APOE ε variants increase risk of warfarin-related intracerebral hemorrhage

Neurology. 2014 Sep 23;83(13):1139-46. doi: 10.1212/WNL.0000000000000816. Epub 2014 Aug 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apolipoprotein E2 / genetics*
  • Case-Control Studies
  • Cerebral Hemorrhage / chemically induced
  • Cerebral Hemorrhage / genetics*
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Prospective Studies
  • Risk
  • Warfarin / adverse effects*


  • Apolipoprotein E2
  • Warfarin