Systematic Reviews and Meta- and Pooled Analyses

in Apolipoprotein E Frequency With Age in a Pooled Analysis of a Large of Older People

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, Centre for Public Health, Queen’s University Belfast, Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland (e-mail: g.j.mckay@qub.ac.uk).

Initially submitted August 24, 2010; accepted for publication January 14, 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 asso- ciated 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 ¼ 14.9 (1 df); P ¼ 0.0001), with a concomitant increase in the ’3 isoform (v2 for trend ¼ 11.3 (1 df); P ¼ 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.

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 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, multifunc-

tional 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 pe- ripheral nervous systems. Variation in 2 single nucleotide polymorphisms (SNPs) within the APOE gene, rs429358 and rs7412, results in different isoforms reported to exert op- posite 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 these SNPs are commonly referred to as e2, e3, and e4 and are differentiated on the basis of cysteine (Cys) and arginine (Arg) residue interchanges at positions 112 and 158 in the amino acid sequence. The 3 variants give rise to 6 biallelic genotypes (e3/e3, e3/e4, e2/e3, e4/e4, e2/e4, and e2/e2, ranked from most to least common among European pop- ulations (3)). The e2 allele has a cysteine residue at positions 112 and 158 in the receptor-binding region of apolipopro- tein E. The e3 allele has residues Cys-112 and Arg-158, and the e4 allele has arginine residues at both positions. These amino acid substitutions have strong physiologic conse- quences for protein function.

through population-based surveys (n ¼ 7,023). The der of the data came from case-control (association)

Data on age at examination, gender, smoking status (ever vs. never), APOE genotype, and AMD phenotype were re- quested from each contributing center (Table 1). All of the studies were approved by local ethics review boards, and each participant provided written informed consent prior to recruitment. Recruitment procedures and detailed AMD grading methods for each study center have been described previously (15–28).

Statistical analysis