| First Author | Jiang Y | Year | 2022 |
| Journal | Nat Aging | Volume | 2 |
| Issue | 7 | Pages | 616-634 |
| PubMed ID | 37117777 | Mgi Jnum | J:348882 |
| Mgi Id | MGI:7645578 | Doi | 10.1038/s43587-022-00241-9 |
| Citation | Jiang Y, et al. (2022) An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-epsilon4 in female patients with Alzheimer's disease. Nat Aging 2(7):616-634 |
| abstractText | 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)-epsilon4 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 (Abeta) pathology through the modulation of microglial activation and Abeta clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD. |
