Overview

Clinical Phenotype: Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44906322 C>T
Position: (GRCh37/hg19):Chr19:45409579 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs769448
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: Intron 1

Findings

This intronic variant has been associated with blood lipoprotein levels. In a large genome-wide association study including nearly 350,000 individuals of different ancestries, an association with increased low-density lipoprotein cholesterol (LDL-C) and ApoB levels was identified (GWAS catalog, 2022; Sinnott-Armstrong et al., 2021). Also, in two smaller studies—including 623 non-Hispanic whites and 788 African blacks—the variant was associated with elevated high-density lipoprotein cholesterol (HDL-C) levels, but only in white individuals (Radwan et al., 2014; Pirim et al., 2019). 

The variant was reported in the gnomAD variant database at a frequency of 0.021, including 414 carriers, most of European ancestry (gnomAD, v2.1.1 Mar 2022). Data on the linkage between this variant and other nearby variants, across several populations, can be found in the GWAS catalog (click on “Linkage Disequilibrium” tab in the “Available data” section).

Biological Effect

This variant was predicted to break up a CpG island, a stretch of DNA with a large number of CG repeats which are usually unmethylated in gene promoters (Shyamala et al., 2022). Introns can regulate gene transcription, and APOE methylation has been found to be inversely proportional to expression, suggesting this variant may affect ApoE levels. Indeed, the variant was predicted to abolish binding of the Sp1 transcription factor.

However, an integrative computational tool to predict variant deleteriousness suggested a low likelihood of this variant being damaging (PHRED-scaled CADD = 3.69; CADD v1.6, Mar 2022).

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References

Paper Citations

1. Sinnott-Armstrong N, Tanigawa Y, Amar D, Mars N, Benner C, Aguirre M, Venkataraman GR, Wainberg M, Ollila HM, Kiiskinen T, Havulinna AS, Pirruccello JP, Qian J, Shcherbina A, FinnGen, Rodriguez F, Assimes TL, Agarwala V, Tibshirani R, Hastie T, Ripatti S, Pritchard JK, Daly MJ, Rivas MA. Genetics of 35 blood and urine biomarkers in the UK Biobank. Nat Genet. 2021 Feb;53(2):185-194. Epub 2021 Jan 18 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.
3. Pirim D, Radwan ZH, Wang X, Niemsiri V, Hokanson JE, Hamman RF, Feingold E, Bunker CH, Demirci FY, Kamboh MI. Apolipoprotein E-C1-C4-C2 gene cluster region and inter-individual variation in plasma lipoprotein levels: a comprehensive genetic association study in two ethnic groups. PLoS One. 2019;14(3):e0214060. Epub 2019 Mar 26 PubMed.
4. Shyamala N, Kongettira CL, Puranam K, Kupsal K, Kummari R, Padala C, Hanumanth SR. In silico identification of single nucleotide variations at CpG sites regulating CpG island existence and size. Sci Rep. 2022 Mar 4;12(1):3574. PubMed.

External Citations

1. GWAS catalog, 2022

Further Reading

No Available Further Reading