Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke

Auer, Paul L.; Nalls, Mike A.; Meschia, James F.; Worrall, Bradford B.; Longstreth, W. T.; Seshadri, Sudha; Kooperberg, Charles; Burger, Kathleen; Carlson, Christopher S.; Carty, Cara L.; Chen, Wei Min; Cupples, L. Adrienne; DeStefano, Anita L.; Fornage, Myriam; Hardy, John; Hsu, Li; Jackson, Rebecca D.; Jarvik, Gail P.; Kim, Daniel S.; Lakshminarayan, Kamakshi; Lange, Leslie A.; Manichaikul, Ani; Quinlan, Aaron R.; Singleton, Andrew B.; Thornton, Timothy A.; Nickerson, Deborah A.; Peters, Ulrike; Rich, Stephen S.

doi:10.1001/jamaneurol.2015.0582

Cited by 53 publications

(43 citation statements)

References 39 publications

(35 reference statements)

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“…This led to the identification of 76 SNPs. The remaining SNPs (n=43) were identified through recent GWAS/meta‐analyses on CHD and stroke performed in African Americans, which, together with the 298 SNPs, were examined for significant LEA associations with clinical events. Because these individual results are replications of previous studies, we set the statistical significance at P <0.05 for each test in the current study.…”

Section: Methodsmentioning

confidence: 99%

Local Ancestry and Clinical Cardiovascular Events Among African Americans From the Atherosclerosis Risk in Communities Study

Shendre

Irvin

Wiener

et al. 2017

JAHA

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BackgroundLocal ancestry in relation to clinical cardiovascular events (CVEs) among African Americans can provide insight into their genetic susceptibility to the disease.Methods and ResultsWe examined local European ancestry (LEA) association with CVEs among 3000 African Americans from the Atherosclerosis Risk in Communities Study (ARIC). We estimated LEA using Local Ancestry Inference in adMixed Populations using Linkage Disequilibrium (LAMP‐LD) and examined its association with myocardial infarction, stroke, coronary heart disease and its composite and cardiovascular disease composite using logistic regression. Genome‐wide significance was achieved by 121 LEA regions in relation to myocardial infarction and 2 in relation to the cardiovascular disease composite. The LEA region downstream of 4q32.1 was significantly associated with 2 times higher odds of myocardial infarction (P=1.45×10−6). The LEA region upstream of 6q11.1 was associated with 0.37 times lower odds of fatal coronary heart disease (P=7.34×10−4), whereas the LEA region downstream of 21q21.1 was associated with 1.55 times higher odds of composite coronary heart disease (P=3.45×10−4). Association of LEA with stroke was observed in the region upstream of 6p22.3 with a 1.57 times higher odds of stroke (P=9.69×10−4). Likewise, the LEA region on 4q32.3 was associated with a 1.53 times higher odds of composite cardiovascular disease (P=3.04×10−4). We also found 20 of the LEA regions at previously significant cardiovascular disease single‐nucleotide polymorphisms to be associated with CVE in our study.ConclusionsFuture studies are needed to replicate and/or determine the causal variants driving our associations and explore clinical applications for those consistently associated with CVEs.

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Section: Methodsmentioning

confidence: 99%

Local Ancestry and Clinical Cardiovascular Events Among African Americans From the Atherosclerosis Risk in Communities Study

Shendre

Irvin

Wiener

et al. 2017

JAHA

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“…Ischemic stroke (IS), the most common type of stroke, accounts for approximately 85% of all strokes. Recently, various epidemiologic studies in families and twins have revealed that genetic factors played an important role in the pathogenesis of IS, including IL1- β, HDAC9 , TNF- α, and ACOT4 [3,4]. These genetic findings permit the early detection of people at risk for IS.…”

Section: Introductionmentioning

confidence: 99%

No Association Between SNP56 in PDE4D Gene and Susceptibility to Ischemic Stroke: A Meta-Analysis of 15 Studies

2016

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BackgroundRecent studies demonstrated that polymorphisms in the PDE4D gene were associated with several processes involved in the occurrence of ischemic stroke (IS). The association between specific PDE4D single-nucleotide polymorphism 56 (SNP56) and IS risk was initially identified via genome-wide association studies (GWAS), although the GWAS in different populations produced inconclusive results. Thus, we performed a meta-analysis to better explain the association between PDE4D SNP56 and IS risk.Material/MethodsA literature search was conducted using PubMed, Embase, and Web of Science up to June 1, 2015. A fixed-effects or random-effects model was used to calculate the pooled odds ratios (ORs) based on the results from the heterogeneity tests.ResultsFinally, we performed a meta-analysis of 15 studies, involving 8731 IS patients and 10,756 controls. The results showed nonsignificant association between PDE4D SNP56 and IS risk (T vs. A: OR=1.01, 95%CI=0.88–1.15, P=0.90). Similarly, in the subgroup analysis by ethnicity, no significant association was observed in Asian (T vs. A: OR=1.08, 95%CI=0.80–1.44, P=0.62) or European (T vs. A: OR=0.96, 95%CI=0.86–1.08, P=0.54) population. Moreover, funnel plots and Egger regression testing showed no evidence of publication bias.ConclusionsIn summary, current evidence suggested that PDE4D SNP56 might not be associated with an increased susceptibility to IS. However, this conclusion needs further validation by well-designed studies with large sample sizes.

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“…These studies confirmed that the PITX2 and ZFHX3 SNPs were associated with ischemic stroke and more specifically with cardioembolic stroke, even though only half of their population was sub classified by type of stroke [114]. A recent exome sequencing study replicated the ZFHX3 locus association with ischemic stroke[115]. Using the METASTROKE collaboration data, an association between ischemic stroke with an AF-risk SNP intronic to CUX2 was found, though the AF risk allele was paradoxically associated with a decreased the risk of stroke (OR 0.95.; 95% CI 0.91–0.98).…”

Section: Af Genetics and Strokementioning

confidence: 76%

Genomics of Atrial Fibrillation

Gutiérrez

Chung

2016

Curr Cardiol Rep

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Atrial fibrillation (AF) is a common clinical arrhythmia that appears to be highly heritable, despite representing a complex interplay of several disease processes that generally do not manifest until later in life. In this manuscript we will review the genetic basis of this complex trait established through studies of familial AF, linkage and candidate gene studies of common AF, genome wide association studies (GWAS) of common AF, and transcriptomic studies of AF. Since AF is associated with a five-fold increase in the risk of stroke, we also review the intersection of common genetic factors associated with both of these conditions. Similarly, we highlight the intersection of common genetic markers associated with some risk factors for AF, such as hypertension and obesity, and AF. Lastly, we describe a paradigm where genetic factors predispose to the risk of AF, but which may require additional stress and trigger factors in older age to allow for the clinical manifestation of AF.

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Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke

Cited by 53 publications

References 39 publications

Local Ancestry and Clinical Cardiovascular Events Among African Americans From the Atherosclerosis Risk in Communities Study

Local Ancestry and Clinical Cardiovascular Events Among African Americans From the Atherosclerosis Risk in Communities Study

No Association Between SNP56 in PDE4D Gene and Susceptibility to Ischemic Stroke: A Meta-Analysis of 15 Studies

Genomics of Atrial Fibrillation

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