Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Reference Assembly: GRCh37/hg19
Position: Chr19:45412040 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs769455
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGT to TGT
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant has been associated with an increased risk of Alzheimer’s disease (AD) in individuals of African ancestry with an APOE3/E4 genotype (Le Guen et al., 2023, March news 2023). The findings emerged from a case-control study including nearly 32,000 participants of African ancestry from case-control, family-based, population-based, and longitudinal AD cohorts. In the discovery stage, which included nearly 3,000 AD patients and 5,000 controls, R163C was associated with an increased risk of AD (OR=3.01; 95% CI=1.87-4.85; p=6x10^-6) and a younger age at onset (β, −5.87 years; 95%CI, −8.35 to −3.4 years; P = 3.4 × 10⁻⁶). Secondary analyses of a replication cohort (OR=2.20) and an external validation cohort (OR=1.90) supported these findings. Also, R163C was tied to more rapid cognitive decline. Because R163C was found to be linked to APOE3, stratified analyses were limited to APOE2/E3, APOE3/E3 and APOE3/E4 genotypes. Significant associations were detected only in the APOE3/E4 group.

As noted by the authors, R163C is likely the causal variant underpinning these associations because the results persisted after adjusting for the presence of sequences shared amongst people of African ancestry at the APOE locus. Moreover, the findings were consistent with an earlier study in African Americans that found a weaker association between R163C and AD in a non-stratified analysis (Kunkle et al., 2021). Although another report failed to detect an association (Medway et al., 2014), it was likely due to low allele frequency. The only large group in this earlier study was composed of European Americans and R163C appears to be found only in individuals with African ancestry (see below).

Non-Neurological Conditions

The R163C mutation has long been known as a risk factor for hyperlipoproteinemia type III (HLPP3). The condition, also known as familial dysbetalipoproteinemia, is characterized by elevated cholesterol and triglyceride levels in blood, and early onset atherosclerosis and heart disease (Hopkins et al., 2014; Koopal et al., 2017). In addition to fulfilling one set of criteria for this disorder (non-high density lipoprotein cholesterol (HDLc)/ApoB≥1.7 and triglycerides/ApoB≥1.35), carriers of this mutation have been reported to have elevated levels of very low-density cholesterol (VLDLc) and an increased ratio of VLDLc to VLDL triglycerides (Bea et al., 2023).

The R163C variant was first described in two African Americans with HLPP3 (Rall et al., 1982). The ApoE proteins of both patients migrated on an isoelectric focusing gel to the position of the R176C (ApoE2) variant which previously had been associated, in its homozygous form, with HLPP3. However, the proteins’ receptor binding ability was observed to differ from that of ApoE2. Peptide mapping and amino acid analysis revealed one individual had a single copy of ApoE2, while his other allele carried the R163C substitution. The other subject had two copies of R163C with no copies of ApoE2.

In 1988, a woman from Utah with abnormal lipoprotein particle levels typical of HLPP3 was found to have the same heterozygous substitution and the mutation was sequenced at the DNA level (Emi et al., 1988).

The inheritance pattern of HLPP3 caused by R163C has been described as autosomal dominant with incomplete penetrance (deVilliers et al., 1997; Abou Ziki et al., 2014). The first indication of this pattern emerged from a South African study of 10 unrelated mutation carriers with HLPP3, and 10 affected family members who also carried the mutation. The cholesterol and triglyceride levels of these patients were similar in homozygotes and heterozygotes, suggesting a lack of an allele dosage effect (deVilliers et al., 1997). However, the clinical expression of the disease differed between the two groups. Whereas heart disease affected heterozygotes more often, fat deposits under the skin, known as xanthomas, occurred more often in homozygotes. Some mutation carriers may not develop the disease at all. A compilation of several reported cases identified 20 of 24 mutation carriers with diagnosed HLPP3 (Koopal et al., 2017).

The variant has also been identified in patients with other lipid disorders, including autosomal dominant hypercholesterolemia, also known as hyperlipoproteinemia type IIa (HLPP2a), and familial combined hyperlipidemia, also known as hyperlipoproteinemia type IIb (HLPP2b). Carriers with elevated cholesterol and low-density lipoprotein (LDL) cholesterol in blood, including four diagnosed with HLPP2a, have been reported (Wintjens et al., 2016, Sinnott and Mazzone, 2006, Abou Khalil et al., 2022, Bea et al., 2023), as well as three carriers with elevated triglyceride levels (Abou Khalil et al., 2022, Bea et al., 2023), two diagnosed with HLPP2b (Abou Khalil et al., 2022).

In one family, R163C was found together with E31K. All seven reported carriers of the compound mutation, referred to as ApoE4 Philadelphia based on its migration on an isoelectric focusing gel, had altered blood lipid profiles. The original proband, a 24-year-old homozygous female, suffered from HLPP3 (Lohse et al., 1991; Lohse et al., 1992). The other six carriers were heterozygotes and had only a moderate form of HLPP3, lacking clinical symptoms. The authors concluded the compound mutant exhibits incomplete dominance for HLPP3.

As assessed by local ancestry analysis, R163C is part of a haplotype—a stretch of DNA with variants that are inherited together—tied to African ancestry (Le Guen et al., 2023). This is consistent with previous studies showing a low frequency in European Americans, and a relatively high frequency in some African populations (Abou Ziki et al., 2014, Pirim et al., 2019). The variant’s global frequency in the gnomAD variant database was 0.002, with 339 of 393 heterozygote carriers of African ancestry (v2.1.1, May 2022). Seven homozygotes were also reported, all of African ancestry. Moreover, data from the 1000 Genomes Project indicated it is present in 5–12 percent of individuals in populations with sub-Saharan African ancestry (Abou Ziki et al., 2014). The mutation was also found in 17 percent of a Qatari population, which has a high prevalence of cardiovascular disease.

In these high prevalence populations, the variant might be a common cause of mild hypertriglyceridemia (Abou Ziki et al., 2014; Pirim et al., 2019). Consistently, several genome-wide association studies (GWAS) each including over 10,000 individuals of non-European ancestry, all reported associations with high triglyceride levels (Peloso et al., 2014; Hoffman et al., 2018; Wojcik et al., 2019; Hu et al., 2020). In two of the studies, reduced levels of cholesterol and LDL-C were also observed (Peloso et al., 2014; Wojcik et al., 2019).

Similar results were obtained in two smaller association studies that included 788 individuals of African ancestry, and the effects were found to be independent of APOE2 and C130R (APOE4) status (Radwan et al., 2014; Pirim et al., 2019). Of note, Pirim et al. reported the variant was tightly linked to APOE intronic variant c.43+349G>A, which also showed association with lower LDL-C levels (Pirim et al., 2019). 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). In addition, an association between R163C and an unknown plasma metabolite, a potential isomer of retinol, was reported in participants of the Jackson Heart Study, a cohort of Black individuals from Jackson, Mississippi (Tahir et al., 2022).

Biological effect

From a neurological perspective, the observation that R163C is associated with AD risk only when paired with APOE4 suggests it is a loss-of-function mutation, lacking a biochemical property that normally ameliorates the risk caused by APOE4 (Le Guen et al., 2023).

In the periphery, the in vivo behavior of this variant, located in the receptor-binding region of ApoE, has been reported to be similar to that of ApoE2, showing reduced efficiency at clearing lipoprotein remnant particles from circulation compared with ApoE3 (Stalenhoef et al., 1986). In vitro experiments using cells or isolated proteins, however, suggest distinct impairments in cell-surface binding. R163C’s affinity for receptors that bind low-density lipoprotein (LDLR) was reduced compared with ApoE3, but greater than that of ApoE2 (Rall et al., 1982, Bea et al., 2023).

On the other hand, R163C’s binding to heparin sulfate proteoglycans was decreased by 65 percent compared with ApoE3, while that of ApoE2 was reduced by only 30 percent (Ji et al., 1994; see also supplement 1 in Le Guen et al., 2023). This effect is consistent with observations indicating that R163 is critical for heparin binding (Libeu et al., 2001, Dong et al., 2001). Also of note, in a cell-free binding assay, R163C’s interaction with very low-density lipoprotein receptors (VLDLR) was substantially weaker than that of wildtype ApoE3 (Ruiz et al., 2005).

In addition, the R163C substitution which results in a change in charge has been predicted to abolish R163’s interaction with Q59 and thus weaken the interaction between ApoE’s N- and C-terminal domains (Chen et al., 2011, Zhou et al., 2018). This alteration could disrupt the way that lipid binding to the C-terminus normally facilitates receptor binding. Moreover, a study using FRET and computational simulations to study monomeric ApoE4 predicted interactions with E27 and E45 when the C-terminal domain is undocked from the N-terminal helix bundle, a form suspected to enable lipid binding (Stuchell-Brereton et al., 2023).

R163 may also play a role in the formation of ApoE dimers which adopt different conformations in an isoform-dependent manner (Nemergut et al., 2023). Interestingly, a metabolite of the AD drug candidate ALZ-801 was observed to interact with several amino acids involved in dimerization, including R163, possibly decreasing the stability of ApoE4 V-shaped dimers (note, however, that the R163C substitution is found mostly or always on an ApoE3 backbone).

In silico analyses using Polyphen2 and SIFT algorithms predicted the variant to be deleterious, and structural analysis predicted impaired LDLR binding (Wintjens et al., 2016). This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, May 2022). Moreover, a study analyzing whole-genome and whole-exome sequencing data from 138,632 individuals, identified R163C as one of six APOE variants likely to have functional consequences and clinical relevance given their high prevalence in at least one population and their classification by five algorithms (SIFT, Polyphen2, MutationAssessor, PROVEAN, and DANN) as deleterious with high confidence (Zhou et al., 2018).

Based on guidelines from the American College of Medical Genetics and Genomics (ACMG) (Richards et al., 2015), this variant was classified as Likely Pathogenic (Mariano et al., 2020).

Note on nomenclature:

Some papers include ApoE2 in the name of this variant because both proteins migrate to the same isoelectric position, while others include APOE3, or ε3, because R163C is co-inherited with APOE3.

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References

News Citations

1. In People with African Ancestry, ApoE3 Variant Ups Alzheimer's Risk 9 Mar 2023

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE E31K
3. APOE C130R (ApoE4)
4. APOE c.43+349G>A (rs61357706)

Therapeutics Citations

1. ALZ-801

Paper Citations

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External Citations

1. GWAS catalog

Further Reading