常见的基因变异在氧化磷酸化影响缺血性中风和脑内出血的危险(S42.002)

文摘

摘要目的:我们评估是否常见的遗传变异基因编码氧化磷酸化(OXPHOS)装置影响缺血性中风的风险(是)和脑出血(我)。

背景:线粒体疾病引起的贫穷OXPHOS函数导致神经表型包括中风和脑病。缺陷在每个五OXPHOS复合物引起人类疾病。先前的研究表明线粒体DNA变异之间的联系,但大部分OXPHOS是由核基因编码的蛋白质。

设计/方法:这个多中心协会研究工作发现的1643个人,一个是验证群2432人,和一个我扩展群1476人。OXPHOS常见变异在核和线粒体基因组是包括在内。单独的分析和我亚型。基因片段的富集分析(GSEA)上执行所有OXPHOS基因,以及基因导致个人OXPHOS复合物。组基因传递GSEA进行了测试,通过构造使用驻留在每一个常见变异基因遗传的分数。每个变体和之间的关联,发现队列中出现在验证和扩展的群组研究中进行检查。

结果:在我们复制队列,与遗传有关风险得分OXPHOS作为一个整体(比值比(或)= 1.17,p = 0.008)和复杂的我(或= 1.06,p = 0.050)。中风亚型中,小血管(SV)显示与OXPHOS(或= 1.16,p = 0.007),复杂的我(或= 1.13,p = 0.027)和复杂的IV(或1.14,p = 0.018)。我扩展队列,一个协会发现深半球之间我和复杂IV(或= 1.08,p = 0.008)。

结论:这个途径分析了常见的基因变异之间的关系在OXPHOS基因和中风。SV中风协会和深OXPHOS我表明,遗传变异可能影响小血管病理学。还需要进一步的研究来确定罪犯的遗传变异和评估其功能的后果。

支持:MGH / MIGen:这些研究是由美国心脏协会/ Bugher基金会资助中风预防研究中心(0775010 n), NIH-National神经疾病和中风研究所(研究所)(R01 NS059727, U01 NS069208),基恩遗传学基金和心房纤维性颤动的迪恩综合研究所和中风。MIGen研究由美国国立卫生研究院和国家心脏,肺和血液研究所的藏书基因组学研究项目(R01 HL087676)和国家研究资源中心的资助。基因型和分析Broad研究所中心支持格兰特U54 RR020278国家研究资源中心。端正,学士,and N.S.R. were supported in part by the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research, and C.D.A. is supported by the American Brain Foundation. ISGS/SWISS: These studies were funded by the NIH-NINDS (R01 NS42733, R01 NS39987), the Intramural Research Program of the NIH-National Institute on Aging (NIA) (Z01 AG000954-06), and by the Marriott Disease Risk and Regenerative Medicine Initiative Award in Individualized Medicine and the Marriott Mitochondrial Fund. The inclusion of BLSA samples was supported in part by the Intramural Research Program of the NIH-NIA (Z01 AG000015-50). O.A.R. is supported by the American Heart Association, James and Esther King Biomedical Research Program, the Florida Department of Health, and the Myron and Jane Hanley Award in Stroke Research. ISGC ICH: The Differences in the Imaging of Primary Hemorrhage based on Ethnicity or Race (DECIPHER) project was supported by Award Number U54NS057405 from the NIH-NINDS and National Institute on Minority Health and Health Disparities (NIMHD) (U54NS057405). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health (DECIPHER). The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study was supported by NIH-NINDS (NS36695 and NS30678), and by the Greater Cincinnati Foundation Grant (Cincinnati Control Cohort). The MGH ICH GWAS study was funded by NIH-NINDS (K23NS042695, 5K23NS059774, R01NS059727, and 5R01NS042147), the Keane Stroke Genetics Research Fund, the Edward and Maybeth Sonn Research Fund, by the University of Michigan General Clinical Research Center (M01 RR000042), and by a grant from the National Center for Research Resources. The Hospital del Mar ICH (HM-ICH) study was funded by the Instituto de Salud Carlos III, Spanish Research Networks “Red HERACLES” (RD06/009) FEDER. The Jagiellonian University Hemorrhagic Stroke Study (JUHSS) was supported by a grant funded by the Polish Ministry of Education (NN402083934). The Lund Stroke Register (LSR) was funded by Lund University, Region Skåne, King Gustaf V's and Queen Victoria's Foundation, and the Swedish Medical Research Council (K2010-61X-20378-04-3). Biobank services and genotyping were done at Region Skåne Competence Centre (RSKC Malmö), Skåne University Hospital, Malmö, Sweden. Controls from the Medical University of Graz ICH (MUG-ICH) study were from the Austrian Stroke Prevention Study, which is a population-based study funded by the Austrian Science Fond grant numbers P20545-P05 and P13180; The Medical University of Graz supports the databank of the Austrian Stroke Prevention Study.

披露:安德森博士已经收到个人活动与保利的补偿和哈雷,LLP)担任顾问。Biffi博士没有披露。纳尔博士没有披露。德文博士没有披露。施瓦布博士没有披露。艾尔斯博士没有披露。Valant博士没有披露。罗斯博士没有披露。罗斯特博士获得了个人与Genzyme公司补偿的活动。罗斯特博士接到Genzyme公司研究支持。 Dr. Saxena has nothing to disclose. Dr. Viswanathan has received personal compensation for activities with Athena Diagnostics. Dr. Worrall has received personal compensation in an editorial capacity for Neurology. Dr. Worrall has received royalty payments from Merritt's Neurology. Dr. Brott has received personal compensation for activities with 3D Communications and Edwards Lifesciences, LLC. Dr. Goldstein has nothing to disclose. Dr. Brown has nothing to disclose. Dr. Broderick has received personal compensation for activities as a speaker. Dr. Broderick has received research support from EKOS Corporation, Concentric Inc., and Genentech, Inc. Dr. Norrving has nothing to disclose. Dr. Greenberg has received personal compensation from Hoffman-Laroche for serving on a MRI review committee. Dr. Siliman has received personal compensation for activities with Biogen Idec as a consultant and from Teva for speaking. Dr. Silliman has received research support from Biogen Idec and Novartis. Dr. Hansen has nothing to disclose. Dr. Tirschwell has received personal compensation for activities with Bristol-Myers Squibb Company, Sanofi-Aventis Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Inc., as a consultant and/or speaker. Dr. Tirschwell has received research support from Axio Research, Amplatzer Corporation, and NovoNordisk. Dr. Lindgren has nothing to disclose. Dr. Slowik has nothing to disclose. Dr. Schmidt has received personal compensation for activities with Pfizer, Janssen, Lundbeck, Merz, Novartis, Austroplant, GE Healthcare, and Probiodrug as speaker and advisory board. Dr. Schmidt has received research support from Merz Austria. Dr. Selim has received personal compensation for activities with Boehringer Ingelheim as an Advisory Board member. Dr. Selim has received personal compensation in an editorial capacity with American College of Physicians. Dr. Roquer Gonzalez has nothing to disclose. Dr. Montaner has nothing to disclose. Dr. Singleton has nothing to disclose. Dr. Kidwell has nothing to disclose. Dr. Woo has nothing to disclose. Dr. Furie has received personal compensation for activities with Watermark. Dr. Furie has received personal compensation in an editorial capacity for the American Heart Association's Stroke journal and UpToDate. Dr. Meschia has nothing to disclose. Dr. Rosand has nothing to disclose.