Contribution of regulatory and structural variations in APOE to predicting dyslipidemia

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

^* National Public Health Institute, Helsinki, Finland
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
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 singlenucleotide polymorphisms-coding (non-cSNP) in the apolipoproteinE gene (APOE) identified by resequencing studies contributeto statistically explaining dyslipidemia if variations in thetwo cSNPs in exon 4 that define the ${epsilon}$ 2, ${epsilon}$ 3, and ${epsilon}$ 4 alleles areignored, and 2) whether the contribution of these additionalSNPs persists when variations in the cSNPs are considered. Weused an ecological, multiple-population, data-mining strategyto identify single-SNP and two-SNP genotypes that distinguishbetween high and low levels of plasma lipids in three trainingsamples, European-Americans from Rochester, MN, African-Americansfrom Jackson, MS, and Europeans from North Karelia, Finland.We found that a pair of SNPs located in the 5' region definegenotypes 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 bothgenders in a large independent test sample from Copenhagen,Denmark. Prediction of high T-C in the Danish females was dependenton genotypes defined by the cSNPs. Our study suggests that bothregulatory and structural variations should be considered whenevaluating the utility of APOE for predicting dyslipidemia inthe population at large.

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

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