title: Assessment of the contribution of APOE gene variants to metabolic phenotypes associated with familial longevity at middle age.
abstract: Offspring of long-lived families are characterized by beneficial metabolic phenotypes in glucose and lipid metabolism and low 25-hydroxyvitamin D. Although the genetic basis for human longevity remains largely unclear, the contribution of variation at the APOE locus has been repeatedly demonstrated. We aimed to assess whether ApoE isoforms mark the familial longevity status in middle age and subsequently to test to what extend this association is mediated by the metabolic characteristics marking this status. From the Leiden Longevity Study (LLS), we included offspring from nonagenarian siblings and partners as controls. Using the metabolic phenotypes of familial longevity as mediators, we investigated how APOE gene variants associated with LLS offspring/control status (in 1,515 LLS offspring and 715 controls). Within the LLS (mean age = 59.2 years), ApoE ε4 was not associated with a lower likelihood of being an LLS offspring, whereas ApoE ɛ2 was significantly associated with a higher likelihood of being an LLS offspring (odds ratio = 1.43), but this difference was not mediated (p-values>0.05) by any of the investigated metabolic phenotypes (e.g., diabetes and glucose). Therefore, variation at the APOE locus may not influence familial longevity status in middle age significantly through any of the metabolic mechanisms investigated.
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Raymond
authors.initials: R
authors.lastname: Noordam
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Oudt
authors.affiliation: Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.affiliation: Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: van Heemst
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001057:Apolipoproteins E / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008136:Longevity / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010641:Phenotype
chemical_list: D001057:Apolipoproteins E; D001786:Blood Glucose; D007328:Insulin; D008055:Lipids
keywords: 25-hydroxyvitamin D; APOE; glucose; human longevity; mediation