Williams Stephen R, Hsu Fang-Chi, Keene Keith L, Chen Wei-Min, Nelson Sarah, Southerland Andrew M, Madden Ebony B, Coull Bruce, Gogarten Stephanie M, Furie Karen L, Dzhivhuho Godfrey, Rowles Joe L, Mehndiratta Prachi, Malik Rainer, Dupuis Josée, Lin Honghuang, Seshadri Sudha, Rich Stephen S, Sale Michèle M, Worrall Bradford B
From the Center for Public Health Genomics (S.R.W., K.L.K., W.-M.C., S.S.R., M.M.S.), Cardiovascular Research Center (S.R.W.), and Departments of Public Health Sciences (A.M.S., B.B.W.), Neurology (P.M., B.B.W.), Medicine (M.M.S.), Biochemistry and Molecular Genetics (M.M.S.), and Public Health Sciences (S.S.R.), University of Virginia, Charlottesville; Department of Biostatistical Sciences (F.-C.H.), Wake Forest School of Medicine, Winston-Salem, NC; National Human Genome Research Institute (E.B.M.), Bethesda, MD; Departments of Neurology (A.M.S., K.L.F.) and Neuroscience (K.L.F.), Brown University, Providence, RI; Department of Neurology (B.C.), University of Arizona, Tucson; Department of Biology (K.L.K.) and Center for Health Disparities (K.L.K.), East Carolina University, Greenville, NC; Department of Biostatistics (S.N., S.M.G.), University of Washington, Seattle; Department of Clinical Laboratory Sciences (G.D.), University of Cape Town, South Africa; Department of Biochemistry (J.L.R.), University of Missouri, Columbia; Institute for Stroke and Dementia Research (R.M.), Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany; Department of Biostatistics (J.D.), Boston University School of Public Health; and Departments of Neurology (S.S.) and Medicine (H.L.), Boston University School of Medicine, MA.
Neurology. 2016 Jan 26;86(4):351-9. doi: 10.1212/WNL.0000000000002319. Epub 2015 Dec 30.
To investigate the genetic contributors to cerebrovascular disease and variation in biomarkers of ischemic stroke.
The Vitamin Intervention for Stroke Prevention Trial (VISP) was a randomized, controlled clinical trial of B vitamin supplementation to prevent recurrent stroke, myocardial infarction, or death. VISP collected baseline measures of C-reactive protein (CRP), fibrinogen, creatinine, prothrombin fragments F1+2, thrombin-antithrombin complex, and thrombomodulin prior to treatment initiation. Genome-wide association scans were conducted for these traits and follow-up replication analyses were performed.
We detected an association between CRP single nucleotide polymorphisms (SNPs) and circulating CRP levels (most associated SNP, rs2592902, p = 1.14 × 10(-9)) in 2,100 VISP participants. We discovered a novel association for CRP level in the AKR1D1 locus (rs2589998, p = 7.3 × 10(-8), approaching genome-wide significance) that also is an expression quantitative trait locus for CRP gene expression. We replicated previously identified associations of fibrinogen with SNPs in the FGB and LEPR loci. CRP-associated SNPs and CRP levels were significantly associated with risk of ischemic stroke and recurrent stroke in VISP as well as specific stroke subtypes in METASTROKE. Fibrinogen levels but not fibrinogen-associated SNPs were also found to be associated with recurrent stroke in VISP.
Our data identify a genetic contribution to inflammatory and hemostatic biomarkers in a stroke population. Additionally, our results suggest shared genetic contributions to circulating CRP levels measured poststroke and risk for incident and recurrent ischemic stroke. These data broaden our understanding of genetic contributors to biomarker variation and ischemic stroke risk, which should be useful in clinical risk evaluation.
研究脑血管疾病的遗传因素以及缺血性中风生物标志物的变异情况。
中风预防维生素干预试验（VISP）是一项关于补充B族维生素以预防复发性中风、心肌梗死或死亡的随机对照临床试验。VISP在开始治疗前收集了C反应蛋白（CRP）、纤维蛋白原、肌酐、凝血酶原片段F1+2、凝血酶-抗凝血酶复合物和血栓调节蛋白的基线测量值。对这些性状进行了全基因组关联扫描，并进行了后续的重复分析。
在2100名VISP参与者中，我们检测到CRP单核苷酸多态性（SNP）与循环CRP水平之间存在关联（最相关的SNP，rs2592902，p = 1.14×10⁻⁹）。我们在AKR1D1基因座中发现了CRP水平的新关联（rs2589998，p = 7.3×10⁻⁸，接近全基因组显著性），该基因座也是CRP基因表达的表达数量性状基因座。我们重复了先前确定的纤维蛋白原与FGB和LEPR基因座中的SNP之间的关联。在VISP中，CRP相关的SNP和CRP水平与缺血性中风和复发性中风的风险以及METASTROKE中的特定中风亚型显著相关。在VISP中还发现纤维蛋白原水平而非纤维蛋白原相关的SNP与复发性中风有关。
我们的数据确定了中风人群中炎症和止血生物标志物的遗传因素。此外，我们的结果表明，中风后测量的循环CRP水平与新发和复发性缺血性中风风险存在共同的遗传因素。这些数据拓宽了我们对生物标志物变异和缺血性中风风险的遗传因素的理解，这在临床风险评估中应会有所帮助。
