From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Stroke. 2014 Jul;45(7):1920-4. doi: 10.1161/STROKEAHA.114.005208. Epub 2014 May 20.
Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes.
Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs.
One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes.
This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.
已知血浆总同型半胱氨酸（tHcy）水平升高与缺血性中风（IS）风险增加有关。鉴于 tHcy 和 IS 都是可遗传的特征，我们通过评估先前与 tHcy 水平相关的 18 个多态性，来研究同型半胱氨酸水平与中风风险之间的潜在遗传关系，评估其与 IS 及其亚型的关系。
利用国际中风协作网络 METASTROKE 的先前荟萃分析结果，评估 12389 例 IS 病例和 62004 例对照中 18 个与 tHcy 相关的单核苷酸多态性（SNP）与 IS 的相关性。我们还研究了位于 18 个与 tHcy 相关 SNP 附近的 50 kb 区域内的相关性，以及包括 18 个 SNP 的遗传风险评分的相关性。
在进行多次检验校正后，位于 RASIP1 基因中的一个 SNP 和位于 SLC17A3 及其附近的 3 个 SNP 簇与 IS 显著相关（P<0.0003）。对于中风亚型，位于 MUT 上游的前哨 SNP 与小血管疾病显著相关（P=0.0022），而 MTHFR 中的 1 个 SNP 与大血管疾病显著相关（P=0.00019）。包括 18 个 SNP 的遗传风险评分与 IS 或其亚型无显著相关性。
本研究发现了与 IS 及其亚型的几个潜在关联：MUT 变体与小血管疾病的关联，MTHFR 变体与大血管疾病的关联，以及 RASIP1 和 SLC17A3 变体与总体 IS 的关联。
