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A more recent version of this article appeared on February 1, 2006

Papers In Press, published online ahead of print November 29, 2005
J. Lipid Res., doi:10.1194/jlr.M500491-JLR200
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Submitted on November 8, 2005
Accepted on November 28, 2005

Contribution of regulatory and structural variations in the APOE gene to predicting dyslipidemia

Jari H. Stengard, Sharon L.R. Kardia, Sara Hamon, Ruth Frikke-Schmidt, Anne Tybjaerg-Hansen, Veikko Salomaa, Eric Boerwinkle, and Charles F. Sing

Human Genetics, University of Michigan, Ann Arbor, MI 48109-0618

Corresponding Author: lilleck{at}umich.edu

Objective - Evaluate: 1) whether additional non-cSNP variations in the APOE gene identified by resequencing studies contribute to statistically explaining dyslipemia if variations in the cSNPs in exon four at positions 3937 and 4075 are ignored and 2) whether the contribution of these additional SNPs to prediction persists when variations in the two cSNPs are considered. Methods and Results - We employed an ecological, multiple population, data mining strategy to identify single-SNP and two-SNP genotypes that distinguish between high and low levels of multiple plasma measures of lipid metabolism in three training samples, European-Americans from Rochester, MN, African-Americans from Jackson, MS and Europeans from North Karelia, FI. We found that a pair of SNPs located in the 5' promoter region at positions 560 and 832 define a group of genotypes, A560T(sub832}/A560T832, A560T832/A560G832 and A560T832/T560T832, that distinguish between high and low levels of HDL-C, TG and/or T-C. The A560T832/A560T832 predicted low HDL-C in females and the group of A560T832/- genotypes predicted high TG and high T-C in both genders in a large independent sample from Copenhagen, DK. The utility of the A560T832/- genotypes in predicting high T-C in Danish females was dependent on genotypes defined by the epsilon 2, epsilon 3 and epsilon 4 alleles. Conclusions - Our study suggest that both regulatory and structural variations should be considered when evaluating the utility of the APOE gene for predicting dyslipidemia in the population at large.


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