Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type IIa, Hyperlipoproteinemia Type IIb
Position: (GRCh38/hg38):Chr19:44909275 C>T
Position: (GRCh37/hg19):Chr19:45412532 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs374329439
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4, 3' UTR

Findings

This variant was identified in two French patients in a cohort of nearly 6,000 unrelated individuals with primary dyslipidemia (Abou Khalil et al., 2022). One carrier had elevated levels of triglycerides in blood and was diagnosed with familial combined hyperlipidemia, also known as hyperlipoproteinemia type IIb (HLPP2b). The other had elevated low-density lipoprotein (LDL) cholesterol in blood and was diagnosed with autosomal dominant hypercholesterolemia, also known as hyperlipoproteinemia type IIa (HLPP2a).

Neither of the carriers had mutations in LDLR, PCSK9, or APOB, the genes most commonly associated with HLPP2a, and both were homozygous for the APOE3 allele. Of note, the weighted polygenic risk scores for both carriers were in decile IX, which, in the case of HLPP2a, strongly suggests the involvement of multiple genes in causing the disease.

The variant was also associated with elevated triglycerides in a population of 623 non-Hispanic whites, after adjusting for the common APOE alleles APOE2 and APOE4 (p=0.022; FDR=0.071; Radwan et al., 2014).

The frequency of this variant in the gnomAD variant database  was 0.00071 (gnomAD v3.1.1, Nov 2021). More than half of the 108 heterozygotes reported in gnomAD were of European (non-Finnish) ancestry and, within this population, the frequency was 0.00096. Of note, the frequency of the variant in the French cohort described above was lower (0.00017; Abou Khalil et al., 2022)

Biological Effect

The biological effect of this variant is unknown, but it is predicted to be part of a target for microRNA miR7704, and thus could affect the regulation of ApoE expression (Abou Khalil et al., 2022). miR7704 has been implicated in tumorigenesis. However, the computational algorithm Mutation Taster did not predict this variant to be disease-causing and the variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was 5.51, well below the commonly used threshold of 20 to predict deleteriousness.

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References

Paper Citations

1. Abou Khalil Y, Marmontel O, Ferrières J, Paillard F, Yelnik C, Carreau V, Charrière S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrié A, Rabès JP, Varret M. APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int J Mol Sci. 2022 May 21;23(10) PubMed.
2. Radwan ZH, Wang X, Waqar F, Pirim D, Niemsiri V, Hokanson JE, Hamman RF, Bunker CH, Barmada MM, Demirci FY, Kamboh MI. Comprehensive evaluation of the association of APOE genetic variation with plasma lipoprotein traits in U.S. whites and African blacks. PLoS One. 2014;9(12):e114618. Epub 2014 Dec 12 PubMed.

Further Reading

No Available Further Reading