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A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease

BACKGROUND: Late-onset Alzheimer’s disease (LOAD), the most common form of dementia, results from complicated interactions among multiple environmental and genetic factors. Despite recent advances in genetic analysis of LOAD, more than half of the heritability for the disease remains unclear. Althou...

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Autores principales: Asanomi, Yuya, Shigemizu, Daichi, Miyashita, Akinori, Mitsumori, Risa, Mori, Taiki, Hara, Norikazu, Ito, Kaoru, Niida, Shumpei, Ikeuchi, Takeshi, Ozaki, Kouichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585023/
https://www.ncbi.nlm.nih.gov/pubmed/31216982
http://dx.doi.org/10.1186/s10020-019-0090-5
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author Asanomi, Yuya
Shigemizu, Daichi
Miyashita, Akinori
Mitsumori, Risa
Mori, Taiki
Hara, Norikazu
Ito, Kaoru
Niida, Shumpei
Ikeuchi, Takeshi
Ozaki, Kouichi
author_facet Asanomi, Yuya
Shigemizu, Daichi
Miyashita, Akinori
Mitsumori, Risa
Mori, Taiki
Hara, Norikazu
Ito, Kaoru
Niida, Shumpei
Ikeuchi, Takeshi
Ozaki, Kouichi
author_sort Asanomi, Yuya
collection PubMed
description BACKGROUND: Late-onset Alzheimer’s disease (LOAD), the most common form of dementia, results from complicated interactions among multiple environmental and genetic factors. Despite recent advances in genetic analysis of LOAD, more than half of the heritability for the disease remains unclear. Although genetic studies in Caucasians found rare risk variants for LOAD with large effect sizes, these variants are hardly detectable in the Japanese population. METHODS: To identify rare variants possibly explaining part of the genetic architecture for LOAD in Japanese people, we performed whole-exome sequencing analyses of 202 LOAD individuals without the APOE ε4 risk allele, a major genetic factor for LOAD susceptibility. We also implemented in vitro functional analyses of the variant(s) to reveal possible functions associated with LOAD risk. RESULTS: Via step-by-step selection of whole-exome variants, we found seven candidate risk variants. We then conducted a case-control association study in a large Japanese cohort consisting of 4563 cases and 16,459 controls. We finally identified a rare nonsynonymous variant, rs572750141 (NM_030974.3:p.Gly186Arg), in SHARPIN that was potentially associated with increased risk of LOAD (corrected P = 8.05 × 10(− 5), odds ratio = 6.1). The amino acid change in SHARPIN resulted in aberrant cellular localization of the variant protein and attenuated the activation of NF-κB, a central mediator of inflammatory and immune responses. CONCLUSIONS: Our work identified a rare functional SHARPIN variant as a previously unknown genetic risk factor for LOAD. The functional alteration in SHARPIN induced by the rare coding variant is associated with an attenuated inflammatory/immune response that may promote LOAD development. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s10020-019-0090-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-65850232019-06-27 A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease Asanomi, Yuya Shigemizu, Daichi Miyashita, Akinori Mitsumori, Risa Mori, Taiki Hara, Norikazu Ito, Kaoru Niida, Shumpei Ikeuchi, Takeshi Ozaki, Kouichi Mol Med Research Article BACKGROUND: Late-onset Alzheimer’s disease (LOAD), the most common form of dementia, results from complicated interactions among multiple environmental and genetic factors. Despite recent advances in genetic analysis of LOAD, more than half of the heritability for the disease remains unclear. Although genetic studies in Caucasians found rare risk variants for LOAD with large effect sizes, these variants are hardly detectable in the Japanese population. METHODS: To identify rare variants possibly explaining part of the genetic architecture for LOAD in Japanese people, we performed whole-exome sequencing analyses of 202 LOAD individuals without the APOE ε4 risk allele, a major genetic factor for LOAD susceptibility. We also implemented in vitro functional analyses of the variant(s) to reveal possible functions associated with LOAD risk. RESULTS: Via step-by-step selection of whole-exome variants, we found seven candidate risk variants. We then conducted a case-control association study in a large Japanese cohort consisting of 4563 cases and 16,459 controls. We finally identified a rare nonsynonymous variant, rs572750141 (NM_030974.3:p.Gly186Arg), in SHARPIN that was potentially associated with increased risk of LOAD (corrected P = 8.05 × 10(− 5), odds ratio = 6.1). The amino acid change in SHARPIN resulted in aberrant cellular localization of the variant protein and attenuated the activation of NF-κB, a central mediator of inflammatory and immune responses. CONCLUSIONS: Our work identified a rare functional SHARPIN variant as a previously unknown genetic risk factor for LOAD. The functional alteration in SHARPIN induced by the rare coding variant is associated with an attenuated inflammatory/immune response that may promote LOAD development. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s10020-019-0090-5) contains supplementary material, which is available to authorized users. BioMed Central 2019-06-20 /pmc/articles/PMC6585023/ /pubmed/31216982 http://dx.doi.org/10.1186/s10020-019-0090-5 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Asanomi, Yuya
Shigemizu, Daichi
Miyashita, Akinori
Mitsumori, Risa
Mori, Taiki
Hara, Norikazu
Ito, Kaoru
Niida, Shumpei
Ikeuchi, Takeshi
Ozaki, Kouichi
A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease
title A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease
title_full A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease
title_fullStr A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease
title_full_unstemmed A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease
title_short A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease
title_sort rare functional variant of sharpin attenuates the inflammatory response and associates with increased risk of late-onset alzheimer’s disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585023/
https://www.ncbi.nlm.nih.gov/pubmed/31216982
http://dx.doi.org/10.1186/s10020-019-0090-5
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