Mutations

APOE c.-24+69C>G (rs440446)

Other Names: rs440446, +113C/G, IE1, IVS1+69, +969

Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44905910 C>G
Position: (GRCh37/hg19):Chr19:45409167 C>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs440446
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: Intron 1

Findings

This common intronic variant is strongly associated with Alzheimer’s disease (AD) risk, but the association appears to be primarily due to its genetic linkage to C130R (APOE4). It was first identified in a search for polymorphisms affecting AD risk that included portions of the APOE promoter, nearby enhancer elements, and the receptor binding domain (Mui et al., 1996). Located in the intron 1 enhancer element (IE1), the G allele of this polymorphism was reported as significantly associated with AD in a cohort of 94 Americans. The authors also found that when they adjusted their analyses for the presence of APOE4, the association was no longer statistically significant. They concluded that the apparent association of c.-24+69C>G with AD was a consequence of its linkage to APOE4.

Most subsequent studies, including cohorts of different ancestries, yielded results consistent with this conclusion (e.g., Rebeck et al., 1999; Cui et al., 2000; Yang et al., 2003;  Nicodemus et al., 2004; Belbin et al., 2007; Yu et al., 2007; Takei et al., 2009; Limon-Sztencel et al., 2016; Rantalainen et al., 2018). Moreover, more recent analyses of larger cohorts, including genome-wide association studies (GWAS) and meta-analyses, have been supportive of these findings, with association p-values that fall dramatically after APOE4 adjustment or stratification (see table below).

Nevertheless, located in a site thought to regulate transcription, this variant may do more than simply tag along with APOE4. Although based on observations in small cohorts, some studies suggest it may modulate the impact of APOE4 (Lambert et al., 1998), affect the rate of cognitive decline in AD without affecting risk (Belbin et al. 2007), modulate cognitive ability in elderly, nondemented APOE3 homozygotes (Rantalainen et al., 2016), and/or alter the risk for ischemic stroke independently of APOE4 (Abboud et al., 2008). 

Teasing out its effects has been complicated, not only because of its linkage to APOE4, but because of its linkage to other variants in APOE and nearby genes. Early reports, for example, found a tight linkage between c.-24+69C>G and the APOE promoter variant c.-286T>G (Lambert et al., 1998, Myllykangas et al., 2002, Belbin et al., 2007). Indeed, some studies suggest late-onset AD genetic risk can be better understood by studying the combined effects of multiple variants that tend to be inherited together, also known as haplotypes. In this context, a haplotype including c.-24+69C>G has been reported to modify the effect of the protective allele R176C (APOE2) (Kulminski et al., 2020). Data on the linkage between c.-24+69C>G and neighboring variants, across several populations, can be found in the GWAS catalog (click on “Linkage Disequilibrium” tab in the “Available data” section). 

Also of note, the frequencies of c.-24+69C>G vary across groups of different ancestries. Globally, the G allele is found at a frequency of 0.62, with a higher frequency in African Americans (0.88) than in Europeans (0.64) or East Asians (0.40) (gnomAD v2.1.1, Aug 2022). Interestingly, in a study of 19,398 East Asians, 15,836 individuals of European ancestry, and 4,985 African Americans, even larger differences were reported pertaining to the GG genotype (African=0.75, European=0.46, East Asian=0.18), but the differences were much smaller among APOE4 homozygotes (African=0.99, European=0.90, East Asian=0.71), consistent with these two variants being strongly linked to each other (Choi et al., 2019). 

Non-neurological effects

Multiple studies have examined the relationship of this variant with cardiovascular disease, but results have been mixed and most have not accounted for linkage with other APOE variants. A study of nearly 2,000 German patients found no association with death and myocardial infarction, nor with formation of new arterial blockages after treatment with a stent (Koch et al., 2004). Also, a study of young Finns failed to detect an association with markers of subclinical atherosclerosis (Viiri et al., 2006), and a study of a small cohort of Chinese individuals found no association with essential hypertension (Yang et al,, 2012). On the other hand, in two Finnish studies, the c.-24+69C allele was associated with an elevated risk for coronary heart disease (Silander et al., 2008), and with larger aortic atherosclerotic lesions in nonsmokers and smaller lesions in smokers (Viiri et al., 2008).

Studies of blood lipid profiles have also yielded mixed results. Possible explanations for these discrepancies include differences in cohorts, particularly ancestryand gender, as well as whether and how studies accounted for linkage with other APOE variants. For example, elevated levels of cholesterol and low density lipoprotein (LDL) were reported in Finnish and Chinese carriers of the C allele (Viiri et al., 2006; Andreotti et al., 2009), while lower cholesterol levels were associated with the C allele in an American cohort of non-Hispanic whites (Radwan et al., 2014, Pirim et al., 2019). Of note, Radwan and colleagues adjusted for the presence of APOE2 and APOE4, and Viiri et al. included only APOE3 homozygotes. Also, the latter study examined the c.-24+69C>G variant in the context of APOE variant c.-286T>G, which resides in the APOE promoter and appears to modulate transcription. They found that male, but not female, carriers of the c.-286T/c.-24+69C/APOE3 haplotype had higher LDL-cholesterol and total cholesterol concentrations across a 21-year follow-up period compared with homozygous G allele carriers or noncarriers of c.-286T/c.-24+69C/APOE3.

In addition, carriers of c.-24+69C were reported to have higher levels of ApoB, a marker of cardiovascular disease risk, in African Blacks, and lower levels of triglycerides and very low-density lipoprotein (VLDL) in non-Hispanic whites (Pirim et al., 2019). Both the triglyceride and ApoB associations were also observed in a study of Finnish individuals, although this study did not adjust for the common APOE isoforms (Viiri et al., 2005). Some studies, on the other hand, have failed to find distinct patterns of blood lipid profiles associated with this variant. For example, a study of approximately 500 Spaniards reported no differences between individuals with a c.-24+69GG genotype versus heterozygotes or CC homozygotes (Gomez-Delgado et al., 2019).

The c.-24+69C>G variant has also been studied in the context of other phenotypes. A large GWAS including 440,000 Europeans, for example, found an association of the variant with eosinophil counts, although the effect allele was not noted (Kichaev et al., 2018). Studies of small cohorts of patients with diabetes and diabetes-related phenotypes (Geng et al., 2011; Komurcu-Bayrak et al., 2011; Araki et al., 2000), and patients with reduced bone density (Tolonen et al., 2011; Singh et al., 2010; Tong et al., 2010) have yielded inconsistent results. One study found an association of the c.-24+69G allele with risk for cancer and stones in the biliary tract (Andreotti et al., 2008).

Biological Effect

The c.-24+69C>G variant resides within the evolutionarily conserved IE1 intronic sequence which is thought to regulate transcriptional activity (Paik et al., 1998; Viiri et al., 2008). In a reporter assay, transcription of a construct carrying a C allele upstream of the luciferase gene was approximately 1.4-fold higher than that of a construct carrying the G allele (Viiri et al., 2008). Interestingly, an antisense C-allele construct placed downstream of the luciferase gene performed similarly, enhancing transcription roughly 1.6 times compared with the G allele.

Consistent with these findings, proteins in nuclear extracts from human hepatoma cells and Chinese hamster ovary cells showed affinity for IE1 (Paik et al., 1998). Overall, proteins from hepatoma extracts had a lower affinity for constructs carrying the C allele than the G allele. In addition, NFκB and RBP-Jκ were identified as transcription factors likely to interact with IE1, with NFκB having a fourfold higher affinity for the C allele (Viiri et al., 2008).

In addition, it has been noted that c.-24+69C>G contributes to determining the CG dinucleotide composition of this region, affecting methylation status, which may impact gene expression (Babenko et al., 2018).

Also of note, although c.-24+69C>G resides in an intron of the canonical APOE transcript, it localizes in an exon in an alternate APOE mRNA species that encodes a truncated protein (ENST_434152.1, Ensembl RNA database). In this case, the substitution of a cytosine for a guanine results in the substitution of an asparagine for a lysine at position 14 (see dbSNP; Lee et al., 2020). The transcript has not been described in the literature, and it remains unclear if it is of physiological significance or simply an artefact.

This variant's PHRED-scaled CADD score (5.86), which integrates diverse information in silico, did not reach 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Nov 2022).

Table

Study Type Risk Allele(s) Allele Freq.
AD | CTRL		 N
Cases | CTRL		 Association Results

Ancestry
(Cohort)

 Reference
GWAS Meta-analysis C   71,8880a | 383,378 Z score=-25.41
Effect size = -0.056
p=1.81x10-142		 European
(PGC-ALZ, IGAP, ADSP)		 Jansen et al., 2019
GWAS Meta-analysis C   21,982 | 41,944 p=2.28x10-112 European
(IGAP Rare Variants: Stage 1)		 Kunkle et al., 2019b
GWAS C   21,392 | 38,164 p=9.5x10-70 Mixed
(ADGC: Transethnic LOAD: All Samples)		 Jun et al., 2017b
GWAS C   21,392 | 38,164

p=1.27x10-6

(Adjusted for APOE4)

 Mixed
(ADGC: Transethnic LOAD: All Samples)		 Jun et al., 2017b
GWAS Meta-analysis C   17,008 | 37,154 p=2.3x10-67 European
(IGAP 2013: Stage 1)		 Lambert et al., 2013b
GWAS G 0.686 14,895 (total) OR = 1.64
[CI=1.56-1.75]
p=9x10-59		 European Lo et al., 2019c
GWAS C   12,738 | 13,850 p=5.08x10-7 Mixed 
(ADGC Transethnic LOAD: APOE4 carriers)		 Jun et al., 2017b
GWAS
Meta-analysis		 C   10,352 | 9,207

p=2.17x10-7

(APOE-Stratified Analysis)

 (IGAP - APOE4 carriers) Jun et al., 2016b
Whole Exome Meta-analysis     5,740 | 5,096 p=5.0 x10-11 Mostly European
(ADSP)		 Bis et al., 2018b
GWAS C 0.321 4,010 | 4,672 OR = 0.65
[CI = 0.60-0.71]
p=7x10-25		 European, U.S. Wang et al., 2021c
Targeted G 0.663 2,302 | 17,096 p=1.08x10-18 East Asian Choi et al., 2019
Targeted C 0.35 1,873 | 1,443d HetLODe=7.96  (PDT)=98.39 p<0.001
χ2 (Pearson) = 171.62
p<0.001		 Caucasian Thornton-Wells et al., 2008
Meta-analysis C vs G   1,113 | 978 OR = 0.58
[CI=0.50-0.68]
p=3x10-12		 Mixed
(Alzgene Dec 1, 2005 data)		 Bertram et al., 2007

a24,087 LOAD cases; 47,793 offspring of parents with AD
bData from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), rs440446, Aug 2022
cData from GWAS Catalog rs440446, August 2022
dFamily-based: 1,422 cases, 744 controls; and case-control: 451 cases, 699 controls
eHetLOD = herogeneity LOD score; PDT= pedigree disequilibrium test

OR=odds ratio, GWAS=genome-wide association study. Statistically significant associations (as assessed by the authors) are in bold. For data retrieved from NIAGADS, GWAS p-values <5x10-8 and whole-exome association p-values <1x10-3 are in bold. All data retrieved from the GWAS catalog (p-values <1x10-5) are in bold.
All genome-wide association studies in this table included >2,000 cases, and all targeted association studies included >500 cases (subgroups within a study may be smaller).

This table is meant to convey the range of results reported in the literature. As specific analyses, including co-variates, differ among studies, this information is not intended to be used for quantitative comparisons, and readers are encouraged to refer to the original papers. Thresholds for statistical significance were defined by the authors of each study. (Significant results are in bold.) Note that data from some cohorts may have contributed to multiple studies, so each row does not necessarily represent an independent dataset. While every effort was made to be accurate, readers should confirm any values that are critical for their applications.

Last Updated: 05 Dec 2022

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References

Mutations Citations

  1. APOE C130R (ApoE4)
  2. APOE c.-286T>G (rs405509)
  3. APOE R176C (ApoE2)

Paper Citations

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External Citations

  1. GWAS catalog
  2. dbSNP

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Mui S, Briggs M, Chung H, Wallace RB, Gomez-Isla T, Rebeck GW, Hyman BT. A newly identified polymorphism in the apolipoprotein E enhancer gene region is associated with Alzheimer's disease and strongly with the epsilon 4 allele. Neurology. 1996 Jul;47(1):196-201. PubMed.

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