ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease
Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB et al.. Molecular neurodegeneration, 2014-03-10
Topic: Amyloid, tau and blood-test diagnosis
Recent genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) have identified single nucleotide polymorphisms (SNPs) which show significant association at the well-known APOE locus and at nineteen additional loci. Among the functional, disease-associated variants at these loci, missense variants are particularly important because they can be readily investigated in model systems to search for novel therapeutic targets. It is now possible to perform a low-cost search for these "actionable" variants by genotyping the missense variants at known LOAD loci already cataloged on the Exome Variant Server (EVS). In this proof-of-principle study designed to explore the efficacy of this approach, we analyzed three rare EVS variants in APOE, p.L28P, p.R145C and p.V236E, in our case control series of 9114 subjects. p.R145C proved to be too rare to analyze effectively. The minor allele of p.L28P, which was in complete linkage disequilibrium (D' = 1) with the far more common APOE ϵ4 allele, showed no association with LOAD (P = 0.75) independent of the APOE ϵ4 allele. p.V236E was significantly associated with a marked reduction in risk of LOAD (P = 7.5 × 10⁻⁰⁵; OR = 0.10, 0.03 to 0.45). The minor allele of p.V236E, which was in complete linkage disequilibrium (D' = 1) with the common APOE ϵ3 allele, identifies a novel LOAD-associated haplotype (APOE ϵ3b) which is associated with decreased risk of LOAD independent of the more abundant APOE ϵ2, ϵ3 and ϵ4 haplotypes. Follow-up studies will be important to confirm the significance of this association and to better define its odds ratio. The ApoE p.V236E substitution is the first disease-associated change located in the lipid-binding, C-terminal domain of the protein. Thus our study (i) identifies a novel APOE missense variant which may profitably be studied to better understand how ApoE function may be modified to reduce risk of LOAD and (ii) indicates that analysis of protein-altering variants cataloged on the EVS can be a cost-effective way to identify actionable functional variants at recently discovered LOAD loci.
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APA 7th
Medway, C. W., Abdul-Hay, S., Mims, T., Ma, L., Bisceglio, G., Zou, F., et al. (2014). ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. Molecular neurodegeneration. https://doi.org/10.1186/1750-1326-9-11
Vancouver
Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, et al. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. Molecular neurodegeneration. 2014. doi:10.1186/1750-1326-9-11. PMID: 24607147.
BibTeX
@article{medway2014-24607147,
author = {Medway, C. W. and Abdul-Hay, S. and Mims, T. and Ma, L. and Bisceglio, G. and Zou, F. and Pankratz, S. and Sando, S. B. and others},
title = {{ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease}},
journal = {Molecular neurodegeneration},
year = {2014},
doi = {10.1186/1750-1326-9-11},
pmid = {24607147},
url = {https://doi.org/10.1186/1750-1326-9-11}
}
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Key findings
- Recent genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) have identified single nucleotide polymorphisms (SNPs) which show significant association at the well-known APOE locus and at nineteen additional loci.
- The minor allele of p.L28P, which was in complete linkage disequilibrium (D' = 1) with the far more common APOE ϵ4 allele, showed no association with LOAD (P = 0.75) independent of the APOE ϵ4 allele. p.V236E was significantly associated with a marked reduction in risk of LOAD (P = 7.5 × 10⁻⁰⁵; OR = 0.10, 0.03 to 0.45).
- The minor allele of p.V236E, which was in complete linkage disequilibrium (D' = 1) with the common APOE ϵ3 allele, identifies a novel LOAD-associated haplotype (APOE ϵ3b) which is associated with decreased risk of LOAD independent of the more abundant APOE ϵ2, ϵ3 and ϵ4 haplotypes.
- Thus our study (i) identifies a novel APOE missense variant which may profitably be studied to better understand how ApoE function may be modified to reduce risk of LOAD and (ii) indicates that analysis of protein-altering variants cataloged on the EVS can be a cost-effective way to identify actionable functional variants at recently discovered LOAD loci.
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Study details
- Participants9,114
- Effect sizeOR = 0.10
- Evidence strengthLow
How this study scored 55/100
Published in a peer-reviewed journal. Scored zero for study design and randomized / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 32 of the 58 points we could judge it on, which is 55 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular neurodegeneration) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2014 — within 20 year(s) of the newest study here |
| Sample size | 3 / 4 | 9,114 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 24607147) |
| Free to read | 2 / 2 | Free to read |
| Points | 32 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 32 of the 58 points we could judge it on is 55 out of 100. |
| Total | 55 / 100 | — |
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