Background: Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the two main types of HL. It has been reported that the proteome in blood was an important source for biomarker and therapeutic target discovery. However, up to now, few proteomes have been identified with the risk of HL.
Methods: Here, we conducted a proteome-wide Mendelian randomization (MR) study and colocalization analyses to decipher candidate protein markers and therapeutic targets for Hodgkin's lymphoma (HL). Genome-wide association studies (GWASs) on 3083 plasma proteins are derived from 54,219 UK Biobank participants (UKB-PPP) and 35,559 Icelanders (deCODE). Genetic associations with HL were obtained from the FinnGen cohort (864 cases and 324650 controls). Additional analyses including Bayesian colocalization, protein-protein interaction, pathway enrichment analysis, and evaluation of drug targets were conducted to deepen the understanding and identify potential therapeutic targets of HL.
Results: Our research suggested that 10 candidate proteins might have a significant causal relationship with the risk of HL. Elevated levels of 5 proteins (ADK, ADAMTSL2, DKKL1, BRD2, BCL2) and decreased levels of 5 proteins (DBNL, CD270, S100P, ISOS1, BTN3A1) were associated with an increased risk of HL, in which ADK was prioritized with the most convincing evidence (p-value <1.62e-05, 0.05/3083 proteins). ADAMTSL2 was supported by strong evidence of genetic co-localization. 4 proteins were found to be the targets of existing or potential drugs. BCL2 was a successful target, ADK and BRD2 were clinical trial targets, and CD270 was a literature-reported target.
Conclusions: Our study identified several important proteins that were associated with HL risk. It might shed light on protein-mediated mechanisms of HL and offer promising therapeutic targets for HL patients.
Tao Pan, Jiyue Zhang, Xiaomin Wang, Yuqin Song