Gender- and age-specific contributions of additional DNA sequence variation in the 5' regulatory region of the APOE gene to prediction of measures of lipid metabolism.
In the present study of 9,000 individuals representative of the general population, we have considered whether the addition of common single nucleotide polymorphisms (SNPs) in the promoter region of Apolipoprotein E (APOE) improve the statistical explanation of variation in lipid traits and test the hypothesis that the estimated genotype effects are independent of factors indexed by gender and age. To address these questions, we have asked, for each gender and for each 20-year age strata (young: 20-39 years; middle-aged: 40-59 years; old: 60-79 years; very old: 80-100 years), how much trait variation is associated with the traditional epsilon2, epsilon3, and epsilon4 allelic variations defined by the g.2059T --> C and g.2197C --> T SNPs in the fourth exon of the APOE gene, and how much additional trait variation is associated with genotypes defined by combining the g.2059T --> C and g.2197C --> T SNPs with one, two, or three promoter SNPs. Our study demonstrates that the pleiotropic effects of genotype variation defined by the traditional epsilon2, epsilon3, and epsilon4 alleles on five plasma measures of lipid metabolism manifest differently in women and men and change significantly during the life cycle for high-density lipoprotein cholesterol in women. Multi-site genotypes defined by adding SNPs located in the 5' promoter region to the traditional g.2059T --> C and g.2197C --> T SNPs doubled the estimate of genetic variance of high-density lipoprotein and apolipoprotein Al in middle-aged females.
Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.
Ruth
R
Frikke-Schmidt
Charles F
CF
Sing
Børge G
BG
Nordestgaard
Anne
A
Tybjaerg-Hansen
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012737:Sex Factors
D001057:Apolipoproteins E; D017931:DNA Primers; D008055:Lipids