Falcone Guido J, Radmanesh Farid, Brouwers H Bart, Battey Thomas W K, Devan William J, Valant Valerie, Raffeld Miriam R, Chitsike Lennox P, Ayres Alison M, Schwab Kristin, Goldstein Joshua N, Viswanathan Anand, Greenberg Steven M, Selim Magdy, Meschia James F, Brown Devin L, Worrall Bradford B, Silliman Scott L, Tirschwell David L, Flaherty Matthew L, Martini Sharyl R, Deka Ranjan, Biffi Alessandro, Kraft Peter, Woo Daniel, Rosand Jonathan, Anderson Christopher D
From the Center for Human Genetic Research (G.J.F., F.R., H.B.B., T.W.K.B., W.J.D., V.V., M.R.R., L.P.C., A.M.A., K.S., A.V., S.M.G., A.B., J.R., C.D.A.), J. Philip Kistler Stroke Research Center (G.J.F., F.R., H.B.B., T.W.K.B., W.J.D., V.V., M.R.R., A.B., J.R., C.D.A.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (G.J.F., F.R., H.B.B., T.W.K.B., W.J.D., M.R.R., A.B., J.R., C.D.A.), and Department of Emergency Medicine (J.N.G.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (G.J.F., F.R., H.B.B., T.W.K.B., W.J.D., M.R.R., A.B., J.R., C.D.A.), Broad Institute, Cambridge, MA; Department of Epidemiology (G.J.F., P.K.), Harvard School of Public Health, Boston; Department of Neurology (M.S.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Neurology (J.F.M.), Mayo Clinic, Jacksonville, FL; Stroke Program (D.L.B.), Department of Neurology, University of Michigan Health System, Ann Arbor; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia Health System, Charlottesville; Department of Neurology (S.L.S.), University of Florida College of Medicine, Jacksonville; Stroke Center (D.L.T.), Harborview Medical Center, University of Washington, Seattle; and University of Cincinnati College of Medicine (M.L.F., S.R.M., R.D., D.W.), OH.
Neurology. 2014 Sep 23;83(13):1139-46. doi: 10.1212/WNL.0000000000000816. Epub 2014 Aug 22.
We aimed to assess the effect of APOE ε variants on warfarin-related intracerebral hemorrhage (wICH), evaluated their predictive power, and tested for interaction with warfarin in causing wICH.
This was a prospective, 2-stage (discovery and replication), case-control study. wICH was classified as lobar or nonlobar based on the location of the hematoma. Controls were sampled from ambulatory clinics (discovery) and random digit dialing (replication). APOE ε variants were directly genotyped. A case-control design and logistic regression analysis were utilized to test for association between APOE ε and wICH. A case-only design and logistic regression analysis were utilized to test for interaction between APOE ε and warfarin. Receiver operating characteristic curves were implemented to evaluate predictive power.
The discovery stage included 319 wICHs (44% lobar) and 355 controls. APOE ε2 was associated with lobar (odds ratio [OR] 2.46; p < 0.001) and nonlobar wICH (OR 1.67; p = 0.04), whereas ε4 was associated with lobar (OR 2.09; p < 0.001) but not nonlobar wICH (p = 0.35). The replication stage (63 wICHs and 1,030 controls) confirmed the association with ε2 (p = 0.03) and ε4 (p = 0.003) for lobar but not for nonlobar wICH (p > 0.20). Genotyping information on APOE ε variants significantly improved case/control discrimination of lobar wICH (C statistic 0.80). No statistical interaction between warfarin and APOE was found (p > 0.20).
APOE ε variants constitute strong risk factors for lobar wICH. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary. Evaluation of the predictive ability of APOE in cohort studies is warranted.
我们旨在评估APOEε变异体对华法林相关脑出血（wICH）的影响，评估其预测能力，并测试其与华法林在引发wICH方面的相互作用。
这是一项前瞻性的两阶段（发现和验证）病例对照研究。根据血肿位置，wICH分为脑叶型或非脑叶型。对照组来自门诊诊所（发现阶段）和随机数字拨号（验证阶段）。直接对APOEε变异体进行基因分型。采用病例对照设计和逻辑回归分析来测试APOEε与wICH之间的关联。采用病例单组设计和逻辑回归分析来测试APOEε与华法林之间的相互作用。绘制受试者工作特征曲线以评估预测能力。
发现阶段包括319例wICH患者（44%为脑叶型）和355名对照。APOEε2与脑叶型wICH相关（优势比[OR]2.46；p<0.001）和非脑叶型wICH相关（OR 1.67；p=0.04），而ε4与脑叶型wICH相关（OR 2.09；p<0.001），但与非脑叶型wICH无关（p=0.35）。验证阶段（63例wICH患者和1030名对照）证实了ε2（p=0.03）和ε4（p=0.003）与脑叶型wICH相关，但与非脑叶型wICH无关（p>0.20）。APOEε变异体的基因分型信息显著提高了脑叶型wICH的病例/对照区分度（C统计量0.80）。未发现华法林与APOE之间存在统计学相互作用（p>0.20）。
APOEε变异体是脑叶型wICH的强风险因素。APOE独立于华法林发挥作用，尽管由于检验效能有限，这种无相互作用的结果尚属初步。有必要在队列研究中评估APOE的预测能力。
