Traylor Matthew, Anderson Christopher D, Hurford Robert, Bevan Steve, Markus Hugh S
From Clinical Neurosciences (M.T., R.H., H.S.M.), University of Cambridge, UK; School of Life Science (S.B.), University of Lincoln, UK; and the Center for Human Genetic Research (C.D.A.), Department of Neurology, Massachusetts General Hospital, Boston.
Neurology. 2016 Jan 12;86(2):141-5. doi: 10.1212/WNL.0000000000002260. Epub 2015 Dec 16.
We investigated whether oxidative phosphorylation (OXPHOS) abnormalities were associated with lacunar stroke, hypothesizing that these would be more strongly associated in patients with multiple lacunar infarcts and leukoaraiosis (LA).
In 1,012 MRI-confirmed lacunar stroke cases and 964 age-matched controls recruited from general practice surgeries, we investigated associations between common genetic variants within the OXPHOS pathway and lacunar stroke using a permutation-based enrichment approach. Cases were phenotyped using MRI into those with multiple infarcts or LA (MLI/LA) and those with isolated lacunar infarcts (ILI) based on the number of subcortical infarcts and degree of LA, using the Fazekas grading. Using gene-level association statistics, we tested for enrichment of genes in the OXPHOS pathway with all lacunar stroke and the 2 subtypes.
There was a specific association with strong evidence of enrichment in the top 1% of genes in the MLI/LA (subtype p = 0.0017) but not in the ILI subtype (p = 1). Genes in the top percentile for the all lacunar stroke analysis were not significantly enriched (p = 0.07).
Our results implicate the OXPHOS pathway in the pathogenesis of lacunar stroke, and show the association is specific to patients with the MLI/LA subtype. They show that MRI-based subtyping of lacunar stroke can provide insights into disease pathophysiology, and imply that different radiologic subtypes of lacunar stroke subtypes have distinct underlying pathophysiologic processes.
我们研究了氧化磷酸化（OXPHOS）异常是否与腔隙性卒中相关，假设在多发性腔隙性梗死和脑白质疏松（LA）患者中这种关联更为密切。
在从普通全科诊所招募的1012例经MRI确诊的腔隙性卒中病例和964例年龄匹配的对照中，我们使用基于置换的富集方法研究了OXPHOS途径内常见基因变异与腔隙性卒中之间的关联。根据皮质下梗死数量和LA程度，使用Fazekas分级，通过MRI将病例分为多发性梗死或LA（MLI/LA）组和孤立性腔隙性梗死（ILI）组。使用基因水平的关联统计，我们测试了OXPHOS途径中的基因在所有腔隙性卒中和两种亚型中的富集情况。
在MLI/LA组中，前1%的基因有显著富集的证据显示存在特定关联（亚型p = 0.0017），而ILI亚型中无此关联（p = 1）。所有腔隙性卒中分析中前百分之一的基因没有显著富集（p = 0.07）。
我们的结果表明OXPHOS途径参与腔隙性卒中的发病机制，并且显示这种关联特定于MLI/LA亚型的患者。结果表明基于MRI的腔隙性卒中分型能够为疾病病理生理学提供见解，这意味着腔隙性卒中不同的放射学亚型具有不同的潜在病理生理过程。
