title: Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study.
abstract: The apolipoprotein E (apoE) is a classic example of a gene exhibiting pleiotropism. We examine potential pleiotropic associations of the apoE2 allele in three biodemographic cohorts of long-living individuals, offspring, and spouses from the Long Life Family Study, and intermediate mechanisms, which can link this allele with age-related phenotypes. We focused on age-related macular degeneration, bronchitis, asthma, pneumonia, stroke, creatinine, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, diseases of heart (HD), cancer, and survival. Our analysis detected favorable associations of the ε2 allele with lower LDL-C levels, lower risks of HD, and better survival. The ε2 allele was associated with LDL-C in each gender and biodemographic cohort, including long-living individuals, offspring, and spouses, resulting in highly significant association in the entire sample (β = -7.1, p = 6.6 × 10-44). This allele was significantly associated with HD in long-living individuals and offspring (relative risk [RR] = 0.60, p = 3.1 × 10-6) but this association was not mediated by LDL-C. The protective effect on survival was specific for long-living women but it was not explained by LDL-C and HD in the adjusted model (RR = 0.70, p = 2.1 × 10-2). These results show that ε2 allele may favorably influence LDL-C, HD, and survival through three mechanisms. Two of them (HD- and survival-related) are pronounced in the long-living parents and their offspring; the survival-related mechanism is also sensitive to gender. The LDL-C-related mechanism appears to be independent of these factors. Insights into mechanisms linking ε2 allele with age-related phenotypes given biodemographic structure of the population studied may benefit translation of genetic discoveries to health care and personalized medicine.
authors.affiliation: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, USA. Alexander.Kulminski@duke.edu.
authors.forename: Alexander M
authors.identifier: 0000-0002-0205-8228
authors.initials: AM
authors.lastname: Kulminski
authors.affiliation: National Institute on Aging, 31 Center Drive, MSC 2292, Bethesda, MD, 20892, USA.
authors.forename: Nalini
authors.initials: N
authors.lastname: Raghavachari
authors.affiliation: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, USA.
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Arbeev
authors.affiliation: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Culminskaya
authors.affiliation: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, USA.
authors.forename: Liubov
authors.initials: L
authors.lastname: Arbeeva
authors.affiliation: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, USA.
authors.forename: Deqing
authors.initials: D
authors.lastname: Wu
authors.affiliation: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, USA.
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Ukraintseva
authors.affiliation: The Danish Aging Research Center, University of Southern Denmark, 5000, Odense C, Denmark.|Department of Clinical Genetics and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, 5000, Odense C, Denmark.
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.affiliation: Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, USA.
authors.forename: Anatoliy I
authors.initials: AI
authors.lastname: Yashin
mesh_terms: D017677:Age Distribution; D000375:Aging / Q000235:genetics*; D000483:Alleles; D053329:Apolipoprotein E2 / Q000235:genetics*; D002908:Chronic Disease / Q000401:mortality; D016638:Critical Illness / Q000401:mortality*; D019317:Evidence-Based Medicine; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D038622:Internationality; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D040641:Quantitative Trait Loci / Q000235:genetics; D012307:Risk Factors; D017678:Sex Distribution; D015996:Survival Rate
chemical_list: D053329:Apolipoprotein E2; D005819:Genetic Markers
keywords: ApoE; Health span; Life span