General Information
- Project ID
- OEP003544
- Project Name
- MTMR3 in IgA nephropathy
- Description
- Multiple genome-wide association studies (GWASs) have identified the MTMR3/HORMAD2/LIF/OSM region to be associated with IgA nephropathy (IgAN), but the causal variants, implicated genes, and altered functions are poorly understood. Here, we performed fine-mapping analyses based on the GWAS datasets consisting of 2,762 IgAN cases and 5,803 controls. We identified two variants explaining the entire GWAS signal, rs4823074 and rs16988135, both of which linked to the MTMR3 promoters in B-lymphoblastoid cells. Mendelian randomization studies suggested that the risk alleles may modulate disease susceptibility by affecting serum IgA levels through increased MTMR3 expression. Consistently, we observed elevated MTMR3 expression in PBMCs from IgAN patients. Further mechanistic studies in vitro demonstrated that MTMR3 increased IgA production dependent upon its PtdIns3P binding domain. Moreover, our study provided the in vivo functional evidence that Mtmr3−/− mice exhibited defective TLR9-induced IgA production and glomerular IgA deposition. Collectively, the present study indicated the role of MTMR3 in IgAN pathogenesis by enhancing TLR9-induced IgA immunity, and provided novel insights into using genetic data to explore a novel intervention target for IgAN.
- Publications
-
MTMR3 risk alleles enhance Toll Like Receptor 9-induced IgA immunity in IgA nephropathy
(PMID: 37414396) (DOI: 10.1016/j.kint.2023.06.018)
Project information
Author Information
- Create Date
- 2022-07-25
- Last Modified
- 2023-09-07
- Submission
- Yan-na Wang
- Peking University First Hospital