Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44905371 T>C
Position: (GRCh37/hg19):Chr19:45408628 T>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs769446
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: 2kb upstream

Findings

This common polymorphism was identified in a search for regulators of APOE gene expression (Artiga et al., 1998a). Sequencing nucleotides −1017 to +406 in samples of 75 unrelated Spanish individuals, the authors identified three polymorphisms, including c.-494T>C, in the APOE promoter. The minor allele, C, is found at a global frequency of 0.07 (gnomAD v2.1.1, August 2022). 

Studies evaluating the association of this variant with Alzheimer’s disease (AD) risk have yielded mixed results (see table below). The largest genome-wide association studies (GWAS) have revealed statistically significant associations, but the reported effect sizes are weak, and it remains unclear whether the variant itself modifies risk or travels together with a causal variant. Also, the location of the variant relative to the common APOE2/3/4 alleles on individual chromosomes (i.e., whether in cis or trans) is likely to be relevant to this variant's effects, given its location in the APOE promoter.

Artiga and colleagues first reported an association between the c.-494C allele and AD studying small Spanish and American cohorts (Artiga et al., 1998b). A few subsequent studies of small cohorts were consistent with these findings and two meta-analyses identified modest associations with AD risk (Bertram et al., 2007; Xiao et al., 2017). However, the effects reported by these meta-analyses were in opposite directions. The association found by Bertram et al. implicated the T allele and reached significance only after excluding a study to correct for between-study heterogeneity, whereas the association found by Xiao et al. implicated the C allele and was not reflected in analyses of the CC and CT genotypes.

Moreover, a few subsequent studies observed associations of c.-494T>C with AD that did not hold after adjusting for the common APOE alleles R176C (APOE2) and C130R (APOE4) (Yang et al., 2003; Nicodemus et al., 2004; Lynch et al., 2008), and some larger association analyses stratified by APOE2/3/4 genotype have failed to reach thresholds for statistical significance (see table below).

Artiga and colleagues noted an association between the c.-494C allele and APOE2 in a small Spanish population (Artiga et al., 1998). However, larger studies have revealed that linkage is relatively weak between c.-494T>C and the APOE2/E4 alleles. For example, in a study of approximately 75,000 Danish individuals, scores of r²=0.140 and D’=0.436 were obtained for APOE2 and c.-494C, and r²=0.002 and D’=0.308 for APOE4 and c.-494T (Rasmussen et al., 2020). Also of note, a large meta-analysis of AD GWAS listed the c.-494T>C polymorphism in a group of independent significant single nucleotide polymorphisms (p < 5 × 10⁻⁸, independent at r² < 0.6 with APOE2 as the lead SNP at r² < 0.1; Marioni et al., 2018).

The effect of c.-494T>C on AD risk may also depend on other variants beyond the common APOE isoforms, but results have been inconsistent. Two studies of small cohorts indicated c.-494T>C may boost AD risk together with the c.-558A allele, but one study implicated the C allele of the c.-494T>C variant while the other implicated the T allele (TT genotype) (Artiga et al., 1998b; Parker et al., 2005). Other studies have failed to detect any effect of the c.-494T>C polymorphism as part of different variant sets, or haplotypes (Bizzarro et al., 2009; Nicodemus et al., 2004).  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). Note that even weak linkages can be of importance as they can lead to confounding effects without proper adjustment (e.g., Andrews et al., 2019).

A few studies have reported associations of this variant with other neurological disorders, but they have involved limited numbers of patients. A study of a small cohort of Italian individuals, for example, reported an association with frontotemporal dementia (OR=4.4, 95% CI [1.9-10.2]) (Seripa et al., 2011). Moreover, a study of 350 Chinese infants with cerebral palsy and 242 healthy controls identified this variant as associated with disease (p=0.025 all patients; p=0.005 patients with preterm births; Xu et al., 2014). As a component of a group of five APOE variants, the C allele was associated with a decreased risk for the disease (OR=2.06, 95% CI [1.20-3.53], p=0.035). Isolated studies of dementia in post-stroke patients (Arpa et al., 2003) and subarachnoid hemorrhage (Kaushal et al., 2007) failed to detect an association, as did a meta-analysis of studies examining primary open-angle glaucoma (Guo et al., 2015). 

Interestingly, a GWAS of 2,580 European Americans revealed an association of the C allele with elevated levels of ApoE in plasma (β=0.49, p= 8.33 x 10^-18) a trait that correlated with better cognitive function (Aslam et al., 2023). The effect appeared to be independent from other variants in the region based on linkage disequilibrium analysis and a p-value that remained significant (6.91 x 10^-3) after adjusting for APOE2, the variant within the APOE region with the highest positive effect on plasma ApoE levels. A previous study, also in individuals of European ancestry, reported higher ApoE plasma levels associated with a lower risk of dementia, and specifically AD (Rasmussen et al., 2020). Some earlier studies have been consistent with Aslam and colleagues’ findings: one found lower ApoE plasma levels in AD patients with the TT genotype (Scacchi et al., 2001), and another recorded increased APOE mRNA levels in human liver samples of carriers of the c.-494C allele (Mannila et al., 2013). However, two other studies failed to detect similar effects (Lambert et al., 2000; Corbo et al., 2001).

Non-Neurological Effects

There are no clear associations between the 494T>C genotype and non-neurological conditions—other than increased ApoE plasma levels—in individuals of European ancestry. One study, for example, found no effect of the c.-494T>C variant on plasma lipid levels or on the risk for myocardial infarction in a small European cohort (Lambert et al., 2000). Another found no relationship between the c.-494T>C genotype and plasma lipoprotein levels in two cohorts of healthy middle-aged Swedes, each including more than 1,000 individuals (Mannila et al., 2013).

However, GWASs of large Japanese populations, including over 50,000 individuals, have detected moderate cardiovascular associations. For example, Matsunaga and colleagues found an association between the T allele and coronary artery disease (OR=1.34, 95% CI [1.22-1.47], p=2.44 X 10^-9; Matsunaga et al., 2020). In addition, the C variant was found to be associated with decreased levels of total cholesterol (Matsunaga et al., 2020) and cholesterol in low-density lipoprotein (Kanai et al., 2018). The relationships of these associations with the common APOE2/3/4 polymorphisms have yet to be clarified.

Biological effects

In vitro experiments designed to assess the biological effects of c.-494T>C have yielded mixed results. In transfected human hepatoma cells (Artiga et al., 1998a) and in transfected human neuroblastoma and rat PC12 cells (Maloney et al., 2010), the variant had no detectable effect on APOE promoter activity. However, a subsequent study reported increased transcription mediated by the C allele in human hepatoma cells (Mannila et al., 2013). This study also reported evidence of differences in the binding of nuclear proteins to c.-494C and c.-494T probes, yet no such differences were detected in an earlier study (Artiga et al., 1998a).

Transcriptional effects may vary between populations and depend on other variants beyond c.-494T>C. For example, while Corbo and colleagues found no effect of the variant on ApoE plasma concentrations in patients with coronary heart disease (Corbo et al., 2001), the same group found increased ApoE levels in a cohort of AD patients with the TT genotype (Scacchi et al., 2001). In addition, Artiga et al. reported that in astrocytoma cells, the c.-494C allele boosted transcription together with the A allele of c.-558A>T (Artiga et al., 1998b).

c.-494T is in the APOE promoter region (Paik et al., 1988), within the HuD functional domain which spans nucleotides -651 to -366 (Maloney et al., 2007). HuD was shown to act as a negative regulatory element of transcription in multiple cell types, including neuronal-like rat chromaffin cells (PC12), SK-N-SH neuroblastoma cells, C6 glial cells, and U373 astroctyoma cells. Also of note, c.-494T is close to the liver X receptor-retinoid X receptor (LXR/RXR) response element which regulates lipid synthesis and transport in multiple tissues (Aslam et al., 2023).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, did not reach 20 (3.024) , a commonly used threshold to predict deleteriousness (CADD v.1.6, Nov 2022).

Table

^aData from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage.
^bData from one study excluded to correct for between-study heterogeneity.

OR=odds ratio, GWAS=genome-wide association study. Statistically significant associations (as assessed by the authors) are in bold. For data retrieved from NIAGADS, p-values <5x10^-8 are in bold.
All GWAS in this table included >=2,000 cases, and all targeted association studies included >=500 cases (subgroups within a study may be smaller).

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References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE C130R (ApoE4)
3. APOE c.-558A>T (rs449647)

Paper Citations

1. Artiga MJ, Bullido MJ, Sastre I, Recuero M, García MA, Aldudo J, Vázquez J, Valdivieso F. Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett. 1998 Jan 9;421(2):105-8. PubMed.
2. Artiga MJ, Bullido MJ, Frank A, Sastre I, Recuero M, García MA, Lendon CL, Han SW, Morris JC, Vázquez J, Goate A, Valdivieso F. Risk for Alzheimer's disease correlates with transcriptional activity of the APOE gene. Hum Mol Genet. 1998 Nov;7(12):1887-92. PubMed.
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6. Nicodemus KK, Stenger JE, Schmechel DE, Welsh-Bohmer KA, Saunders AM, Roses AD, Gilbert JR, Vance JM, Haines JL, Pericak-Vance MA, Martin ER. Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease. Neurogenetics. 2004 Dec;5(4):201-8. Epub 2004 Sep 29 PubMed.
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18. Aslam MM, Fan KH, Lawrence E, Bedison MA, Snitz BE, DeKosky ST, Lopez OL, Feingold E, Kamboh MI. Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer's disease risk. Mol Psychiatry. 2023 Oct;28(10):4451-4462. Epub 2023 Sep 5 PubMed.
19. Scacchi R, Gambina G, Martini MC, Ruggeri M, Ferrari G, Silvestri M, Schiavon R, Corbo RM. Polymorphisms of the apolipoprotein E gene regulatory region and of the LDL receptor gene in late-onset Alzheimer's disease in relation to the plasma lipidic pattern. Dement Geriatr Cogn Disord. 2001 Mar-Apr;12(2):63-8. PubMed.
20. Mannila MN, Mahdessian H, Franco-Cereceda A, Eggertsen G, de Faire U, Syvänen AC, Eriksson P, Hamsten A, van 't Hooft FM. Identification of a functional apolipoprotein E promoter polymorphism regulating plasma apolipoprotein E concentration. Arterioscler Thromb Vasc Biol. 2013 May;33(5):1063-9. Epub 2013 Feb 21 PubMed.
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22. Corbo RM, Scacchi R, Vilardo T, Ruggeri M. Polymorphisms in the apolipoprotein E gene regulatory region in relation to coronary heart disease and their effect on plasma apolipoprotein E. Clin Chem Lab Med. 2001 Jan;39(1):2-6. PubMed.
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External Citations

1. GWAS catalog

Further Reading