroke.

Certain alleles of cytokine genes interleukin-1 beta (IL-1beta), interleukin-1 receptor antagonist (IL-1Ra), and tumor necrosis factor alpha (TNF-alpha) are correlated with increased production of the proteins. The aim of this study was to investigate polymorphisms of these genes and their possible correlation with the development of stroke. This matched case-control study was nested within the population-based Västerbotten Intervention Program (VIP) cohort and the Northern Sweden World Health Organization MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Diseases) cohort, based on individuals who were free from cardiovascular events when the cohorts were established. After an average period of 34.1 months, 113 individuals developed stroke and to each case 2 individuals not suffering from cardiovascular events were matched to serve as controls. Polymerase chain reaction amplification was used to analyze genetic polymorphisms. There was no association between polymorphic sites of the IL-1beta and IL-1Ra genes and stroke. Carriage of haplotype A2+IL-1beta/A2+IL-1Ra was significantly increased in normotensive cases (23.1%) compared with normotensive controls (8.9%) (odds ratio [OR] = 3.07; P = .045). In hypertensive male cases, there was an association between the A1A1 genotype of TNF-alpha and risk of stroke (OR = 2.46; P = .034). Our findings indicate an association between allele A1 of the TNF-alpha NcoI polymorphism and stroke in hypertensive male cases, as well as an association between haplotype A2+IL-1beta/A2+IL-1Ra and stroke in normotensive cases.

A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease.

BACKGROUND: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). METHODS AND RESULTS: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3)). CONCLUSIONS: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.

Polymorphisms at the osteoprotegerin and interleukin-6 genes in relation to first-ever stroke.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.