Rannikmäe Kristiina, Sivakumaran Vhinoth, Millar Henry, Malik Rainer, Anderson Christopher D, Chong Mike, Dave Tushar, Falcone Guido J, Fernandez-Cadenas Israel, Jimenez-Conde Jordi, Lindgren Arne, Montaner Joan, O'Donnell Martin, Paré Guillaume, Radmanesh Farid, Rost Natalia S, Slowik Agnieszka, Söderholm Martin, Traylor Matthew, Pulit Sara L, Seshadri Sudha, Worrall Brad B, Woo Daniel, Markus Hugh S, Mitchell Braxton D, Dichgans Martin, Rosand Jonathan, Sudlow Cathie L M
From the Centre for Clinical Brain Sciences (K.R., C.L.M.S.), College of Medicine and Veterinary Medicine (V.S., H.M.), and Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Institute for Stroke and Dementia Research (R.M., M.D.), Klinikum der Universität München, Munich, Germany; Center for Human Genetic Research (C.D.A., F.R., J.R.) and J. Philip Kistler Stroke Research Center (C.D.A., F.R., N.S.R., J.R.) and Division of Neurocritical Care and Emergency Neurology (C.D.A., F.R., J.R.), Department of Neurology, Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (C.D.A., F.R., J.R.), Broad Institute, Cambridge, MA; Population Health Research Institute (M.C., M.O., G.P.), McMaster University, Hamilton Health Sciences Centre, Ontario, Canada; Department of Medicine (T.D., B.D.M.), University of Maryland School of Medicine, Baltimore; Division of Neurocritical Care and Emergency Neurology (G.J.F.), Department of Neurology, Yale University School of Medicine, New Haven, CT; Stroke Pharmacogenomics and Genetics (I.F.-C.), Fundació Docència i Recerca Mutua Terrassa, Mutua de Terrassa Hospital; Neurovascular Research Unit (J.J.-C.), Department of Neurology, and Program in Inflammation and Cardiovascular Disorders (J.J.-C.), Institut Municipal d'Investigacio´Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Spain; Department of Clinical Sciences Lund (A.L.), Neurology, Lund University; Department of Neurology and Rehabilitation Medicine (A.L., M.S.), Neurology, Skåne University Hospital, Lund, Sweden; Neurovascular Research Laboratory and Neurovascular Unit (J.M.), Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Spain; HRB Clinical Research Facility (M.O.), NUI Galway, and University Hospital Galway, Ireland; Department of Neurology (A.S.), Jagiellonian University Medical College, Krakow, Poland; Cardiovascular Epidemiology Research Group (M.S.), Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Clinical Neurosciences (M.T., H.S.M.), University of Cambridge, UK; Department of Neurology (S.L.P.), Brain Centre Rudolf Magnus, University Medical Center Utrecht, the Netherlands; Boston University Schools of Medicine and Public Health (S.S.); Framingham Heart Study (S.S.), Framingham, MA; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia, Charlottesville; Department of Neurology (D.W.), University of Cincinnati College of Medicine, OH; Geriatrics Research and Education Clinical Center (B.D.M.), Baltimore Veterans Administration Medical Center, MD; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Neurology. 2017 Oct 24;89(17):1829-1839. doi: 10.1212/WNL.0000000000004560. Epub 2017 Sep 27.
To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.
We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (, , , , , and ) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.
A locus in was associated (significance threshold < 3.5 × 10) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11-1.24, = 6.62 × 10) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13-1.44, = 5.76 × 10). A SNP in was associated (significance threshold < 5.5 × 10) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10-1.37, = 1.90 × 10) and less robustly with deep ICH. There was no clear evidence for association of common variants in either or with non-SVD strokes or in any of the other genes with any stroke phenotype.
These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.
确定家族性脑小血管病（SVD）基因中的常见变异是否会增加散发性脑SVD的风险。
我们对欧洲血统个体的基因型数据进行了荟萃分析，以确定6个家族性脑SVD基因（、、、、、和）中的常见单核苷酸多态性（SNP）与脑出血（ICH）（深部、叶性、所有类型；1878例病例，2830例对照）和缺血性卒中（IS）（腔隙性、心源性栓塞性、大血管疾病性、所有类型；19569例病例，37853例对照）之间的关联。我们应用了数据质量过滤器，并设置了考虑连锁不平衡和多重检验的统计显著性阈值。
基因座中的一个位点与腔隙性IS（领先SNP rs9515201：优势比[OR]1.17，95%置信区间[CI]1.11 - 1.24，= 6.62 × 10）和深部ICH（领先SNP rs4771674：OR 1.28，95% CI 1.13 - 1.44，= 5.76 × 10）均相关（显著性阈值< 3.5 × 10）。基因中的一个SNP与腔隙性IS（rs79043147：OR 1.23，95% CI 1.10 - 1.37，= 1.90 × 10）相关（显著性阈值< 5.5 × 10），与深部ICH的相关性较弱。没有明确证据表明基因或基因中的常见变异与非SVD性卒中相关，也没有证据表明其他任何基因中的常见变异与任何卒中表型相关。
这些结果提供了共享遗传决定因素的证据，并提示不同缺血性和出血性脑SVD卒中表型具有共同的病理生理机制，为脑SVD的病因机制提供了新的见解。
