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Genetic overlap between diagnostic subtypes of ischemic stroke.

ABSTRACT: BACKGROUND AND PURPOSE:Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. METHODS:Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. RESULTS:High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor ?1 (OPRM1) gene. CONCLUSIONS:Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.

SUBMITTER: Holliday EG

PROVIDER: S-EPMC4342266 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Genetic overlap between diagnostic subtypes of ischemic stroke.

Holliday Elizabeth G EG Traylor Matthew M Malik Rainer R Bevan Steve S Falcone Guido G Hopewell Jemma C JC Cheng Yu-Ching YC Cotlarciuc Ioana I Bis Joshua C JC Boerwinkle Eric E Boncoraglio Giorgio B GB Clarke Robert R Cole John W JW Fornage Myriam M Furie Karen L KL Ikram M Arfan MA Jannes Jim J Kittner Steven J SJ Lincz Lisa F LF Maguire Jane M JM Meschia James F JF Mosley Thomas H TH Nalls Mike A MA Oldmeadow Christopher C Parati Eugenio A EA Psaty Bruce M BM Rothwell Peter M PM Seshadri Sudha S Scott Rodney J RJ Sharma Pankaj P Sudlow Cathie C Wiggins Kerri L KL Worrall Bradford B BB Rosand Jonathan J Mitchell Braxton D BD Dichgans Martin M Markus Hugh S HS Levi Christopher C Attia John J Wray Naomi R NR

Stroke 20150122 3

<h4>Background and purpose</h4>Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.<h4>Methods</h4>Analyses used genome-wide summary data for 12 389 ischemic stroke cases ...[more]

PMID: 25613305

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Project description:Ischemic stroke (IS) is the main cause of mortality and disability among the old people in China and is a multifactorial disease influenced by many factors including genetic factors like the allele for CYP 2J2. It has been demonstrated that CYP2J2 polymorphisms alter the transcriptional activity. However, studies on the association between CYP2J2-50G/T polymorphism and IS have reported conflicting results. Thus, our study aimed to examine the association between 4 variants in the CYP2J2 gene and the risk of IS and its subtypes, in the Chinese population.In this study, genotyping was performed by using polymerase chain reaction (PCR) sequencing for 202 IS patients and 206 age- and sex-matched controls. Odds ratios (ORs) and confidence interval (CI) were estimated by multivariate logistic regression and PCR results were confirmed by DNA sequencing. A meta-analysis was conducted to evaluate the association of CYP2J2-50G>T polymorphism with the risk of IS in Chinese population by calculating pooled OR.We found this polymorphism was significantly associated with IS (17.82% vs. 10.68%, P = 0.039). Multiple logistic regression analysis revealed that GT genotype was associated with a significantly high risk of IS (OR = 2.32, 95% CI: 1.21-4.45, P = 0. 011) after adjustment for other confounding factors such as hypertension, diabetes, heart disease, smoking habit, family history, triglyceride and low-density lipoprotein levels. We also found a significant association of GT genotype with small artery occlusion (SAA) (P < 0.05; OR = 2.22; 95% CI: 1.043-4.72). Meta-analysis results also showed that the GT genotype carriers had a negative effect on the risk of IS in Chinese population with overall OR of 1.40 (95% CI: 1.06-1.84).The findings of the present study suggested that polymorphism in -50G/T position of CYP2J2 gene might be a risk factor for IS in Chinese population. Further large prospective studies were required to confirm these findings.

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Genetic overlap between diagnostic subtypes of ischemic stroke.

Publications

Genetic overlap between diagnostic subtypes of ischemic stroke.

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