Systematic Reviews and Meta- and Pooled Analyses of Apolipoprotein E Frequency with Age in a Pooled Analysis of a Large Group of Older People by J. McKay*, Giuliana Silvestri, Usha Chakravarthy, Shilpa Dasari, Lars G. Fritsche, Bernhard Weber, Claudia N. Keilhauer, Michael L. Klein, Peter J. Francis, Caroline C. Klaver, Johannes Vingerling, Lintje Ho, Paulus T. D. V. De Jong, Michael Dean, Julie Sawitzke, Paul N. Baird, H. Guymer, Dwight Stambolian, Anton Orlin, Johanna M. Seddon, Inga Peter, Alan F. Wright, Hayward, Andrew J. Lotery, Sarah Ennis, Michael B. Gorin, Daniel E. Weeks, Kuo, Aroon D. Hingorani, Reecha Sofat, Valentina Cipriani, Anand Swaroop, Mohammad Atsuhiro Kanda, Wei Chen, Goncalo R. Abecasis, John R. Yates Andrew R. Webster T. Moore Johan H. Seland Mati Rahu Gisele Soubrane Laura Tomazzoli Topouzis Jesus Vioque Ian S. Young Astrid E. Fletcher and Chris C. Patterson.
* Correspondence to Dr. Gareth J. McKay at the Centre for Public Health at Queens University Belfast Royal Victoria Hospital Belfast BT12 6BA Northern Ireland (email: g.j.mckay@qub.ac.uk). Initially submitted on August 24th 2010; accepted for publication on January 14th 2011.
Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms 2, 3, and 4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE 4 isoform with increasing age (v2 for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the 3 isoform (v2 for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in 4 homozygotes; the frequency of 4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the 3/4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.
Keywords: aged; apolipoprotein E2; apolipoprotein E3; apolipoprotein E4; apolipoproteins E; longevity; meta-analysis; multicenter study.
Abbreviations: AMD, age-related macular degeneration; APOE, apolipoprotein E gene; Arg, arginine; Cys, cysteine; LDL, low-density lipoprotein; SNP, single-nucleotide polymorphism.
The human apolipoprotein E gene (APOE; OMIM 107741), located on chromosome 19q13.2, is central to the metabolism of low-density lipoprotein (LDL) cholesterol and triglycerides and has been associated with an increased risk of a variety of complex and age-related disorders (1). These include coronary heart disease events (2), atherosclerosis (3), age-related macular degeneration (AMD) (4), Alzheimer's disease (5), and other dementias (6). The small, multifunctional apolipoprotein E lipid transport protein acts as a ligand for the LDL receptor and is also involved in the maintenance and repair of neuronal cell membranes in the central and peripheral nervous systems. Variation in two single-nucleotide polymorphisms (SNPs) within the APOE gene, rs429358 and rs7412, results in different isoforms reported to exert opposite effects in relation to the metabolism of coronary heart disease-related blood products such as LDL cholesterol and triglycerides (3, 7, 8). The allelic variants derived from theseAssociated with the E2/E3 genotype (11, 12), furthermore, a gender-specific survival effect associated with E2 has been reported. However, it is still unclear whether this is specific to males or females, with opposing associations being reported for both genders (13, 14). The analyses carried out in this study were subsidiary to a pooled data analysis assessing APOE variation in the context of AMD. The authors examined the association of APOE with age as a marker for longevity and assessed the potential for a gender-specific effect.

RESULTS

APOE allele frequency with age

MATERIALS AND METHODS

No significant differences were detected for either SNP by center or within the entire dataset. APOE allele frequencies varied between studies (data not shown), with ranges of 6.7%-10.0% (APOE E2), 75.3%-82.8% (APOE E3), and 7.5%-15.6% (APOE E4). APOE genotype frequencies for the 10,623 controls are shown in Table 2. The frequency of the E4 allele decreased from 17.6% to 8.3% (9.3%) with increasing age, while the frequency of the E3 allele increased from 73.3% to 83.3% (10.0%) (Table 3, Figure 1). Following adjustment for center and smoking status to limit potential confounding, we observed a significant decrease in the frequency of E4 with increasing age (χ2 =14.9; P=0.0001), representing a 5% decrease in odds per 5-year increase in age (odds ratio=0.95, 95% confidence interval: 0.92, 0.97), as well as a significantly increased frequency of E3 (χ2=11.3; P=0.001), representing a 4% increase in odds per 5-year increase in age (odds ratio=1.04, 95% confidence interval: 1.02, 1.07). The frequency of the E2 allele showed little variation with age. The relations between allele frequency and age in males and females were compared by including an age x gender interaction in the logistic regression analysis, but none of the interactions were significant (likelihood ratio χ2 test: E2, P=0.13; E3, P=0.25; E4, P=0.80). Tests of age x center interactions were also conducted and showed no evidence of heterogeneity in age effects by center (likelihood ratio χ2 test: E2, P=0.21; E3, P=0.88; E4, P=0.38).