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Apolipoprotein E and familial longevity

Schupf et al. conducted a study to investigate the association between apolipoprotein E (APOE) and exceptional longevity. The APOE gene has three common alleles, 2, 3, and 4. The 4 allele has been associated with early mortality and a decreased frequency of the allele in the oldest old. However, the association of the 4 allele with mortality risk is inconsistent and varies by population. Recent studies have identified a variant in TOMM40, marked by the single nucleotide polymorphism rs2075650, which is associated with longevity but is close to and in linkage disequilibrium with rs429358, the marker for the APOE 4 allele.

The study recruited offspring from long-lived families and spouse controls at three sites in the United States and Denmark. The likelihood of carrying an APOE 4 allele or a G allele in rs2075650 was lower among family members in the offspring generation than among their spouse controls, while the likelihood of carrying an APOE 2 allele was higher among family members than among their spouse controls.

The findings support the hypothesis that both a reduction in the frequency of the 4 allele and an increase in the frequency of the 2 allele contribute to longevity. Because longevity is heritable, a family-based study design might serve well to address the question of the relation of APOE to longevity. 

Mortality associated with the presence of a risk allele might lead to reduced frequencies of risk alleles in the parental generation. Thus, it might be more informative to examine if there is a reduced frequency of risk alleles in offspring of people achieving exceptional longevity, where mortality is unlikely to confound the association between genetic risk factors and longevity.

The study recruited long-lived individuals, their siblings, and their offspring for an examination that characterized key intermediate phenotypes of longevity. A referent group consisting of the spouses, primarily of the offspring generation, was also recruited and examined. For this study, the analysis was restricted to the offspring generation and the examined sons, daughters, nieces, and nephews and their spouses.

Genotyping of APOE polymorphisms was based on SNPs rs7412 and rs429358 and was performed at the Biomedical Genomics Center at the University of Minnesota. Genotyping of the TOMM40 SNP rs2075650 was performed as part of the LLFS genome-wide association study and was typed via the Illumina HumanOmni 2.5 at the Center for Inherited Disease Research at Johns Hopkins University.

Overall, the study indicates that both a reduction in the frequency of the APOE 4 allele and an increase in the frequency of the APOE 2 allele contribute to familial longevity.Current information on names, including past names such as maiden names for women, addresses, place of birth, marriages, and vital status (Pedersen et al., 2006). Second, using information on the place of birth and the names, parish registers available in regional archives were searched to locate the parents of the elderly individuals to identify sibships. Based on the above information, potentially eligible families were identified, and contact was made with potential probands to further assess the family's eligibility for and willingness to participate in the LLFS using criteria parallel to that used in the United States. Recruitment, informed consent, and study procedures were approved by the Institutional Review Boards of all participating sites.

2.4. Statistical analysis

We checked Weinberg Equilibrium using the Haploview program (Barrett, 2009; Barrett et al., 2005) and did not find deviations of genotype frequencies from Hardy-Weinberg Equilibrium for any of the SNPs. To minimize population stratification, analysis was restricted to subjects of white ethnicity, resulting in the loss of 8 spouses (1%) and 5 relatives (0.2%) from the analysis. We used logistic regression procedures in generalized estimating equations to estimate the likelihood of carrying one or more APOE 4 alleles, one or more APOE 2 alleles, or one or more rs2075650 G alleles in TOMM40. Generalized estimating equations adjust for the relatedness of the LLFS offspring and controls and for the possibility that the characteristics of family members are correlated by both shared genetics and shared environment by treating family membership as a cluster. LLFS offspring were compared with spouse controls, adjusting for age, sex, level of education, and family membership (model A) and then adjusting for age, sex, level of education, family membership and a history myocardial infarction, hypertension, stroke, diabetes, and Parkinson's disease (model B). In the offspring generation, only 2 people were reported as suffering from dementia, so we did not include dementia as a covariate for these analyses. SNPs in TOMM40 have been shown to be in linkage disequilibrium with the APOE 4 allele, and it has been suggested that rs2075650 might not have an independent effect on longevity (Deelen et al., 2011; Nebel et al., 2011; Sebastiani et al., 2012). To examine this possibility, we repeated the analysis for TOMM40 including APOE in the model as a covariate and also among those with the APOE 3/3 genotype.

2.2. Eligibility and enrollment