Mutations

APOE c.-1334G>A (rs7259620)

Other Names: rs7259620

Overview

Clinical Phenotype: Alzheimer's Disease, Blood Lipids/Lipoproteins, Cardiovascular Disease
Reference Assembly: GRCh37/hg19
Position: Chr19:45407788 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs7259620
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: 2kb upstream

Findings

The A allele of this common single nucleotide polymorphism (SNP) has been associated with reduced risk of Alzheimer’s disease, but whether the variant itself modifies risk or is simply inherited together with a causal variant is unknown. The largest study, a genome-wide association study (GWAS) including 17,480 Europeans, found an association of the G allele with increased AD risk (OR=1.68, [CI 95% 1.51-1.84], p=2x10-23GWAS CatalogNazarian et al., 2019). Similarly, studies of small cohorts of individuals of Japanese and North Indian ancestry reported the A allele as being associated with reduced AD risk (Japanese: OR=0.71, [95%CI 0.59-0.85], p=2.54x10-4, Takei et al., 2009; Indian: OR = 0.56, [95% CI=0.37–0.85], p =7x10-3, Talwar et al., 2021).

One study of a small cohort of eldery Chinese, however, reported a weak association of the AA genotype with an increased risk of cognitive impairment compared with GA and GG genotypes (OR=1.56 [95%CI 1.02–2.38], p=0.04) and suggested an interaction with cadmium plasma levels (Ye et al., 2023).

Of note, in the Indian study, the variant was reported to be in linkage disequilibrium (r2=0.88) with another SNP in the APOE promoter region, c.-286T>G, which has been extensively studied in the context of AD (Talwar et al., 2021). Additional data on the linkage between c.-1334G>A and other nearby variants, across several populations, can be found in the GWAS catalog (click on “Linkage Disequilibrium” tab in the “Available data” section).

The global frequency of c.-1334G>A in the gnomAD variant database was 0.45, ranging from 0.32 in East Asians to 0.56 in Latino/Admixed Americans (gnomAD v2.1.1, Oct 2022).

Non-neurological Findings

The relationship of the c.-1334G>A polymorphism with blood lipid profiles and cardiac health has also been examined, yielding mixed results. A large GWAS including more than 100,000 individuals of European ancestry found the G allele associated with a decreased ratio of phospholipids to total lipids in large high-density lipoproteins (HDL) (beta=0.027 unit decrease, [CI 95% 0.019-0.035], p=3x10-11, GWAS Catalog, Richardson et al., 2022).

Moreover, a study of 28,445 Koreans over the age of 40 identified the A allele of c.-1334G>A as one of a set of five variants in nearby genes (TOMM40, PVRL2, EXOC3L2, and CD3EAP) associated with reduced risk of elevated total cholesterol and elevated low-density lipoprotein (LDL) cholesterol, especially when coupled with a high-protein diet (p < 1x10-4, Park and Kang, 2020). This set of variants, or haplotype, was also associated with reduced risk of myocardial infarction. Similarly, the A allele was reported as tied to reduced coronary heart disease in a study of more than 1,000 Chinese men (OR=0.743, p=0.029, Ji et al., 2019).

However, some studies have tied the variant to harmful lipid and cardiovascular phenotypes. For example, a study of 1,014 Chinese Yao adults reported an association with dyslipidemia (OR=0.540 [95% CI 0.336–0.869], p= 0.001, Cai et al., 2022), and a study of 1,523 Chinese Han individuals found an association with coronary heart disease, but only in males (χ2=5.190, df=1, p=0.023 by allele, Wu et al., 2018).

Biological Effect

This variant lies upstream of the APOE promoter region (see e.g., Maloney et al., 2007) and its biological function is unknown. Its PHRED-scaled CADD score (0.15), which integrates diverse information in silico, was well below 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Oct 2022).

Last Updated: 31 Aug 2023

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References

Mutations Citations

  1. APOE c.-286T>G (rs405509)

Paper Citations

  1. . Genome-wide analysis of genetic predisposition to Alzheimer's disease and related sex disparities. Alzheimers Res Ther. 2019 Jan 12;11(1):5. PubMed.
  2. . Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese. Genomics. 2009 May;93(5):441-8. Epub 2009 Feb 3 PubMed.
  3. . Validating a Genomic Convergence and Network Analysis Approach Using Association Analysis of Identified Candidate Genes in Alzheimer's Disease. Front Genet. 2021;12:722221. Epub 2021 Dec 9 PubMed.
  4. . ApoE gene polymorphisms and metals and their interactions with cognitive function. BMC Med Genomics. 2023 Aug 29;16(1):206. PubMed.
  5. . Characterising metabolomic signatures of lipid-modifying therapies through drug target mendelian randomisation. PLoS Biol. 2022 Feb;20(2):e3001547. Epub 2022 Feb 25 PubMed.
  6. . A minor allele of the haplotype located in the 19q13 loci is associated with a decreased risk of hyper-LDL-cholesterolemia, and a balanced diet and high protein intake can reduce the risk. Lipids Health Dis. 2020 Jul 29;19(1):178. PubMed.
  7. . APOE hypermethylation is significantly associated with coronary heart disease in males. Gene. 2019 Mar 20;689:84-89. Epub 2018 Dec 18 PubMed.
  8. . Associations between Apolipoprotein E Gene Polymorphism, Diet and Dyslipidemia in a Yao Minority Area, China. J Am Nutr Assoc. 2022 Sep-Oct;41(7):690-696. Epub 2021 Aug 2 PubMed.
  9. . Study of the association of 17 lipid-related gene polymorphisms with coronary heart disease. Anatol J Cardiol. 2018 Jun;19(6):360-367. PubMed.
  10. . Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer's disease. J Neurochem. 2007 Nov;103(3):1237-57. PubMed.

External Citations

  1. GWAS Catalog

Further Reading

Papers

  1. . Correlation between ESR1 and APOE gene polymorphisms and risk of osteonecrosis of the femoral head: a case-control study. J Orthop Surg Res. 2023 Dec 15;18(1):968. PubMed.

Protein Diagram

Primary Papers

  1. . Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese. Genomics. 2009 May;93(5):441-8. Epub 2009 Feb 3 PubMed.

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