Overview

Clinical Phenotype: Alzheimer's Disease, Blood Lipids/Lipoproteins, Diabetes Mellitus
Position: (GRCh38/hg38):Chr19:44908799 G>A
Position: (GRCh37/hg19):Chr19:45412056 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs376170967
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

The association of this variant with Alzheimer’s disease (AD) was examined in a study of individuals of African ancestry from case-control, family-based, population-based, and longitudinal AD cohorts (Le Guen et al., 2023). Because R168H is co-inherited with APOE2, the analysis focused on APOE2 carriers, and because there were no E2 homozygotes and only three E2/E4 heterozygotes, the analysis included only carriers of the APOE2/E3 genotype (4 AD cases and 10 controls). No significant association was observed (OR=1.08, 95% CI=0.33-3.55, p=0.90). 

The variant was originally identified in a U.K. study of 765 individuals with type 2 diabetes (Stephens et al, 2005). The proband was a 65-year-old man of African ancestry who had suffered from diabetes for 16 years. However, his blood lipid profile, including levels of cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides, was normal, and neither he nor his family had a history of coronary heart disease. He was an APOE2 homozygote.

R168H was also reported in another APOE2 homozygote, a 52-year-old Spanish individual with dysbetalipoproteinemia (Bea et al., 2023). Importantly, this condition, also known as hyperlipoproteinemia type III (HLPP3), is often associated with APOE2 homozygosity.

This variant was reported in the gnomAD variant database at a global frequency of 0.00018 and an allele count of 31. Most carriers were African/African American (21 heterozygotes) or Latino/Admixed American (eight heterozygotes) (gnomAD v2.1.1, Nov 2021).

Biological Effect

The biological effect of this mutation is unknown. Although R168 is an evolutionarily conserved residue in the ApoE receptor-binding region (Frieden et al., 2015), the substitution of an arginine by a histidine preserves the position’s positive charge which is thought to contribute to LDL receptor binding (Lund-Katz et al., 2001). Of note, the orientation of R168 differs between the common ApoE alleles, ApoE 2,3, and 4 (Chen et al., 2021). In particular, ApoE2 forms a salt bridge with R168 which may contribute to ApoE2’s weak receptor binding. Thus, the effect of the R168H substitution may vary between allelic backgrounds.

Interestingly, an artificial substitution at this site, R168A, substantially reduced binding of ApoE4 to the microglial leukocyte immunoglobulin-like receptor B3 (LilrB3), a receptor that binds to ApoE4 more strongly than to ApoE3 or ApoE2 and activates pro-inflammatory pathways (Zhou et al., 2023).

Two other variants at this site, R168C and R168P, have been tied to lipoprotein glomerulopathy, a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate lipoprotein-rich aggregates.

At least three of four pathogenicity prediction algorithms classified R168H as damaging (Bea et al., 2023) and the 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).

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References

Mutations Citations

1. APOE R168C

Paper Citations

1. Le Guen Y, Raulin AC, Logue MW, Sherva R, Belloy ME, Eger SJ, Chen A, Kennedy G, Kuchenbecker L, O'Leary JP, Zhang R, Merritt VC, Panizzon MS, Hauger RL, Gaziano JM, Bu G, Thornton TA, Farrer LA, Napolioni V, He Z, Greicius MD. Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease. JAMA. 2023 Feb 21;329(7):551-560. PubMed.
2. Stephens JW, Sozen MM, Whittall RA, Caslake MJ, Bedford D, Acharya J, Hurel SJ, Humphries SE. Three novel mutations in the apolipoprotein E gene in a sample of individuals with type 2 diabetes mellitus. Clin Chem. 2005 Jan;51(1):119-24. Epub 2004 Oct 28 PubMed.
3. Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C, Cenarro A. Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol. 2023 Jun;43(6):1066-1077. Epub 2023 Apr 13 PubMed.
4. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 PubMed.
5. Lund-Katz S, Wehrli S, Zaiou M, Newhouse Y, Weisgraber KH, Phillips MC. Effects of polymorphism on the microenvironment of the LDL receptor-binding region of human apoE. J Lipid Res. 2001 Jun;42(6):894-901. PubMed.
6. Chen Y, Strickland MR, Soranno A, Holtzman DM. Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis. Neuron. 2021 Jan 20;109(2):205-221. Epub 2020 Nov 10 PubMed.
7. Zhou J, Wang Y, Huang G, Yang M, Zhu Y, Jin C, Jing D, Ji K, Shi Y. LilrB3 is a putative cell surface receptor of APOE4. Cell Res. 2023 Feb;33(2):116-130. Epub 2023 Jan 2 PubMed.

Other Citations

1. APOE2

External Citations

1. R168P

Further Reading

No Available Further Reading