Identification of prospective novel drug targets for immune thrombocytopenia by integrating plasma proteome.

OBJECTIVES

The etiology of immune thrombocytopenia (ITP) is heterogeneous and intricate, with some unresponsive to current treatments. We used Mendelian randomization (MR) to identify new therapeutic targets.

METHODS

Genetic instruments for 2923 plasma proteins from the UKBPPP study and ITP data from a genome-wide study (GWAS) by the FinnGen project were used to perform MR analyses. Data sets from the deCODE project and eQTLGen consortium were used to perform replication analysis. A protein-protein interactions (PPI) network was employed to predict the relationship between the identified proteins and drug targets of current clinical medicines. Potential side effects of targeting these proteins were predicted using Phenome-wide association studies (PheWAS).

RESULTS

Co-localization analysis identified 27 plasma proteins associated with ITP. Summary data-based MR (SMR) analysis and heterogeneity in dependent instrument (HEIDI) tests indicated that four proteins (AGER, FKBPL, NOTCH3, and DNAJC21) are correlated with ITP. Replication analysis validated two: DNAJC21 (OR = 2.417; 95% CI 1.391-4.200; adjusted P = 1.747 × 10-3) as a risk factor, and NOTCH3 (OR = 0.090; 95% CI 0.019-0.431; adjusted P = 2.593 × 10-2) as protective. The PPI network and protein druggability assessment showed that both proteins were related to current drug targets of ITP. PheWAS indicated that drugs targeting DNAJC21 or NOTCH3 had few side effects.

DISCUSSION AND

CONCLUSION

Numerous efforts are still needed to identify novel therapies for treatment of ITP. These results indicate that DNAJC21 and NOTCH3 could be prospective therapeutic targets for managing ITP.