Christina Kourkoulis

Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration.

Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.

Oral Anticoagulation and Functional Outcome after Intracerebral Hemorrhage

Oral anticoagulation treatment (OAT) resumption is a therapeutic dilemma in intracerebral hemorrhage (ICH) care, particularly for lobar hemorrhages related to amyloid angiopathy. We sought to determine whether OAT resumption after ICH is associated with long‐term outcome, accounting for ICH location (ie, lobar vs nonlobar).

Recommendations From the International Stroke Genetics Consortium, Part 2: Biological Sample Collection and Storage

The revolution in human genetics, catalyzed by the sequencing of the human genome in 2003 and the development of genome-wide genotyping technologies, has led to the identification of >2000 trait-associated genetic variants. Because most of these variants have individually small effects on disease risk, successful gene discovery efforts have required large sample sizes (involving thousands, tens, or hundreds of thousands of cases and controls) to achieve sufficient study power. Amassing such sample sizes has depended on international collaboration on a scale never seen before in human genetics or even in clinical research. Disease-specific consortia bringing together many individual sites and collaborators have now evolved for many major diseases. Each consortium has faced with ≥2 fundamental questions: how to assemble a study sample of sufficient size, homogeneity, and phenotypic quality and how to retain and analyze, sometimes repeatedly over several years, biological samples from enrolled subjects. The International Stroke Genetics Consortium (ISGC) has addressed these 2 challenges by taking into account the nature of the disease—stroke occurs suddenly with high case fatality (≤251 per 100 000; 5.9 million of 53 million reported deaths in 2010)1,2 and develops through multiple biological mechanisms. Because the stroke community consists of clinicians and investigators from across the world practicing in a range of environments with varied resources and constraints, the ISGC has developed processes that allow maximum flexibility while maintaining standardization, reliability, and quality. A central tenet of the consortium involves transparency and trust, without which large-scale collections and studies would not be possible. The growing collection of stroke samples created at the Massachusetts General Hospital under the auspices of the ISGC includes physical samples for ≈5000 cases and 4500 controls from >20 institutions in Europe, North America, South America, Australia, and Asia. …

Cerebrovascular Disease Knowledge Portal: An Open-Access Data Resource to Accelerate Genomic Discoveries in Stroke

Stroke is a leading cause of death and disability across the globe, affecting 15 million people each year.1 Stroke represents an archetypical common complex disease with both genetic and environmental determinants2,3 playing a role in its occurrence. The proportion of stroke risk that can be attributed to genetic variation has been estimated to be 30%.4–6 Although this estimate provides an indication of the overall importance of genetic variation in stroke, the key to developing new treatment strategies is to identify the specific genetic variants (mutations) that modify an individual’s risk of stroke. Genetic association studies (GWAS) seek to identify these variants and link them to specific genes, which, in turn, point to specific cellular processes to become therapeutic targets for drug development. In addition, newly discovered genetic risk loci can be used to improve existing phenotyping systems, enhance prediction tools aimed to identify high-risk patients, and aid in establishing causality for associations involving nongenetic exposures. Successfully identifying the range of genetic variants that cause stroke and leveraging these discoveries to reduce the suffering caused by this condition requires overcoming several key challenges. First, stroke is the final result of multiple different pathological processes and must, therefore, be accurately subtyped to identify underlying biology. Second, because large number of cases and controls are required to identify the culprit genetic variants, tens (even hundreds) of thousands of cases must be studied, requiring the collaboration of multiple centers, many of which use different ascertainment methods and criteria. Third, because genetic variation differs across the globe, representative populations from all ethnicities must be studied. Finally, all these data must be shared rapidly and widely to ensure the most expedited progress in research and enable investigators with the brightest ideas to utilize these data provided by patients to …

Sex differences in intracerebral hemorrhage expansion and mortality

BACKGROUND AND OBJECTIVE Due to conflicting results in multiple studies, uncertainty remains regarding sex differences in severity and mortality after intracerebral hemorrhage (ICH). We investigated the impact of sex on ICH severity, expansion, and mortality. METHODS We analyzed prospectively collected ICH patients and assessed clinical variables and mortality rate. Mediation analyses were used to examine associations between sex and mortality and sex and hematoma expansion. RESULTS 2212 patients were investigated, 53.5% male. Men with ICH were younger (72 vs. 77years), had greater smoking and alcohol use, and were more likely to have hypertension, diabetes, hypercholesterolemia and coronary artery disease (all p<0.05). Lobar hemorrhages were more frequent in women (47.6% vs 38.4%, p<0.001). Male sex was a risk factor for hematoma expansion (Odd Ratio (OR) 1.7, 95% confidence interval (CI) 1.15-2.50, p=0.007). Multivariable analysis found that male sex was independently associated with 90-day mortality (OR 2.15 (95% CI 1.46-3.19), p<0.001), and one-year mortality (Hazard Ratio 1.28 (95% CI: 1.09-1.50), p=0.003). Early hematoma expansion mediated a portion of the association between sex and mortality (mediation p=0.02). CONCLUSIONS Men with ICH experience a higher risk of both expansion and early and late mortality, even after controlling for known risk factors. Further research is needed to explore the biological mechanisms underlying these observed differences.

17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

Background and Purpose— Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. Methods— We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10−8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0–2 versus 3–6) modified Rankin Scale using ordinal and logistic regression, respectively. Results— The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: &bgr;, 1.84; SE, 0.32; P=4.4×10−8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: &bgr;, 0.95; SE, 0.17; P=4.3×10−8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10−9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045). Conclusions— We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

Hypertension and intracerebral hemorrhage recurrence among white, black, and Hispanic individuals

Objective To clarify whether recurrence risk for intracerebral hemorrhage (ICH) is higher among black and Hispanic individuals and whether this disparity is attributable to differences in blood pressure (BP) measurements and their variability. Methods We analyzed data from survivors of primary ICH enrolled in 2 separate studies: (1) the longitudinal study conducted at Massachusetts General Hospital (n = 759), and (2) the ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) study (n = 1,532). Participants underwent structured interview at enrollment (including self-report of race/ethnicity) and were followed longitudinally via phone calls and review of medical records. We captured systolic BP (SBP) and diastolic BP measurements, and quantified variability as SBP and diastolic BP variation coefficients. We used multivariable (Cox regression) survival analysis to identify risk factors for ICH recurrence. Results We followed 2,291 ICH survivors (1,121 white, 529 black, 605 Hispanic, and 36 of other race/ethnicity). Both black and Hispanic patients displayed higher SBP during follow-up (p < 0.05). Black participants also displayed greater SBP variability during follow-up (p = 0.032). In univariable analyses, black and Hispanic patients were at higher ICH recurrence risk (p < 0.05). After adjusting for BP measurements and their variability, both Hispanic (hazard ratio = 1.51, 95% confidence interval 1.14–2.00, p = 0.004) and black (hazard ratio = 1.98, 95% confidence interval 1.36–2.86, p < 0.001) patients remained at higher risk of ICH recurrence. Conclusion Black and Hispanic patients are at higher risk of ICH recurrence; hypertension severity (average BP and its variability) does not fully account for this finding. Additional studies will be required to further elucidate determinants for this health disparity.