Early-onset Ischemic Stroke Research Articles

Exome Array Analysis of Early-Onset Ischemic Stroke.

The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease. Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases. Gene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10-6). Pathway analysis of the top 517 genes (P<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P<2.05×10-7), several were near, including an intronic variant in LEXM (rs7549251; P=4.08×10-7) and an exonic variant in TRAPPC11 (rs67383011; P=5.19×10-6). Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.

Sickle Cell Trait and Risk of Ischemic Stroke in Young Adults.

Approximately 8% of Blacks have sickle cell trait (SCT), and there are conflicting reports from recent cohort studies on the association of SCT with ischemic stroke (IS). Most prior studies focused on older populations, with few data available in young adults. A population-based case-control study of early-onset IS was conducted in the Baltimore-Washington region between 1992 and 2007. From this study, 342 Black IS cases, ages 15 to 49, and 333 controls without IS were used to examine the association between SCT and IS. Each participant's SCT status was established by genotyping and imputation. For analysis, χ2 tests and logistic regression models were performed with adjustment for potential confounding variables. Participants with SCT (n=55) did not differ from those without SCT (n=620) in prevalence of hypertension, previous myocardial infarction, diabetes mellitus, and current smoking status. Stroke cases had increased prevalence in these risk factors compared with controls. We did not find an association between SCT and early-onset IS in our overall population (odds ratio=0.9 [95% CI, 0.5-1.7]) or stratified by sex in males (odds ratio=1.26 [95% CI, 0.56-2.80]) and females (odds ratio=0.67 [95% CI, 0.28-1.69]). Our data did not find evidence of increased risk of early-onset stroke with SCT.

Ischemic Stroke in Young Adults.

This article reviews current knowledge on epidemiology, risk factors and causes, diagnostic considerations, management, and prognosis of ischemic stroke in young adults (those 55 years old and younger). The incidence of ischemic stroke in young adults has been increasing since the 1980s, which has occurred in parallel with increasing prevalence of vascular risk factors and substance abuse among the younger population. Young adults have a considerably wider range of risk factors than older patients, including age-specific factors such as pregnancy/puerperium and oral contraceptive use. Behavioral risk factors such as low physical activity, excess alcohol consumption, and smoking are factors as well. More than 150 identified causes of early-onset ischemic stroke exist, including rare monogenic disorders. Several recent advances have been made in diagnosis and management of stroke in young adults, including molecular characterization of monogenic vasculitis due to deficiency of adenosine deaminase 2 and transcatheter closure of patent foramen ovale for secondary prevention. Compared with the background population of the same age and sex, long-term mortality in patients remains fourfold higher with cardiovascular causes underlying most of the deaths. The cumulative rate of recurrent stroke extends up to 15% at 10 years. Patients with atherosclerosis, high-risk sources of cardioembolism, and small vessel disease underlying their stroke seem to have the worst prognosis regarding survival and recurrent vascular events. Young stroke survivors also often have other adverse outcomes in the long term, including epilepsy, pain, cognitive problems, and depression. Systematic identification of risk factors and causes and the motivation of patients for long-term prevention and lifestyle changes are of utmost importance to improve the prognosis of early-onset ischemic stroke.

Abstract 152: Genome-wide Association Study of Early-Onset Ischemic Stroke Identifies Novel Locus on Chromosome 12 Near BCL7A/MLXIP

Introduction: Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets relevant to later-onset disease. Few studies have investigated the role of common genetic variation in the etiology of early-onset ischemic stroke (IS). Methods: We performed a GWAS meta-analysis of 38 studies from 10 countries, comprised of 5,847 IS cases of European ancestry under age 60 and 32,533 controls. Results: We identified two genome-wide significant (p&lt; 5 x 10 -8 ) loci (see Figure). The ABO locus has previously been associated with venous thrombosis and ischemic stroke in predominantly older adults, but the effect size of our top SNP (OR 1.18; p = 9.1 x 10 -12 ) is larger than the effect size for this same SNP in MEGASTROKE (OR: 1.05; p = 6.5 x 10 -5 ). The lead SNP at the BCL7A/MLXIP locus is a novel GWAS finding for stroke (OR 1.14, 95% CI 1.08-1.19; p = 1.7 x 10 -8 ) and is noteworthy because of prior reports linking SNPs in these genes to BMI and blood pressure. Conclusions: We identified a novel locus that is near variants associated with BMI and blood pressure. Further studies are needed to confirm this locus, examine subtype specificity, and determine its function. The larger effect size observed at the ABO in this early-onset IS sample compared to older-onset IS samples is consistent with a larger role for prothrombotic mechanisms in early-onset IS.

P3718Identification of nine genes as novel susceptibility loci for early-onset ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage

Abstract Background Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), a heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders in Japanese individuals remain to be identified definitively. Purpose The purpose of the study was to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in Japanese. We have now performed exome-wide association studies (EWASs) in early-onset subjects with these conditions and corresponding controls. Methods A total of 6649 individuals aged ≤65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6224 individuals (450 subjects with ischemic stroke, 5774 controls) or 6179 individuals (261 subjects with ICH, 176 subjects with SAH, 5742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of &lt;0.05 for statistical significance of association. Results The relation of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher's exact test, and 31 SNPs were significantly (FDR &lt;0.05) associated with ischemic stroke. The relation of allele frequencies of 31,253 or 30,970 SNPs to ICH or SAH, respectively, was examined with Fisher's exact test, and six or two SNPs were significantly (FDR &lt;0.05) associated with ICH or SAH, respectively. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension and diabetes mellitus revealed that 12 SNPs were significantly [P &lt;0.0004 (Bonferroni's correction, 0.05/124)] related to ischemic stroke. Similar analysis with adjustment for age, sex, and the prevalence of hypertension revealed that six or two SNPs were significantly [P &lt;0.0016 (0.05/32)] related to ICH or SAH, respectively. After examination of linkage disequilibrium of identified SNPs and results of previous genome-wide association studies, we have newly identified HHIPL2, CTNNA3, LOC643770, UTP20, and TRIB3 as susceptibility loci for ischemic stroke, DNTTIP2 and FAM205A as susceptibility loci for ICH, and FAM160A1 and OR52E4 as such loci for SAH. Conclusion We have thus newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.

Impact Of Sirt6 And Sirt7 Genetic Polymorphisms On Risk Of Early-Onset Ischemic Stroke

Background and Aims: SIRT6 and SIRT7 have been implicated in the repression of inflammation, oxidative stress, and aging. Polymorphisms in SIRT6 and SIRT7 may be important for increasing carotid plaque burden and promoting atherosclerosis. The aim of this study was to investigate the association of SIRT6 and SIRT7 genetic polymorphisms with risk of early-onset ischemic stroke in Taiwan.

Significant Associations Of Nrf1 Genetic Polymorphisms With The Risk Of Early-Onset Ischemic Stroke

Background and Aims: Nuclear respiratory factor 1 (NRF1) has been reported to regulate mitochondrial biogenesis. Mitochondrial dysfunction would result in increased oxidative stress and inflammation. Eventually, mitochondrial dysfunction may lead to the development of atherosclerosis and ischemic stroke. In this study, we aim to investigate the relationship between the genetic polymorphisms of NRF1 and the risk of early-onset ischemic stroke in Taiwan.

Sickle Cell Trait and Risk for Early-Onset Ischemic Stroke (P4.3-018)

Sickle Cell Trait and Risk for Early-Onset Ischemic Stroke (P4.3-018)

Abstract WP267: Lower Left Ventricular Longitudinal Contraction is Associated With Early-onset Cryptogenic Ischemic Stroke

Introduction: At least one third of ischemic strokes at a young age (&lt;50 years) remain cryptogenic after complete diagnostic work-up. We hypothesized that based on their neuroimaging presentation majority of these strokes may originate from the heart and that advanced cardiac ultrasound imaging might reveal hints from underlying left ventricular pathology. Methods: We prospectively recruited 26 patients aged 18-49 with cryptogenic ischemic stroke and 26 age- and sex-matched stroke-free controls. We examined all participants with transthoracic echocardiography and analyzed the left ventricular (LV) ejection fraction (LVEF) with 3-dimensional volumetry. We used speckle-tracking imaging in three planes (apical 4-chamber, 3-chamber and 2-chamber views), to determine LV global longitudinal strain (GLS), and only patients with visibility allowing analysis of all 18 LV segments were included. Tissue Doppler velocity imaging was used to determine the mitral annular plane systolic excursion (MAPSE), as a mean of six annular points in the 3 apical planes. Measurements were normally distributed and group-level differences were analyzed by paired-samples T-tests. Results: A total of 26 pairs had adequate visibility to examine LVEF, 20 to assess GLS, and 25 to examine MAPSE. There was no significant difference in LV ejection fraction between patients and controls (mean 59.0 vs 61.4 (%); P=0.300). LV global longitudinal strain was significantly lower in patients compared with controls (mean 18.0 vs 19.9 (%); P=0.012). Furthermore, MAPSE was lower in patients (mean 13.3 vs 14.2(mm); P=0.044). Conclusion: Young patients with cryptogenic ischemic stroke had lower longitudinal LV contraction than stroke-free individuals of the same age—without differences in LVEF—suggesting that subclinical LV systolic dysfunction may play a role in cryptogenic strokes.

Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke.

Background and purposePolymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin−protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication.MethodsDiscovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15–49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case–control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base.ResultsAmong GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity.ConclusionPROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.

Significant association of SIRT1 rs12765828 T allele with risk of early-onset ischemic stroke

Significant association of SIRT1 rs12765828 T allele with risk of early-onset ischemic stroke

Identification of nine genes as novel susceptibility loci for early-onset ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage.

Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies (GWASs) have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders remain to be identified definitively. We performed exome-wide association studies (EWASs) to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in early-onset subjects with these conditions. A total of 6,649 individuals aged ≤65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6,224 individuals (450 subjects with ischemic stroke, 5,774 controls) or 6,179 individuals (261 subjects with ICH, 176 subjects with SAH, 5,742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association. The association of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher's exact test, and 31 SNPs were significantly (FDR <0.05) associated with ischemic stroke. The association of allele frequencies of 31,253 or 30,970 SNPs to ICH or SAH, respectively, was examined with Fisher's exact test, and six or two SNPs were significantly associated with ICH or SAH, respectively. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension and diabetes mellitus revealed that 12 SNPs were significantly [P<0.0004 (0.05/124)] related to ischemic stroke. Similar analysis with adjustment for age, sex, and the prevalence of hypertension revealed that six or two SNPs were significantly [P<0.0016 (0.05/32)] related to ICH or SAH, respectively. After examination of linkage disequilibrium of identified SNPs and results of previous GWASs, we identified HHIPL2, CTNNA3, LOC643770, UTP20, and TRIB3 as susceptibility loci for ischemic stroke, DNTTIP2 and FAM205A as susceptibility loci for ICH, and FAM160A1 and OR52E4 as such loci for SAH. Therefore, to the best of our knowledge, we have newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.

Abstract WP160: Exome Array Analysis of Early-Onset Ischemic Stroke

Background: The genetic architecture of ischemic stroke (IS) is poorly understood and may differ by age of onset. To identify stroke susceptibility variants, genes and pathways for IS in young adults, we genotyped participants in the Genetics of Early-Onset Stroke (GEOS) with an exome array to interrogate the protein-coding portion of genes. Methods: The GEOS Study was initiated as a biracial population-based study of cases with first-ever ischemic stroke 15 to 49 years of age (n=828) and controls (n=850). All participants had prior GWAS and underwent Illumina exome-chip genotyping. Mixed model regression in EMMAX was conducted to calculate variant-specific associations using pooled European-Caucasians (EUR) and African-Americans (AA) samples, with population structure controlled by kinship matrix relationships using GWAS data. Gene-based burden testing and meta-analysis were performed using seqMeta with ethnicity-specific GWAS PCs. In both analyses covariates included age and gender. This was followed by Ingenuity Pathway Analyses on the top genes. Results: While no individual SNPs reached chip-wide significance (3x10 -7 ), several were near, including one exonic variant in TRAPPC11 (rs67383011, p=1.7*10 -6 ). Gene-based burden testing using a filter (cumulative MAC&gt;40, # of SNPs per gene≥2, missingness=0) was performed on 6934 genes in EURs and 9423 genes in AAs. While several interesting genes were identified, notably in methylation pathways, none reached statistical significance in the ethnicity-stratified (p=3.3*10 -4 ) or meta-analyses (p=1.1*10 -4 ). Pathway analyses on the top 448 genes (p&lt;0.05) from the gene-based results identified several metabolism and signaling pathways, including: (1) those implicated in the risk for vascular diseases: glucose metabolism, lipid metabolism, and inflammation (leukocyte extravasation, IL-17A); (2) neurotrophic signaling: CTNF and NGF, and; (3) neurotransmitter and neuroactive compound signaling: GABA receptor signaling and tryptophan degradation pathways. Efforts in additional data sets to replicate these findings are ongoing. Conclusion: Exome-based analyses in the setting of early-onset stroke is a promising methodology to identify novel genetic risk variants, loci and pathways.

Association of GWAS-Reported Variant rs11196288 near HABP2 with Ischemic Stroke in Chinese Han Population.

A recent genome-wide association analysis identified a novel single nucleotide polymorphism locus on chromosome 10q25.3 (rs11196288, near HABP2) associated with the risk of early-onset ischemic stroke (IS) in European population, but not with late-onset IS. However, the role of this genome-wide association study (GWAS)-reported variant in ischemic stroke in Chinese Han population remained unknown. In our study, 389 adult ischemic stroke patients with an age of onset <60years and 389 matched healthy controls were enrolled to investigate association of rs11196288 genotypes with early-onset ischemic stroke and its subtypes; the association was further examined in another independent population consisting of 349 ischemic stroke patients with an age of onset ≧60years and 349 matched healthy individuals. Logistic regression analysis showed no significant association between rs11196288 and early-onset ischemic stroke (IS), large artery atherosclerotic (LAA) stroke, or small vessel disease (SVD) stroke (all P>0.050). Nevertheless, in subgroup analysis of the older population, rs11196288 presented significant effect on late-onset SVD stroke susceptibility in the dominant model (GG/GA vs AA, OR 1.70; 95%CI 1.02 to 2.85; P=0.042). The results indicated that the role of rs11196288 polymorphism in ischemic stroke susceptibility in Chinese Han population may be different from that in European. Larger studies with diverse populations are warranted to confirm and extend our findings.

Cocaine Use and Risk of Ischemic Stroke in Young Adults.

Although case reports have long identified a temporal association between cocaine use and ischemic stroke (IS), few epidemiological studies have examined the association of cocaine use with IS in young adults, by timing, route, and frequency of use. A population-based case-control study design with 1090 cases and 1154 controls was used to investigate the relationship of cocaine use and young-onset IS. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between cocaine use and IS with and without adjustment for potential confounders. Ever use of cocaine was not associated with stroke with 28% of cases and 26% of controls reporting ever use. In contrast, acute cocaine use in the previous 24 hours was strongly associated with increased risk of stroke (age-sex-race adjusted odds ratio, 6.4; 95% confidence interval, 2.2-18.6). Among acute users, the smoking route had an adjusted odds ratio of 7.9 (95% confidence interval, 1.8-35.0), whereas the inhalation route had an adjusted odds ratio of 3.5 (95% confidence interval, 0.7-16.9). After additional adjustment for current alcohol, smoking use, and hypertension, the odds ratio for acute cocaine use by any route was 5.7 (95% confidence interval, 1.7-19.7). Of the 26 patients with cocaine use within 24 hours of their stroke, 14 reported use within 6 hours of their event. Our data are consistent with a causal association between acute cocaine use and risk of early-onset IS.

TPP1 RS2555173 A allele significantly associated with the risk of early-onset ischemic stroke

TPP1 RS2555173 A allele significantly associated with the risk of early-onset ischemic stroke

Genetics of ischemic stroke in young adults.

Ischemic stroke (IS) is a complex genetic disorder caused by a combination of multiple genetic and environmental factors. Despite the enormous burden associated with stroke, we know little about its underlying pathogenesis. Unlike many other common age-related diseases (eg, diabetes mellitus and heart disease), there are no good preclinical biomarkers that can provide a foothold for studying the molecular and physiological processes leading up to a stroke event. Because a genetic predisposition to stroke is widely acknowledged, 1 current strategy to study stroke pathogenesis is to start by identifying genes associated with stroke and then to investigate the function of these genes. Toward this goal, numerous candidate gene and genome-wide association studies (GWAS) of stroke have been performed. A strategy successfully used to identify genetic determinants of other common complex diseases has been to focus on subtypes, such as early-onset disease which may be enriched for high-penetrance variants. Variants that are highly penetrant or highly predictive of diseases may be easier to detect and also produce useful insights about disease pathways, even if the same variants play a lesser role in late-onset disease. The goal of this review is to assess the evidence for a genetic basis to early-onset IS. We mainly focus on early-onset stroke occurring between the ages of 15 and 49 years but specify age ranges considered by other studies as they are discussed. We begin with an epidemiological characterization of early-onset stroke, comparing and contrasting risk factors and the heterogeneity of stroke subtypes between early- and late-onset IS. We then review the evidence for a genetic basis of early-onset stroke, contrasting where possible the magnitude of the genetic contribution in younger versus older IS through familial aggregation studies. Finally, we review current status and prospects for identifying genes contributing to susceptibility to early-onset stroke. Throughout the …

Abstract W P152: Obesity Increases Risk of Ischemic Stroke in Young Adults

Background and Purpose: Increased body mass index (BMI) has been associated with ischemic stroke in older populations, but its association with stroke in younger populations, in whom the life-long burden of obesity-associated risk factors is presumably lower, is not known. In light of the current obesity epidemic and evidence for an increasing incidence of stroke in young adults, this topic deserves further investigation. Methods: We investigated the association between BMI and early-onset ischemic stroke using data from a case-control study in the greater Baltimore-Washington area. Cases ages 15-49 (n=1201) and age-gender-race balanced controls (n=1154) were recruited between 1992 and 2008. Presence of hypertension and diabetes was obtained by interview. Study participants were placed into CDC-defined weight categories of underweight (BMI &lt; 18.5 kg/m2), normal weight (18.5 to 24.9), overweight (25.0 to 29.9), and obese (BMI ≥ 30 kg/m2). Logistic regression modeling was used to evaluate the association between BMI and ischemic stroke. Results: Unadjusted analysis indicated a significant association between BMI and ischemic stroke; the overweight group had an OR of 1.2 (95% CI 1.0- 1.5) and the obese group had an OR of 1.8 (95% CI 1.5- 2.2) when compared to the normal weight reference group. But these heightened risks were highly attenuated after further adjustment for hypertension and diabetes mellitus. There was no significant difference in stroke risk between the overweight and normal weight groups. Obese males (OR of 1.3, 95% CI 0.9- 1.8), but not obese females, had an increased stroke risk compared to their normal weight counterparts. Conclusion: We observed a moderate association between BMI and early-onset ischemic stroke that increased in a dose-response fashion. The attenuation of stroke risk in high BMI groups following adjustment for hypertension and diabetes suggest that the effects of obesity may be mediated in part through these and other obesity-related conditions.

Association of a single nucleotide polymorphism of the NPR3 gene promoter with early onset ischemic stroke in an Italian cohort

BackgroundNPR3, located on human chromosome 5 (5p14–p13), encodes the natriuretic peptide receptor type C (NPR-C) that is mainly known as the natriuretic peptide clearance receptor. Involvement of NPR3 in susceptibility to cardiovascular diseases, i.e. hypertension, has been previously shown. With regard to stroke predisposition, evidence for a potential role of genetic variation within or nearby NPR3 has been suggested by a previous genome wide association study. MethodsWe investigated the contribution to early-onset ischemic stroke susceptibility of the NPR3 −55 C>A transition by genotyping this variant in an Italian cohort of 368 cases and 335 controls. ResultsIn a multivariable logistic regression analysis adjusting for age, gender, hypertension, hypercholesterolemia, smoking habit and diabetes, a significant association of the −55 AA genotype with stroke was observed (OR=3.2, 95% CI 1.2–8.3, p=0.016). Remarkably, the polymorphism remained associated with stroke after adjusting for hypertensive status. ConclusionOur observation obtained in an Italian cohort of early onset ischemic strokes suggests that a NPR3 promoter gene variant could have a role on cerebrovascular disease susceptibility.

Association of the functional KL-VS variant of Klotho gene with early-onset ischemic stroke

Genetic variants of Klotho have been reported to be associated with human longevity and atherosclerotic vascular events and risk factors. However, very few studies have explored their association with ischemic stroke. We hypothesized that the functional KL-VS and the exonic C1818T variants of Klotho gene may be associated with ischemic stroke in Indian population. We enrolled a total of 460 patients with ischemic stroke and 574 age- and gender-matched controls for the study. Genotyping was done by polymerase chain reaction and restriction fragment length polymorphism. Contrary to other Asian reports, KL-VS variant was polymorphic in our population, with a frequency distribution similar to that of Caucasians. The frequency distribution of the C1818T variant was similar to previously reports in Asians. A differential effect of age on association of Klotho KL-VS variant with ischemic stroke was observed. In subjects aged ⩽ 40 years, the KL-VS homozygotes, 352FF and 352VV, had ∼1.5-fold (OR = 1.57; 95% CI: 1.02–2.40, p = 0.038) and ∼3-fold (OR = 3.29; 95%CI: 1.02–10.56, p = 0.046) higher risk of stroke compared to heterozygotes, whereas in the older group (aged > 40 years) no significant association was observed. The C1818T variant was not associated with ischemic stroke. We conclude that KL-VS homozygosity could contribute to early-onset stroke in India. Larger studies in other ethnic populations are warranted to determine the role of these gene variants in the etiology of stroke occurring in the young.