APOE ε variants increase risk of warfarin-related intracerebral hemorrhage

Guido J Falcone¹, Farid Radmanesh¹, H Bart Brouwers¹, Thomas W K Battey¹, William J Devan¹, Valerie Valant¹, Miriam R Raffeld¹, Lennox P Chitsike¹, Alison M Ayres¹, Kristin Schwab¹, Joshua N Goldstein¹, Anand Viswanathan¹, Steven M Greenberg¹, Magdy Selim¹, James F Meschia¹, Devin L Brown¹, Bradford B Worrall¹, Scott L Silliman¹, David L Tirschwell¹, Matthew L Flaherty¹, Sharyl R Martini¹, Ranjan Deka¹, Alessandro Biffi¹, Peter Kraft¹, Daniel Woo¹, Jonathan Rosand¹, Christopher D Anderson²; International Stroke Genetics Consortium

Affiliations

¹ 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.
² 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. cdanderson@partners.org.

PMID: 25150286
PMCID: PMC4176027
DOI: 10.1212/WNL.0000000000000816

APOE ε variants increase risk of warfarin-related intracerebral hemorrhage

Guido J Falcone et al. Neurology. 2014.

. 2014 Sep 23;83(13):1139-46.

doi: 10.1212/WNL.0000000000000816. Epub 2014 Aug 22.

Authors

Affiliations

¹ 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.
² 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. cdanderson@partners.org.

PMID: 25150286
PMCID: PMC4176027
DOI: 10.1212/WNL.0000000000000816

Abstract

Objective: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

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Figures

**Figure 1. INR distribution by case/control status**
ICH = intracerebral hemorrhage; INR = international normalized ratio.

**Figure 2. Receiver operating characteristic curves**
(A) Lobar wICH. (B) Nonlobar wICH. M1 = wICH ∼ age + sex; M2 = wICH ∼ age + sex + hypertension + diabetes mellitus + hypercholesterolemia; M3 = ICH ∼ age + sex + hypertension + diabetes mellitus + hypercholesterolemia + ε2 + ε4. Likelihood ratio tests for lobar wICH: M1 vs M2 p < 0.001; M1 vs M3 p < 0.001; M3 vs M2 p = 0.04. Likelihood for ratio tests nonlobar wICH: M1 vs M2 p < 0.001; M1 vs M3 p < 0.001; M3 vs M2 p = 0.23. ICH = intracerebral hemorrhage; wICH = warfarin-related ICH.

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APOE ε variants increase risk of warfarin-related intracerebral hemorrhage

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APOE ε variants increase risk of warfarin-related intracerebral hemorrhage

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