Systematic proteome-wide Mendelian randomization using the human plasma proteome to identify therapeutic targets for osteomyelitis

Abstract

Os teomyelitis is a severe bone infection characterized by inflammation and destruction of bone and bone marrow, often leading to significant morbidity and challenging treatment strategies. Although it is known that many factors such as autoimmune diseases are related to the progress of osteomyelitis, the relationship between plasma protein and osteomyelitis has not been fully studied. We applied two-sample Mendelian randomization (MR) to evaluate causal effects of 4907 circulating plasma proteins on osteomyelitis risk. Proteomic exposure data were derived from a genome-wide association study (GWAS) of 35,559 Icelandic participants, while outcome statistics incorporated 2125 clinically validated osteomyelitis cases and 429,826 population controls from the FinnGen cohort. To ensure robustness, sensitivity analyses were conducted on the identified causal proteins. Additionally, to deepen our understanding of the biological processes, molecular functions, cellular compositions, and relevant metabolic and signaling pathways implicated in osteomyelitis, we performed Gene Ontology (GO) enrichment analysis, KEGG pathway analysis, and GeneMANIA analysis. The study identified five plasma proteins-SYTL1, DEFA1, MICB, FTMT, and TMEM38B-significantly associated with osteomyelitis, with protective effects indicated (inverse variance weighted p < 0.001, OR < 1). The strong statistical evidence highlights the proteins' potential as osteomyelitis biomarkers, which are crucial for enhancing our molecular insights and guiding future therapeutic development. Our findings provide valuable insights into the role of the plasma proteome in osteomyelitis and underscore the significance of the ferroptosis pathway. By identifying potential therapeutic targets associated with this pathway, we can establish a robust biological foundation for future research and therapeutic development in osteomyelitis.

Keywords: Ferroptosis; Mendelian randomization; Osteomyelitis; Plasma proteome; Therapeutic targets.