A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains.
J Alzheimers Dis
; 56(3): 1037-1054, 2017.
Article
en En
| MEDLINE
| ID: mdl-28106546
ABSTRACT
The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of onset of Alzheimer's disease in APOE É4 carriers. Across five datasets, p.D358A had a meta Pâ=â3 ×10-4 and an odds ratioâ=â1.3, 95% confidence interval 1.12 -1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset of Alzheimer's disease in APOE É4 carriers.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Encéfalo
/
Receptores de Interleucina-6
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Polimorfismo de Nucleótido Simple
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Enfermedad de Alzheimer
Tipo de estudio:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
/
Systematic_reviews
Límite:
Aged
/
Aged80
/
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
J Alzheimers Dis
Asunto de la revista:
GERIATRIA
/
NEUROLOGIA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos