The Genetics of the Human APOE Polymorphism

Abstract

The genetic origin of the three common variants of the human apolipoprotein E (apoE) protein, known as E2, E3 and E4, was understood in 1981, and since the mid 1980s these are probably the most-studied protein variants in human races. They have been related to a number of age-related diseases, including Alzheimer disease, as well as to healthy aging and longevity. The gene variants underlying these protein isoforms, known as ε2, ε3, and ε4, are allelic forms of the APOE gene, resulting from different haplotypes at the APOE locus (19q13.31). In particular, they result from three of the four haplotypes expected by the combinations of the alleles of the two single-nucleotide polymorphisms rs429358 and rs7412. The fourth missing haplotype, known as ε3r, has been identified in only two Caucasian families from Italy and in one Yoruba family from Nigeria worldwide. Thus, this fourth APOE gene variant is rare, and it encodes a protein isoform, identified as E3r, showing identical physical characteristics to E3, that conversely, is the most common form of apoE in humans. In this review article, we report the identification of the haplotype ε3r in a third Caucasian family from Italy, and then attempt to re-examine the current knowledge regarding the APOE polymorphism, taking into account this fourth haplotype. We also focus on the commonly accepted hypothesis for the evolution of the common APOE gene variants, in which we include the ε3r haplotype, previously not considered.

Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

“…The APOE ε4 haplotype is by far the most validated genetic variation and has repeatedly been associated with human longevity (e.g., Asada et al 1996;Bathum et al 2006;Deelen et al 2011;Gerdes et al 2000;McKay et al 2011;Nebel et al 2011;Schachter et al 1994), whereas one study has found association of rs2542052 in APOC3 with longevity (Atzmon et al 2006). The APOE polymorphism was recently reviewed in (Seripa et al 2011). Also involved in lipoprotein metabolism is the cholesteryl ester transfer protein (cetp) for which rs5882 in CETP has been reported as a longevity SNP (Barzilai et al 2003).…”

Apolipoprotein E synthesized by adipocyte and apolipoprotein E carried on lipoproteins modulate adipocyte triglyceride content

“…Recently, the rare haplotype has been reported in several subjects. This fourth ApoE allele is similar to ϵ3, and termed as the ϵ3r allele that encodes the ApoE3r isoform [31, 32]. In the lipid-binding function, ApoE3 and ApoE2 preferentially bind the smaller, highly curved lipid emulsions (e.g., HDL), while ApoE4 prefers larger, less curved lipid emulsions (i.e., VLDL).…”

Antioxidant Status andAPOEGenotype As Susceptibility Factors for Neurodegeneration in Alzheimer's Disease and Vascular Dementia

“…17 The e4 allele of the APOE gene is associated with a variety of complex and age-related disorders. 18 Moreover, the APOE e4 alllele has been shown to play an important role in antioxidant status. 19,20 Furthermore, both oxidative stress and APOE e4 have been shown to have significant associations with lipid dyshomeostasis.…”