Overview

Clinical Phenotype: Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44908847 C>A
Position: (GRCh37/hg19):Chr19:45412104 C>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to GAC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a population of 6,716 Southwestern American Indians in the U.S. (Kim et al., 2020). A genome-wide association study showed it was associated with reduced low-density lipoprotein (LDL) cholesterol levels (beta= -2.30, p=1.8 x 10-13). Of note, the variant was not in linkage disequilibrium with either of the two common APOE alleles C130R (APOE4) or R176C (APOE2), suggesting its effects are independent of these two isoforms.

The variant appears to be unique to this American Indian population. It is absent from the gnomAD variant database (v2.1.1, Dec 2021).

Biological Effect

The biological effect of this variant is unknown. Although A184 resides near the N-terminal edge of the ApoE hinge region, beyond the protein’s receptor-binding region, Kim and colleagues hypothesized this amino acid may play a role in ApoE’s binding to LDL receptors, with A184D increasing the affinity of the interaction (Kim et al., 2020). The proposal stems from previous observations suggesting that amino acids located in the hinge region are key to ApoE assuming its receptor-active conformation (Morrow et al., 2000).

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References

Mutations Citations

1. APOE C130R (ApoE4)
2. APOE R176C (ApoE2)

Paper Citations

1. Kim HI, Ye B, Gosalia N, Regeneron Genetics Center, Köroğlu Ç, Hanson RL, Hsueh WC, Knowler WC, Baier LJ, Bogardus C, Shuldiner AR, Van Hout CV. Characterization of Exome Variants and Their Metabolic Impact in 6,716 American Indians from the Southwest US. Am J Hum Genet. 2020 Aug 6;107(2):251-264. Epub 2020 Jul 7 PubMed.
2. Morrow JA, Arnold KS, Dong J, Balestra ME, Innerarity TL, Weisgraber KH. Effect of arginine 172 on the binding of apolipoprotein E to the low density lipoprotein receptor. J Biol Chem. 2000 Jan 28;275(4):2576-80. PubMed.

Further Reading

No Available Further Reading