An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer's disease.
Nat Aging
; 2(7): 616-634, 2022 07.
Article
en En
| MEDLINE
| ID: mdl-37117777
ABSTRACT
Changes in the levels of circulating proteins are associated with Alzheimer's disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33-ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR-Cas9 genome editing identified rs1921622 , a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622 , demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622 /sST2 regulates amyloid-beta (Aß) pathology through the modulation of microglial activation and Aß clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Enfermedad de Alzheimer
Tipo de estudio:
Clinical_trials
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Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Nat Aging
Año:
2022
Tipo del documento:
Article
País de afiliación:
China