Published Online
on August 11, 2005

A more recent version of this article appeared on September 1, 2005

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Submitted on April 18, 2005
Accepted on May 13, 2005

Association of Apolipoprotein E4 and Haplotypes of the Apolipoprotein E Gene With Lobar Intracerebral Hemorrhage

Daniel Woo MD^*; Ritesh Kaushal MD; Ranajit Chakraborty PhD; Jessica Woo PhD; Mary Haverbusch BSN; Padmini Sekar MS; Brett Kissela MD; Arthur Pancioli MD; Edward Jauch MD; Dawn Kleindorfer MD; Matthew Flaherty MD; Alexander Schneider MD; Pooja Khatri MD; Laura Sauerbeck MSN; Jane Khoury MS; Ranjan Deka PhD; and Joseph Broderick MD

From the University of Cincinnati (D.W., R.K., R.C., M.H., P.S., B.K., A.P., E.J., D.K., M.F., A.S., P.K., L.S., J.B.), and Children’s Hospital Medical Center (J.W.), Cincinnati, Ohio.

^* To whom correspondence should be addressed. E-mail: daniel.woo{at}uc.edu.

Background and Purpose--Conflicting reports in the literature exist with regard to the association of apolipoprotein E (apo E) alleles and lobar intracerebral hemorrhage (ICH). We genotyped 12 single-nucleotide polymorphisms in the 5' upstream regulatory, exonic, and intronic regions of the apo E gene and performed genotype and haplotype association analyses.

Methods--We prospectively enrolled subjects with hemorrhagic stroke and matched them with 2 controls based on age, race, and sex. Each case was reviewed by a physician to determine case status and location of the ICH. Multivariate logistic-regression modeling with backward elimination was used to determine significant risk factors for lobar ICH. Associations at the genotype and haplotype levels and linkage disequilibrium were conducted according to standard statistical methods.

Results--Between May 1997 and December 2002, 315 cases of ICH were recruited, of whom 107 were lobar ICH cases matched to 205 controls. No association was found for apo E2, E3, or E4 with nonlobar ICH. Independent, significant risk factors for lobar ICH included apo E4, untreated hypertension, anticoagulant use, a first-degree relative with ICH, and high school education (compared with >high school education). Treated hypercholesterolemia compared with "no history of hypercholesterolemia" was associated with a decreased risk of lobar ICH. Haplotype association analysis demonstrated a significant association of the apo E gene with lobar ICH among whites (P<0.0001) and blacks (P=0.0024).

Conclusions--Apo E4 is independently associated with lobar ICH but not nonlobar ICH. Haplotypes of the apo E gene are associated with lobar ICH. Untreated hypertension is a risk factor for lobar ICH.

Key words: apolipoproteins • intracerebral hemorrhage • genetics • epidemiology

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