APOE R176C - GET-Evidence

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Curation:
Currentness:

APOE R176C

(APOE Arg176Cys)


Short summary

This is generally known as the ApoE2 variant of ApoE and is associated with a decreased risk of Alzheimer’s disease.

Variant evidence
Computational -
Functional -
Case/Control -
Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Insufficiently evaluated pharmacogenetic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

other

Summary of published research, and additional commentary

Not associated with response to Acitretin.

Allele frequency

  • T @ chr19:45412079: 6.8% (547/8056) in EVS
  • T @ chr19:50103918: 6.0% (6/100) in GET-Evidence
  • Frequency shown in summary reports: 6.8% (547/8056)

Publications
 

Utermann G, Hees M, Steinmetz A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature. 1977 Oct 13;269(5629):604-7. PubMed PMID: 199847.

 

Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22-29;278(16):1349-56. PubMed PMID: 9343467.

 

Kaida K, Takeda K, Nagata N, Kamakura K. Alzheimer's disease with asymmetric parietal lobe atrophy: a case report. J Neurol Sci. 1998 Sep 18;160(1):96-9. PubMed PMID: 9804125.

 

Gerdes LU, Gerdes C, Kervinen K, Savolainen M, Klausen IC, Hansen PS, Kesäniemi YA, Faergeman O. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction : a substudy of the Scandinavian simvastatin survival study. Circulation. 2000 Mar 28;101(12):1366-71. PubMed PMID: 10736278.

 

Campalani E, Allen MH, Fairhurst D, Young HS, Mendonca CO, Burden AD, Griffiths CE, Crook MA, Barker JN, Smith CH. Apolipoprotein E gene polymorphisms are associated with psoriasis but do not determine disease response to acitretin. Br J Dermatol. 2006 Feb;154(2):345-52. PubMed PMID: 16433808.

 

Utheim ØA, Ritland JS, Utheim TP, Espeseth T, Lydersen S, Rootwelt H, Semb SO, Elsås T. Apolipoprotein E genotype and risk for development of cataract and age-related macular degeneration. Acta Ophthalmol. 2008 Jun;86(4):401-3. PubMed PMID: 18498549.

 

Golledge J, Biros E, Cooper M, Warrington N, Palmer LJ, Norman PE. Apolipoprotein E genotype is associated with serum C-reactive protein but not abdominal aortic aneurysm. Atherosclerosis. 2010 Apr;209(2):487-91. Epub 2009 Sep 25. PubMed PMID: 19818961; PubMed Central PMCID: PMC2846218.

 

Genomes
 

 

hu4CA5B9 - CGI sample GS01669-DNA_B03 from PGP sample 14427241
het T @ chr19:45412079

 

 

hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het T @ chr19:45412079

 

huD37D14 - CGI sample GS01175-DNA_A04 from PGP sample 13272228
het T @ chr19:45412079

 

GS06994 - var-GS06994-1100-36-ASM
het T @ chr19:50103919

 

GS18940 - var-GS18940-1100-36-ASM
het T @ chr19:50103919

 

GS19700 - var-GS19700-1100-36-ASM
het T @ chr19:50103919

 

GS19703 - var-GS19703-1100-36-ASM
het T @ chr19:50103919

 

GS19834 - var-GS19834-1100-36-ASM
het T @ chr19:50103919

 

GS20509 - var-GS20509-1100-36-ASM
het T @ chr19:50103919

 

Other external references
 

    dbSNP
  • rs7412
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the APOE gene
    Alzheimer Disease Risk Factor (APOE Genotype)
    Alzheimer Disease Type 2
    Cardiovascular Disease Risk Factor (Apolipoprotein E)
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/APOE
    PharmGKB
  • [Psoriasis]
    [acitretin]
    Risk or phenotype-associated allele: ApoE E4 allele (rs429358 C, rs7412 C) (130Arg, 176Arg). Phenotype: Increased incidence of chronic plaque psoriasis and guttate psoriasis, but no difference in response of psoriasis to the drug acitretin. Study size: 306 cases, 137 controls. Study population/ethnicity: Patients with chronic plaque psoriasis (n = 212), guttate psoriasis (n = 94). Significance metric(s): p =0.008 Type of association: CO; GN
    www.ncbi.nlm.nih.gov/pubmed/16433808
  • [HIV; HIV Infections; Hyperlipidemias]
    [ritonavir]
    The ApoE epsilon2 variant (2198T) is associated with hyperlipidemia (elevated triglyceride levels) in HIV-infected individuals treated with ritonavir.
    www.ncbi.nlm.nih.gov/pubmed/15809899; PubMed ID:16417409; PubMed ID:17700365
  • [Neurodegenerative Diseases; Posterior Cortical Atrophy]
    Risk or phenotype-associated allele: APOE: epsilon3/epsilon3 (defined as rs429358 T/T 130Cys/Cys + rs7412 C/C 176Arg/Arg). Phenotype: Neurodegenerative disease characterized by asymmetric parietal atrophy, visuospatial dysfunction, incomplete Balint's syndrome, environmental agnosia, left-sided motor symptoms including dystonic postures and myoclonus in the left hand, without significant dementia (as in posterior cortical atrophy) was observed in a woman with early-onset neurodegenerative disease progressing 10 years from onset at age 52 to death. Study size: 1. Study population/ethnicity: Right-handed female/Japanese. Significance metric(s): non significant case report. Type of association: CO; GN
    www.ncbi.nlm.nih.gov/pubmed/9804125
  • [Infarction; Myocardial Infarction]
    [simvastatin]
    Risk or phenotype-associated allele: The ApoE E4 allele is a combination of rs429358 C (130Arg) and rs7412 C (176Arg). Phenotype: The Apo E4 allele is associated with 80 percent increased risk of dying (mortality risk ratio = 1.8) compared with other patients upon evaluation at 5.5 years following survival of myocardial infarction. ApoE E4 carriers who had high Lp(a) levels had a risk ratio of 3.7 of coronary death. Simvastatin treatment reduced the mortality risk to 0.33 in Apoe E4 carriers and to 0.66 in other patients (p = 0.23 for treatment by genotype interaction). Study size: 966 survivors of myocardial infarction enrolled in the Scandinavian Simvastatin Survival Study. Study population/ethnicity: Danish and Finnish. Significance metric(s): mortality risk ratio = 1.8. Type of association: CO; PD; GN
    www.ncbi.nlm.nih.gov/pubmed/10736278
  • [Alzheimer Disease]
    Risk or phenotype-associated allele: The APOE E4 allele is a combination of rs429358 C (130Arg) and rs7412 C (176Arg). Phenotype: The APOE E4 allele (130Arg, 176Arg) was studied relative to the E3 (130Cys, 176Arg) and E2 (130Cys, 176Cys) alleles. Relative to the homozygous E3/E3 diplotype, Caucasians showed increased risk of Alzheimer Disease (AD): OR = 2.6 for E4/E2, OR = 3.2 for E4/E3, OR = 14.9 for E4/E4. The E2 allele was protective against risk of AD: OR = 0.6 for E2/E2, OR = 0.6 for E3/E2. Japanese showed greater increased risk of AD than Caucasians: OR=5.6 for E3/E4, OR = 33.1 for E4/E4. Study size: 5930 patients who met criteria for probable or definite AD, and 8607 controls without dementia. Study population/ethnicity: A clinic-/autopsy-based case-control study of patients between 40 and 90 years old recruited from clinical, community, and brain bank sources./Caucasian, African American, Hispanic, Japanese. Significance metric(s): OR. Type of association: CO; GN
    www.ncbi.nlm.nih.gov/pubmed/9343467
  • [Cataract; Macular Degeneration]
    Risk or phenotype-associated allele: The E3 and E4 alleles of APOE, defined by the combined genotype at rs429358T>C (Cys130Arg) and rs7412C>T (Arg176Cys). Phenotype: The APOE E3 allele (130Cys, 176Arg) and E4 (130Arg, 176Arg) alleles were protective. Carriers of the E3 allele had significantly higher average macular thickness in both eyes (p = 0.012), and significantly better visual acuity (p = 0.041) than non-E3 carriers. E4 carriers showed reduced incidence of cataract than non-APOE4 carriers (p = 0.039). Study size: 32 patients who underwent cataract surgery in both eyes, and 56 controls. Study population/ethnicity: Patients from London, England aged 50-75 years old. Significance metric(s): p-value. Type of association: CO; GN
    www.ncbi.nlm.nih.gov/pubmed/18498549
  • [Arteriosclerosis; Hyperlipoproteinemia Type III; Hyperlipoproteinemias; Vascular Diseases]
    Risk or phenotype-associated allele: The ApoE E2 allele is a combination of rs429358 T (130Cys) and rs7412 T (176Cys). Phenotype: The Apo E2 allele contributes to increased risk of type III hyperlipoproteinemia, characterized by increased cholesterol and triglyceride levels, the presence of beta-VLDL (cholesterol-enriched remnants of intestinal chylomicrons and hepatic VLDL), xanthomas, and premature vascular disease, both coronary heart disease and peripheral artery disease. Study size: Three multiplex, multigenerational pedigrees, and case control study of 5 probands versus 94 controls. Study population/ethnicity: Germans. Significance metric(s): N/A. Type of association: CO; GN
    www.ncbi.nlm.nih.gov/pubmed/199847
    PolyPhen-2
  • Score: 1.0 (probably damaging)
    Web search results (23 hits -- see all)
  • (WO/2001/079234) HAPLOTYPES OF THE APOE GENE
    HAPLOTYPES OF THE APOE GENE RELATED APPLICATIONS This application ... APOE is a plasma protein that mediates the transport and uptake of cholesterol ...
    www.wipo.int/pctdb/en/wo.jsp?IA=US2001012303&DISPLAY=DESC
  • Blood -- Scan of 977 nonsynonymous SNPs in CLL4 trial ...
    Prepublished online as a Blood First Edition Paper on November 15, ... minority, such as APOE R176C and THBS1 N700S.43,44 Evidence for others is provided by in ...
    bloodjournal.hematologylibrary.org/cgi/content/full/.../1625
  • Controlling Linkage Disequilibrium in Association Tests ...
    genetic effect of the studied APOE variants was re-evaluated ... variants than rs429358 in APOE, which has been doubtful. for associations with Alzheimer's ...
    www.genominfo.org/html/UploadFile/article4_200706.pdf
  • Table 3 Text
    ... total chromosomes genotyped MAF mean MAF stdev chromosomes genotyped ... criterion prediction score number sequences aligned prediction score divergence ...
    icr.ac.uk/research/research_sections/.../2842.txt
  • RealGene - Biotech Company Italiana
    La Real gene è una Biotech Company Italiana, specializzata nello studio dei polimorfismi genetici del DNA (SNPs) predisponenti a patologie sia in ambito umano che ...
    www.realgene.it
  • RealGene - ApoE R158C (R176C) - Novità
    ApoE R158C (R176C) - Novità. Test di screening per: Malattia di Alzheimer e patologie ... L' ApoE svolge la funzione di trasportatore lipidico; sintetizzata ...
    www.realgene.it/dettaglio_prodotto.asp?id_a=60
  • Gene SNP (alias) MAF WARG R2 P Pilot R2 P ABCB1 rs3842 0.137 ...
    APOE. rs429358 (C130R or C112R) 0.173 0. 9.68 × 10. 1. 1.9. 1.67 × 10. 1. APOE. rs7412 (R176C or R158C) 0.07. 0. 9.93 × 10. 1. 1.2. 3.59 × 10. 1. CALU. rs339057. 0.438 0.3. 1.27 × 10. 1 ...
    bloodjournal.hematologylibrary.org/cgi/data/.../DC1/2
  • Parkinson Disease Knowledgebase
    APOE. Variant (mutation/polymorphism) information mined from UniProt : ... R176C (Disease) [ VAR_000664 ] R176C (Disease) R242Q (Polymorphism) ...
    datam.i2r.a-star.edu.sg/mdpd/detail.php?symbol=APOE&sec=2
  • Parkinson Disease Knowledgebase
    Disease from OMIM [5] APOE. Variation Impact. Associated[2] Protective ... p.R176C[1] Variation positions (DNA or mRNA) c.609C>T[1] Reference Collection [14] ...
    datam.i2r.a-star.edu.sg/mdpd/detail.php?symbol=APOE&sec=1
  • JACC -- Mathew et al. 49 (19): 1934 Table BL1
    Minor Allele Frequency in EA Patients Without Cognitive Deficit ... 586C/T. R176C. 0.071. Vascular reactivity. ACE (angiotensin-converting enzyme) ...
    content.onlinejacc.org/cgi/content-nw/full/49/19/1934/TBL1

Other in silico analyses
 

  • NBLOSUM100 score = 8
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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