APOE e variants increase risk of warfarin-related intracerebral hemorrhage

Guido J. Falcone, Farid Radmanesh, H. Bart Brouwers, Thomas W.K. Battey, William J. Devan, Valerie Valant, Miriam R. Raffeld, Lennox P. Chitsike, Alison M. Ayres, Kristin Schwab, Joshua N. Goldstein, Anand Viswanathan, Steven M. Greenberg, Magdy Selim, James F. Meschia, Devin L. Brown, Bradford B. Worrall, Scott L. Silliman, David L. Tirschwell, Matthew L. FlahertySharyl R. Martini, Ranjan Deka, Alessandro Biffi, Peter Kraft, Daniel Woo, Jonathan Rosand, Christopher D. Anderson

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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 e2 was associated with lobar (odds ratio [OR] 2.46; p < 0.001) and nonlobar wICH (OR 1.67; p = 0.04), whereas e4 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 e2 (p =0.03) and e4 (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.

Original languageEnglish (US)
Pages (from-to)1139-1146
Number of pages8
Issue number13
StatePublished - Sep 1 2014

ASJC Scopus subject areas

  • Clinical Neurology


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