rs7412 — APOE E2 determinant

APOE E2 variant - generally protective for cardiovascular health

Established Risk Factor

Details

Gene: APOE
Chromosome: 19
Protein change: p.Arg176Cys
Consequence: Missense
Inheritance: Codominant
Clinical: Risk Factor
Evidence: Established
Chip coverage: v3 v4 v5

Population Frequency

85%

14%

Ancestry Frequencies

african

11%

european

east_asian

south_asian

latino

Related SNPs

rs429358 (APOE)

External

SNPedia ClinVar dbSNP

APOE E2 Determinant — The Protective Variant

This variant, together with rs429358, determines your APOE genotype. The rs7412 variant causes a missense change at position 176 of the APOE protein, substituting arginine with cysteine (p.Arg176Cys). This defines the APOE ε2 isoform.

The Mechanism

The E2 isoform has reduced affinity for the LDL receptor compared to E3, which paradoxically leads to lower LDL cholesterol in most carriers. The arginine-to-cysteine substitution alters the protein's lipid-binding properties, generally leading to more efficient cholesterol clearance from the bloodstream.

The Evidence

The E2 allele is generally protective for cardiovascular health. E2 carriers typically have lower LDL cholesterol and better lipid profiles overall. A large neuropathological study¹¹ large neuropathological study
Reiman et al. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes. Nat Commun, 2020 of over 5,000 individuals confirmed that E2/E2 homozygotes have exceptionally low Alzheimer's risk — roughly 40% lower than E3/E3.

However, the rare E2/E2 genotype (~1% of the population) can sometimes be associated with type III hyperlipoproteinemia²² A rare lipid disorder (OMIM #617347) where cholesterol-rich remnant particles accumulate, causing yellowish skin deposits and elevated cardiovascular risk, particularly when combined with other metabolic triggers such as obesity, diabetes, or hypothyroidism.

Practical Implications

The E2 allele is generally protective for cardiovascular health and Alzheimer's disease. E2 carriers typically have lower LDL cholesterol and better lipid profiles overall. However, the rare E2/E2 genotype (~1% of the population) can sometimes be associated with type III hyperlipoproteinemia, particularly when combined with other metabolic triggers such as obesity, diabetes, or hypothyroidism.

Interactions

The rs7412 and rs429358 variants together determine your complete APOE genotype (E2/E2, E2/E3, E3/E3, E3/E4, E2/E4, or E4/E4), which has implications for both cardiovascular health and Alzheimer's risk.

Nutrient Interactions

dietary cholesterol altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant:

CC “No E2” Normal

No E2 - see rs429358 for E3/E4 status

You don't carry the E2 variant. About 85% of people share this genotype.

TT “E2/E2 Homozygous” Beneficial Caution

APOE E2/E2 - protective but monitor lipids

You have two APOE E2 alleles, a rare genotype (~1% of the population). This is generally protective for cardiovascular disease and Alzheimer's. However, E2/E2 can sometimes cause a condition called type III hyperlipoproteinemia if combined with other metabolic triggers like obesity or hypothyroidism.

CT “E2 Carrier” Beneficial

One APOE E2 - generally protective

You carry one APOE E2 allele, found in about 14% of Europeans and up to 20% of people of African descent. E2 is generally protective for cardiovascular health — carriers typically have lower LDL cholesterol and about 40% reduced Alzheimer's risk compared to E3/E3.