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CD33 rs2455069 SNP: Correlation with Alzheimer’s Disease and Hypothesis of Functional Role
The CD33 gene encodes for a member of the sialic-acid-binding immunoglobulin-type lectin (Siglec) family, and is one of the top-ranked Alzheimer’s disease (AD) risk genes identified by genome-wide association studies (GWAS). Many CD33 polymorphisms are associated with an increased risk of AD, but th...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998932/ https://www.ncbi.nlm.nih.gov/pubmed/35408990 http://dx.doi.org/10.3390/ijms23073629 |
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author | Tortora, Fabiana Rendina, Antonella Angiolillo, Antonella Di Costanzo, Alfonso Aniello, Francesco Donizetti, Aldo Febbraio, Ferdinando Vitale, Emilia |
author_facet | Tortora, Fabiana Rendina, Antonella Angiolillo, Antonella Di Costanzo, Alfonso Aniello, Francesco Donizetti, Aldo Febbraio, Ferdinando Vitale, Emilia |
author_sort | Tortora, Fabiana |
collection | PubMed |
description | The CD33 gene encodes for a member of the sialic-acid-binding immunoglobulin-type lectin (Siglec) family, and is one of the top-ranked Alzheimer’s disease (AD) risk genes identified by genome-wide association studies (GWAS). Many CD33 polymorphisms are associated with an increased risk of AD, but the function and potential mechanism of many CD33 single-nucleotide polymorphisms (SNPs) in promoting AD have yet to be elucidated. We recently identified the CD33 SNP rs2455069-A>G (R69G) in a familial form of dementia. Here, we demonstrate an association between the G allele of the rs2455069 gene variant and the presence of AD in a cohort of 195 patients from southern Italy. We carried out in silico analysis of the 3D structures of CD33 carrying the identified SNP to provide insights into its functional effect. Structural models of the CD33 variant carrying the R69G amino acid change were compared to the CD33 wild type, and used for the docking analysis using sialic acid as the ligand. Our analysis demonstrated that the CD33-R69G variant may bind sialic acid at additional binding sites compared to the wild type, thus potentially increasing its affinity/specificity for this molecule. Our results led to a new hypothesis of rs2455069-A>G SNP as a risk factor for AD, suggesting that a long-term cumulative effect of the CD33-R69G variant results from the binding of sialic acid, acting as an enhancer of the CD33 inhibitory effects on amyloid plaque degradation. |
format | Online Article Text |
id | pubmed-8998932 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89989322022-04-12 CD33 rs2455069 SNP: Correlation with Alzheimer’s Disease and Hypothesis of Functional Role Tortora, Fabiana Rendina, Antonella Angiolillo, Antonella Di Costanzo, Alfonso Aniello, Francesco Donizetti, Aldo Febbraio, Ferdinando Vitale, Emilia Int J Mol Sci Article The CD33 gene encodes for a member of the sialic-acid-binding immunoglobulin-type lectin (Siglec) family, and is one of the top-ranked Alzheimer’s disease (AD) risk genes identified by genome-wide association studies (GWAS). Many CD33 polymorphisms are associated with an increased risk of AD, but the function and potential mechanism of many CD33 single-nucleotide polymorphisms (SNPs) in promoting AD have yet to be elucidated. We recently identified the CD33 SNP rs2455069-A>G (R69G) in a familial form of dementia. Here, we demonstrate an association between the G allele of the rs2455069 gene variant and the presence of AD in a cohort of 195 patients from southern Italy. We carried out in silico analysis of the 3D structures of CD33 carrying the identified SNP to provide insights into its functional effect. Structural models of the CD33 variant carrying the R69G amino acid change were compared to the CD33 wild type, and used for the docking analysis using sialic acid as the ligand. Our analysis demonstrated that the CD33-R69G variant may bind sialic acid at additional binding sites compared to the wild type, thus potentially increasing its affinity/specificity for this molecule. Our results led to a new hypothesis of rs2455069-A>G SNP as a risk factor for AD, suggesting that a long-term cumulative effect of the CD33-R69G variant results from the binding of sialic acid, acting as an enhancer of the CD33 inhibitory effects on amyloid plaque degradation. MDPI 2022-03-26 /pmc/articles/PMC8998932/ /pubmed/35408990 http://dx.doi.org/10.3390/ijms23073629 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Tortora, Fabiana Rendina, Antonella Angiolillo, Antonella Di Costanzo, Alfonso Aniello, Francesco Donizetti, Aldo Febbraio, Ferdinando Vitale, Emilia CD33 rs2455069 SNP: Correlation with Alzheimer’s Disease and Hypothesis of Functional Role |
title | CD33 rs2455069 SNP: Correlation with Alzheimer’s Disease and Hypothesis of Functional Role |
title_full | CD33 rs2455069 SNP: Correlation with Alzheimer’s Disease and Hypothesis of Functional Role |
title_fullStr | CD33 rs2455069 SNP: Correlation with Alzheimer’s Disease and Hypothesis of Functional Role |
title_full_unstemmed | CD33 rs2455069 SNP: Correlation with Alzheimer’s Disease and Hypothesis of Functional Role |
title_short | CD33 rs2455069 SNP: Correlation with Alzheimer’s Disease and Hypothesis of Functional Role |
title_sort | cd33 rs2455069 snp: correlation with alzheimer’s disease and hypothesis of functional role |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998932/ https://www.ncbi.nlm.nih.gov/pubmed/35408990 http://dx.doi.org/10.3390/ijms23073629 |
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