Overview

Clinical Phenotype: Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44907291 A>G
Position: (GRCh37/hg19):Chr19:45410548 A>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs115299243
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: Intron 2

Findings

This intronic variant, mostly found in individuals of African ancestry, has been associated with altered levels of low-density lipoprotein (LDL) cholesterol and triglycerides in blood. However, whether the variant has a direct effect on these traits or is inherited with other causal variants remains unknown.

In 2014, a study of 788 African Blacks and 623 non-Hispanic Whites revealed an association of the variant with decreased levels of LDL cholesterol in Blacks after adjusting for the common alleles R176C (APOE2) and C130R (APOE4) (β = −2.54; p = 0.0008; FDR = 0.008; Radwan et al., 2014). Similarly, a large genome-wide association study (GWAS) including thousands of individuals of diverse ancestries reported an association with LDL-cholesterol levels (β=7.77 unit decrease, [CI 95% 4.5-11.03], p=3x10^-8; Wojcik et al., 2019; data from GWAS catalog, Oct 2022). However, Radwan and colleagues noted that the association could be mediated by R163C, a variant genetically linked to c.44-469A>G and associated with several conditions involving altered lipid and lipoprotein profiles (Radwan et al., 2014). The authors also found an association with decreased levels of apolipoprotein B, but this was thought to be likely attributable to APOE2. Additional data on the linkage between c.44-469A>G and other variants nearby, across several populations, can be found in the GWAS catalog (click on “Linkage Disequilibrium” tab in the “Available data” section).

An association of c.44-469A>G with elevated triglycerides was also identified in African Blacks, but not non-Hispanic whites, independent of APOE2 and APOE4 (β = 0.065; p = 0.038; FDR = 0.20; Radwan et al., 2014). Two GWAS including thousands of subjects of diverse ancestries also tied this variant to blood triglyceride levels (β=0.42, p=7x10^-10, Hoffman et al., 2018; β=0.16, [CI95% 0.12-0.20], p=1x10^-14, Wojcik et al., 2019; data from GWAS catalog, Oct 2022).

In the gnomAD variant database, this variant had a global frequency of 0.0057 (v2.1.1, Oct 2022). Most alleles were from carriers of African ancestry (174 of 180) and, in this group, the frequency was 0.02.

Biological Effect

The biological effect of this variant is unknown, but its PHRED-scaled CADD score (5.91), which integrates diverse information in silico, was well below 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Oct 2022).

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References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE C130R (ApoE4)
3. APOE R163C

Paper Citations

1. 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.
2. Wojcik GL, Graff M, Nishimura KK, Tao R, Haessler J, Gignoux CR, Highland HM, Patel YM, Sorokin EP, Avery CL, Belbin GM, Bien SA, Cheng I, Cullina S, Hodonsky CJ, Hu Y, Huckins LM, Jeff J, Justice AE, Kocarnik JM, Lim U, Lin BM, Lu Y, Nelson SC, Park SL, Poisner H, Preuss MH, Richard MA, Schurmann C, Setiawan VW, Sockell A, Vahi K, Verbanck M, Vishnu A, Walker RW, Young KL, Zubair N, Acuña-Alonso V, Ambite JL, Barnes KC, Boerwinkle E, Bottinger EP, Bustamante CD, Caberto C, Canizales-Quinteros S, Conomos MP, Deelman E, Do R, Doheny K, Fernández-Rhodes L, Fornage M, Hailu B, Heiss G, Henn BM, Hindorff LA, Jackson RD, Laurie CA, Laurie CC, Li Y, Lin DY, Moreno-Estrada A, Nadkarni G, Norman PJ, Pooler LC, Reiner AP, Romm J, Sabatti C, Sandoval K, Sheng X, Stahl EA, Stram DO, Thornton TA, Wassel CL, Wilkens LR, Winkler CA, Yoneyama S, Buyske S, Haiman CA, Kooperberg C, Le Marchand L, Loos RJ, Matise TC, North KE, Peters U, Kenny EE, Carlson CS. Genetic analyses of diverse populations improves discovery for complex traits. Nature. 2019 Jun;570(7762):514-518. Epub 2019 Jun 19 PubMed.
3. Hoffmann TJ, Theusch E, Haldar T, Ranatunga DK, Jorgenson E, Medina MW, Kvale MN, Kwok PY, Schaefer C, Krauss RM, Iribarren C, Risch N. A large electronic-health-record-based genome-wide study of serum lipids. Nat Genet. 2018 Mar;50(3):401-413. Epub 2018 Mar 5 PubMed.

External Citations

1. GWAS catalog

Further Reading

No Available Further Reading