Protein and gene levels of DNAJC21 and RNF5 as drug targets for immune thrombocytopenia: optimized post-GWAS insights

Objectives
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody-mediated platelet (PLT) destruction. Its clinical manifestations are highly heterogeneous, and the unclear pathogenesis poses significant challenges for effective treatment. The limited efficacy of current therapies underscores the need for novel therapeutic targets.

Methods
This study employed an optimized post-genome-wide association study (GWAS) framework, in which proteome-wide or transcriptome-wide Bayesian colocalization analysis was performed first to identify potential trait-linked signals, followed by two-sample Mendelian randomization (MR) to infer causal relationships between candidate molecular traits and clinical phenotypes including ITP and PLT count.

Results
DNAJC21 protein was significantly associated with ITP progression, whereas NOTCH3, FKBPL, and RNF5 proteins exerted protective effects. At the genetic level, DNAJC21 was positively associated with ITP risk, while RNF5 showed a negative association. Bayesian colocalization analysis revealed a strong signal between the RNF5 gene and FKBPL protein. MR analysis supported a role for RNF5 gene in promoting the expression of both RNF5 and FKBPL proteins. Moreover, both the gene and protein forms of DNAJC21 and RNF5 colocalized with PLT-associated proteins, suggesting strong associations with platelet count regulation. DNAJC21 may upregulate CD36 expression, contributing to increased PLT count, while RNF5 was found to regulate nine proteins, notably promoting BRAP and PPP1CC, both of which are associated with elevated PLT levels.

Conclusion
DNAJC21 appears to promote ITP development, whereas RNF5 may exert protective effects through modulation of PLT-related proteins. These findings provide novel mechanistic insights and identify DNAJC21 and RNF5 as promising therapeutic targets for ITP.