Letter by Zheng Regarding Article, “Genome-Wide Polygenic Score and the Risk of Ischemic Stroke in a Prospective Cohort: the Hisayama Study”

Introduction: Although family history studies in ischemic stroke support that genetic factors may be involved in the pathogenesis of two major subtypes of ischemia stroke: large-artery atherosclerosis (LAA) and small-vessel occlusion (SVO), it is still unclear which particular genetic factors contribute to LAA or SVO. Hypothesis: Because the etiology of ischemic stroke is heterogeneous, we hypothesize that genetic factors may vary by etiologic subtypes or ethnicities. Thus, we aim to identify genetic factors that contribute to LAA or SVO based on two independent Han Chinese populations. Methods: Novel genetic variants that predispose individuals to LAA and SVO were identified by genome-wide association study comprising of 824 individuals (including 444 LAA cases and 380 SVO cases) and 1,727 controls in a Han Chinese population residing in Taiwan. The LAA study was replicated in an independent Han Chinese population comprising of an additional 319 LAA cases and 1,802 controls. Results: In LAA cases, from two independent populations, we identified five single-nucleotide polymorphisms (SNPs), including SNP-1 (P = 3.10 х 10–8), SNP-2 (P = 4.00 х 10–9), SNP-3 (P = 3.57 х 10–8), SNP-4 (P = 1.76 х 10–8), and SNP-5 (P = 2.92 х 10–8), at one novel locus on chromosome 14q13.3 within PTCSC3 (encoding papillary thyroid carcinoma susceptibility candidate 3). In SVO cases, from the discovery stage, we identified two novel candidate susceptibility loci on chromosome 3p25.3 (SNP-6, P = 3.24 х 10–5) and chromosome 14 q31.1 (SNP-7, P = 2.58 х 10–4). Conclusions: For LAA, the newly identified SNPs within PTCSC3 gene were found to have genome-wide statistical significance (P < 5 х 10–8) and were shown to be located in a risk locus correlated with papillary thyroid carcinoma. Moreover, the genetic association between PTCSC3 gene and SVO was not identified, which suggested that PTCSC3 is a specific susceptibility locus for LAA. For SVO, we identified two novel candidate genetic loci which were valuable for replication by an independent population with SVO. In conclusion, our findings provide insights into the genetic basis of LAA and SVO, which may be applicable in the study of the pathogenesis of ischemic stroke and in the development of alternative therapeutic interventions.

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Modified 8Ds algorithm improves door-to-needle time in patients with acute ischemic stroke eligible for alteplase or thrombectomy: A prospective Cohort study

Journal of the Neurological Sciences ◽

10.1016/j.jns.2021.119710 ◽

2021 ◽

Vol 429 ◽

pp. 119710

Author(s):

Mojdeh Ghabaee ◽

Ghasem Farahmand ◽

Pargol Balali ◽

Hana Magrouni ◽

Fatemeh Alizadeh-Broujeni ◽

...

Keyword(s):

Cohort Study ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Prospective Cohort Study ◽

Prospective Cohort

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Abstract P629: Genome-Wide Association Study of Individuals of Native Hawaiian Ancestry Reveals Unique Genetic Risk Factors for Stroke and Myocardial Infarction

Stroke ◽

10.1161/str.52.suppl_1.p629 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Stacy C Brown ◽

Cameron Both ◽

Julian N Acosta ◽

Natalia Szejko ◽

Victor Torres ◽

...

Keyword(s):

Myocardial Infarction ◽

Ischemic Stroke ◽

Association Study ◽

Genome Wide Association Study ◽

Native Hawaiian ◽

European Ancestry ◽

Intronic Region ◽

Genome Wide ◽

A Genome ◽

Risk Locus

Background: Several genetic susceptibility risk loci for ischemic stroke have been identified. However, the relative dearth of genetic data from populations of non-European ancestry has the potential to create disparities in access to genomics-based precision medicine strategies. Individuals of Native Hawaiian ancestry represent a particularly understudied group in stroke genomics research despite facing high rates of cerebrovascular disease. Hypothesis: Genetic variants associated with stroke differ between Native Hawaiians and previously studied groups of predominantly European ancestry. Methods: We conducted a genome-wide (GW) association study of stroke and myocardial infarction (MI) in an adult population of Native Hawaiian ancestry, using data from the Multiethnic Cohort study (MEC). Genetic information was ascertained via genome-wide array genotyping using the AB OpenArray and TaqMan platforms followed by imputation to 1000 Genomes reference panels. We pursued replication of variants that were GW significant (p<5x10 -8 ) or yielded suggestive associations (p<5x10 -7 ) in the prior stroke GW association study MEGASTROKE. Results: We identified 2,104 individuals (1,089 [51.8%] female) of Native Hawaiian ancestry, including 173 cases and 1,931 controls. We identified one novel susceptibility risk locus at a narrow intronic region located at chromosome q26.2 (top associated SNP 3:169096251, OR 2.48, 95%CI 1.81-3.41; p=1.93x10 -8 ), overlying the MECOM gene. We also identified 9 other suggestive risk loci at p<5x10 -7 . When replicating in MEGASTROKE, q26.2 did not have available counterpart variants to analyze, and 3 out of 9 suggestive signals were associated with ischemic stroke subtypes at p<0.05. Conclusions: We report the first GW association study of ischemic stroke and myocardial infarction in a Native Hawaiian population. We identified one susceptibility risk locus at q26.2, located in a narrow intronic region of MECOM, a gene that codes for a histone-lysine N-methyltransferase that has transcriptional regulation and oncoprotein functions. The lack of available replication data for this locus in the large MEGASTROKE collaboration emphasizes the importance of developing genomic resources across ancestral groups.

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Abstract TMP50: A Polymorphism in HDAC9 was Associated with Large Vessel Stroke in the Vienna and German Stroke Studies

Stroke ◽

10.1161/str.44.suppl_1.atmp50 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

May M Luke ◽

Carmen H Tong ◽

Joseph J Catanese ◽

James J Devlin ◽

Christine Mannhalter ◽

...

Keyword(s):

Logistic Regression ◽

Ischemic Stroke ◽

Genome Wide Association Study ◽

Multinomial Logistic Regression ◽

Large Vessel ◽

Stroke Subtype ◽

German Study ◽

Genome Wide ◽

Increased Risk ◽

Large Vessel Stroke

Introduction The International Stroke Genetics Consortium (ISGC) and the Wellcome Trust Case Control Consortium 2 (WTCCC2) performed a large genome wide association study of ischemic stroke and its subtypes (large vessel stroke (LVD), small vessel stroke (SVD), cardioembolic stroke (CE)), and identified a polymorphism in HDAC9 (rs11984041) associated with the LVD subtype of ischemic stroke. Hypothesis We assessed the hypothesis that rs11984041 is associated with LVD in two additional studies. Methods The genotype of rs11984041 was determined for participants of the Vienna Study (815 controls, 122 LVD, 165 SVD, 202 CE) and of the German Study (1040 controls, 495 LVD, 230 SVD, 462 CE). The association of rs11984041 with LVD was assessed by logistic regression. Heterogeneity of the effect of rs11984041 on LVD, CE or SVD was assessed by testing the equality of the corresponding regression coefficients from a multinomial logistic regression model. Results Carriers of the minor (T) allele of rs11984041 (23.3% of LVD cases and 17.4% of controls), compared with noncarriers, had increased risk for LVD: the odds ratios (OR) were 1.92 (95%CI 1.25-2.96) for the Vienna Study and 1.33 (95%CI 1.02-1.74) for the German Study. Adjusting for covariates including sex, age, diabetes, and hypertension did not materially change the ORs. Heterogeneity of the effects of rs11984041 on LVD vs CE was significant in the Vienna Study (p = 0.009) and in the German Study (p = 0.005). Heterogeneity of the effects of rs11984041 on LVD vs SVD trended toward significance in the Vienna Study (p = 0.088) and was significant in the German Study (p = 0.047). Adjusting for covariates did not materially change the heterogeneity test p values. Conclusions The HDAC9 polymorphism rs11984041 was associated with the LVD stroke subtype in the Vienna Study and the German Study. These results replicated the ISGC/WTCCC2 findings.

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Can the Previous Therapeutic Control of the Main Risk Factors of Cerebrovascular Disease Influence the Acetylsalicylic Acid–Nonresponsive Status in Acute Ischemic Stroke Patients? Results from a Portuguese Prospective Cohort Study

Journal of Stroke and Cerebrovascular Diseases ◽

10.1016/j.jstrokecerebrovasdis.2015.02.021 ◽

2015 ◽

Vol 24 (6) ◽

pp. 1383-1389 ◽

Cited By ~ 2

Author(s):

Margarida Freitas-Silva ◽

Luciana Gonçalves ◽

Rui Medeiros ◽

José Pedro Nunes

Keyword(s):

Risk Factors ◽

Cohort Study ◽

Ischemic Stroke ◽

Cerebrovascular Disease ◽

Acetylsalicylic Acid ◽

Acute Ischemic Stroke ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Stroke Patients ◽

Therapeutic Control

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Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease

10.1101/218388 ◽

2017 ◽

Cited By ~ 9

Author(s):

Amit V. Khera ◽

Mark Chaffin ◽

Krishna G. Aragam ◽

Connor A. Emdin ◽

Derek Klarin ◽

...

Keyword(s):

Coronary Disease ◽

Fold Increase ◽

Predictive Capacity ◽

Cumulative Impact ◽

Polygenic Score ◽

Genome Wide ◽

A Genome ◽

Increased Risk ◽

Polygenic Scores ◽

Artery Disease

AbstractIdentification of individuals at increased genetic risk for a complex disorder such as coronary disease can facilitate treatments or enhanced screening strategies. A rare monogenic mutation associated with increased cholesterol is present in ~1:250 carriers and confers an up to 4-fold increase in coronary risk when compared with non-carriers. Although individual common polymorphisms have modest predictive capacity, their cumulative impact can be aggregated into a polygenic score. Here, we develop a new, genome-wide polygenic score that aggregates information from 6.6 million common polymorphisms and show that this score can similarly identify individuals with a 4-fold increased risk for coronary disease. In >400,000 participants from UK Biobank, the score conforms to a normal distribution and those in the top 2.5% of the distribution are at 4-fold increased risk compared to the remaining 97.5%. Similar patterns are observed with genome-wide polygenic scores for two additional diseases – breast cancer and severe obesity.One Sentence SummaryA genome-wide polygenic score identifies 2.5% of the population born with a 4-fold increased risk for coronary artery disease.

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Abstract 12: Heritability of Ischemic Stroke and its Subtypes

Stroke ◽

10.1161/str.43.suppl_1.a12 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Andrew E Bluher ◽

Michael A Nalls ◽

John W Cole ◽

Pankaj Sharma ◽

James F Meschia ◽

...

Keyword(s):

Ischemic Stroke ◽

Fixed Effects ◽

Rare Variants ◽

Phenotypic Variability ◽

Fixed Effects Model ◽

Stroke Subtype ◽

Genome Wide ◽

Weighted Means ◽

Family Based ◽

And Gender

Background and Purpose: Family-based methods for estimating heritability cannot discriminate between shared genetic and shared environmental exposures. Recently, methods have been developed for estimating heritability in population samples using genome-wide SNPs. We used the approach developed by Visscher and colleagues to estimate the heritability of ischemic stroke in Caucasian subjects. In addition to evaluating the overall heritability of ischemic stroke, we assessed whether stroke heritability varies by age, gender, and stroke subtype. Methods: Using publicly available software (GCTA and PLINK), we estimated ischemic stroke heritability stratified by age and gender using genome-wide association (GWA) data from three Caucasian ischemic stroke studies: Ischemic Stroke Genetics Study (ISGS), Bio-Repository of DNA in Stroke (BRAINS), and Genetics of Early-Onset Stroke (GEOS). Weighted means of site-specific heritability point estimates were combined according to a standard fixed effects model. Results: Conclusions: A SNP-based approach may be useful in discerning differences in ischemic stroke heritability between different cohorts and subtypes. Overall, our analysis estimated ischemic stroke heritability to be 31% (SE = 7%), with a suggestion of higher heritability for younger cases. Small vessel stroke showed the highest heritability (58 ± 19%), with cardioembolic showing the lowest heritability (16 ± 14%). It should be emphasized that heritability estimates are population-specific and that the method used only reflects the heritability captured by common SNP variants measured in GWA studies, and not phenotypic variability explained by rare variants.

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