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Cited by 47Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

Open access
Asanomi, Yuya, Shigemizu, Daichi, Miyashita, Akinori, Mitsumori, Risa, Mori, Taiki, Hara, Norikazu, Ito, Kaoru, Niida, Shumpei +2 more·2019·Molecular Medicine
DOI 10.1186/s10020-019-0090-5PMC PMC6585023
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Abstract

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. 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. 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. 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.

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  • SHARPIN p.G186R (rs572750141) and p.R274W (rs77359862) have been reported to be associated with late-onset AD in the Japanese.

    “Moreover, two rare variants, p.G186R (rs572750141) and p.R274W (rs77359862), identified in the coding regions of SHARPIN, have been reported to be associated with late-onset AD in the Japanese (Table 3) [46, 47].”

    From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [46]

    The Discussion (page unavailable) reports an association between SHARPIN p.G186R (rs572750141) and increased late-onset Alzheimer’s disease risk in a Japanese population. The Results identify the other variant studied as a TYK2 variant, not SHARPIN p.R274W (rs77359862); our copy does not support attributing the p.R274W association to this paper. (LLM, conf=0.90)

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Authors
Asanomi, Y., Shigemizu, D., Miyashita, A., Mitsumori, R., Mori, T., Hara, N., Ito, K., Niida, S., Ikeuchi, T., & Ozaki, K.
Affiliations
  • Medical Genome Center, National Center for Geriatrics and Gerontology (JP)
  • Tokyo Medical and Dental University (JP)
  • Brain Research Institute, Niigata University (JP)
  • RIKEN Center for Integrative Medical Sciences (JP)
Corresponding author
Ozaki, Kouichi
ORCID
Venue
Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-06-20
Volume
25
Issue
1
Pages
20-20
ISSN
  • 1076-1551 (ISSN-L)
  • 1528-3658
DOI
10.1186/s10020-019-0090-5
PMC
PMC6585023
OpenAlex
W2951312158
Cited by
47
References
4
Citations by year
2026: 6 · 2025: 7 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 11 · 2020: 6 · 2019: 1
FWCI
4.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • The Research Funding for Longevity Sciences from the National Center for Geriatrics and Gerontology (29-45)
  • The grant from Japan Agency for Medical Research and Development (JP18kk0205009, JP18kk0205012, JP19dk0207028)
  • The grant for Research on Dementia from the Japanese Ministry of Health, Labor and Welfare (-)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
late-onset Alzheimer's disease, SHARPIN, rare variants, non-synonymous mutations, NF-κB activation, inflammation, immune response, protein localization, genetic risk factors, Japanese population
MeSH terms
Alzheimer Disease, Apolipoproteins E, Genotype, Humans, Immunohistochemistry, Inflammation, Ubiquitins, Case-Control Studies, Polymerase Chain Reaction, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Asian People, Genome-Wide Association Study, HEK293 Cells, Exome

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