An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer's disease.
Yuanbing JiangXiaopu ZhouHiu Yi WongLi OuyangFanny C F IpVicky M N ChauShun-Fat LauWei WuDaniel Y K WongHeukjin SeoWing-Yu FuNicole C H LaiYuewen ChenYu ChenEstella P S Tongnull nullVincent Chung-Tong MokTimothy C Y KwokKin Y MokMaryam ShoaiBenoit LehallierPatricia Morán LosadaEleanor K O'BrienTenielle PorterSimon M LawsJohn HardyTony Wyss-CorayColin L MastersAmy K Y FuNancy Y IpPublished in: Nature aging (2022)
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 (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.
Keyphrases
- crispr cas
- genome editing
- cognitive decline
- genome wide
- endothelial cells
- genome wide association
- gene expression
- high fat diet
- spinal cord
- inflammatory response
- neuropathic pain
- spinal cord injury
- small molecule
- single cell
- transcription factor
- type diabetes
- lipopolysaccharide induced
- lps induced
- skeletal muscle
- metabolic syndrome
- early onset
- induced pluripotent stem cells
- case control
- amino acid