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Common mitochondrial sequence variants in ischemic stroke.

ABSTRACT: OBJECTIVE:Rare mitochondrial mutations cause neurologic disease, including ischemic stroke and MRI white matter changes. We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV). METHODS:In this multicenter, mitochondrial genome-wide association study (GWAS), 2284 ischemic stroke cases and 1728 controls from the International Stroke Genetics Consortium were genotyped for 64 mitochondrial single nucleotide polymorphisms (SNPs). Imputation resulted in 144 SNPs, which were tested in each cohort and in meta-analysis for ischemic stroke association. A genetic score of all mitochondrial variants was also tested in association with ischemic stroke. RESULTS:No individual SNP reached adjusted significance in meta-analysis. A genetic score comprised of the summation of contributions from individual variants across the mitochondrial genome showed association with ischemic stroke in meta-analysis (odds ratio [OR] = 1.13, p < 0.0001) with minimal heterogeneity (I(2) = 0.00). This ischemic stroke score was robust to permutation, and was also associated with WMHV in 792 nested case individuals with ischemic stroke (p = 0.037). INTERPRETATION:In this mitochondrial GWAS of ischemic stroke, a genetic score comprised of the sum of all common variants in the mitochondrial genome showed association with ischemic stroke. In an independent analysis of a related trait, this same score correlated with WMHV in stroke cases. Despite this aggregate association, no individual variant reached significance. Substantially larger studies will be required to identify precise sequence variants influencing cerebrovascular disease.

SUBMITTER: Anderson CD

PROVIDER: S-EPMC3003764 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Common mitochondrial sequence variants in ischemic stroke.

Anderson Christopher D CD Biffi Alessandro A Rahman Rosanna R Ross Owen A OA Jagiella Jeremiasz M JM Kissela Brett B Cole John W JW Cortellini Lynelle L Rost Natalia S NS Cheng Yu-Ching YC Greenberg Steven M SM de Bakker Paul I W PI Brown Robert D RD Brott Thomas G TG Mitchell Braxton D BD Broderick Joseph P JP Worrall Bradford B BB Furie Karen L KL Kittner Steven J SJ Woo Daniel D Slowik Agnieszka A Meschia James F JF Saxena Richa R Rosand Jonathan J

Annals of neurology 20100913 3

<h4>Objective</h4>Rare mitochondrial mutations cause neurologic disease, including ischemic stroke and MRI white matter changes. We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV).<h4>Methods</h4>In this multicenter, mitochondrial genome-wide association study (GWAS), 2284 ischemic stroke cases and 1728 controls from the International Stroke Genetics Consortium wer ...[more]

PMID: 20839239

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Project description:BackgroundMutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved.MethodsAll 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS).ResultsSequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series.ConclusionCysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.

Project description:IMPORTANCE:Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk. OBJECTIVE:To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome. DESIGN, SETTING, AND PARTICIPANTS:The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed?approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013. MAIN OUTCOMES AND MEASURES:Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis). RESULTS:We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio,?2.15; P?=?2.63?×?10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio,?2.04; P?=?1.24?×?10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke). CONCLUSIONS AND RELEVANCE:Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

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Common mitochondrial sequence variants in ischemic stroke.

Publications

Common mitochondrial sequence variants in ischemic stroke.

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