Contribution of regulatory and structural variations in APOE to predicting dyslipidemia.
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 2, 3, and 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.
Stengård
Jari H
JH
National Public Health Institute, Helsinki, Finland.
Kardia
Sharon L R
SL
Hamon
Sara C
SC
Frikke-Schmidt
Ruth
R
Tybjaerg-Hansen
Anne
A
Salomaa
Veikko
V
Boerwinkle
Eric
E
Sing
Charles F
CF
D001741:Black or African American / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D003718:Denmark / Q000208:ethnology; D050171:Dyslipidemias / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005387:Finland / Q000208:ethnology; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D012307:Risk Factors; D012737:Sex Factors; D014280:Triglycerides / Q000097:blood; D014481:United States; D044465:White People / Q000235:genetics
D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D020033:Protein Isoforms; D014280:Triglycerides; D002784:Cholesterol