J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M500491-JLR200 on November 29, 2005

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Journal of Lipid Research, Vol. 47, 318-328, February 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Contribution of regulatory and structural variations in APOE to predicting dyslipidemia

Jari H. Stengård1,*,{dagger}, Sharon L. R. Kardia§, Sara C. Hamon{dagger}, Ruth Frikke-Schmidt**, Anne Tybjærg-Hansen**, Veikko Salomaa*, Eric Boerwinkle{dagger}{dagger} and Charles F. Sing1,{dagger}

* National Public Health Institute, Helsinki, Finland
{dagger} Department of Human Genetics, University of Michigan, Ann Arbor, MI
§ Department of Epidemiology, University of Michigan, Ann Arbor, MI
** Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
{dagger}{dagger} Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX

Published, JLR Papers in Press, November 29, 2005.

1 To whom correspondence should be addressed. e-mail:jari.stengard{at}ktl.fi (J.H.S.); csing{at}umich.edu (C.F.S.)

The objective of this study was to evaluate 1) whether non single nucleotide polymorphisms-coding (non-cSNP) in the apolipoprotein E gene (APOE) identified by resequencing studies contribute to statistically explaining dyslipidemia if variations in the two cSNPs in exon 4 that define the {epsilon}2, {epsilon}3, and {epsilon}4 alleles are ignored, and 2) whether the contribution of these additional SNPs persists when variations in the cSNPs are considered. We used an ecological, multiple-population, data-mining strategy to identify single-SNP and two-SNP genotypes that distinguish between high and low levels of plasma lipids in three training samples, European-Americans from Rochester, MN, African-Americans from Jackson, MS, and Europeans from North Karelia, Finland. We found that a pair of SNPs located in the 5' region define genotypes A560T832/A560T832, A560T832/A560G832, and A560T832/T560T832, which distinguish between high and low levels of HDL-cholesterol (HDL-C), triglycerides (TG), and/or total cholesterol (T-C). The A560T832/- genotypes predicted high TG and high T-C in both genders in a large independent test sample from Copenhagen, Denmark. Prediction of high T-C in the Danish females was dependent on genotypes defined by the cSNPs. Our study suggests that both regulatory and structural variations should be considered when evaluating the utility of APOE for predicting dyslipidemia in the population at large.

Supplementary key words apolipoprotein E gene • pleiotropy • data mining • regulation • lipids


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