The genetics of the human APOE polymorphism

Area of Science:

• Human Genetics
• Molecular Biology
• Population Genetics

Background:

• The human apolipoprotein E (apoE) protein exists in three common variants: E2, E3, and E4, encoded by APOE gene variants ε2, ε3, and ε4.
• These variants are linked to age-related diseases like Alzheimer's and influence healthy aging and longevity.
• APOE variants arise from specific haplotypes at the 19q13.31 locus, typically formed by combinations of rs429358 and rs7412 single-nucleotide polymorphisms.

Purpose of the Study:

• To report the identification of the rare APOE ε3r haplotype in an additional Caucasian family from Italy.
• To re-examine current knowledge of APOE gene polymorphism and evolution by incorporating the ε3r haplotype.
• To discuss the implications of the E3r protein isoform, which shares physical characteristics with the common E3 isoform.

Main Methods:

• Genetic analysis to identify the APOE ε3r haplotype in a new family.
• Review and re-evaluation of existing literature on APOE polymorphism and evolutionary hypotheses.
• Comparison of the physical characteristics of the E3r protein isoform with the common E3 isoform.

Main Results:

• The APOE ε3r haplotype was identified in a third Caucasian family from Italy.
• This rare haplotype encodes the E3r protein isoform, which is physically indistinguishable from the common E3 apoE protein.
• The identification of ε3r in additional families supports its inclusion in evolutionary models of APOE.

Conclusions:

• The discovery of the ε3r haplotype in more families necessitates an updated understanding of APOE gene diversity.
• Current hypotheses on APOE evolution should be revised to account for the ε3r haplotype and its implications.
• Further research is needed to understand the prevalence and potential functional significance of the E3r isoform.