Potential therapeutic targets for deep vein thrombosis: A proteome-wide Mendelian randomization study

BackgroundThe incidence of deep vein thrombosis (DVT) of the lower extremities is threatening people's health. The development of drug targets for the treatment of DVT is necessary.MethodsWe mainly conducted a proteome-wide Mendelian randomization (MR) study to explore the causal associations of plasma proteins with DVT of the lower extremities. Protein quantitative trait locis were derived from DECODE with 35,559 participants. Multiple analysis methods and two replication analyses were implemented to guarantee the reliability of the results. Mediation MR, protein-protein associations and pathway enrichment analyses were used to reveal the potential mechanisms. Finally, druggability evaluation and phenome-wide MR analysis were performed to assess the priority for drug development of these drug targets.ResultsWe identified 12 plasma proteins showing significant causal associations with DVT of the lower extremities. Genetically predicted higher serum concentration of MAP1LC3A, LRP12, VWF, F2, SYK, F11, KLKB1, and LRP4 were associated with an increased risk of DVT, while higher levels of the serum SERPINE2, XXYLT1, PMVK, and RGS18 can act as protective factors for DVT. LRP12 and F11 had the highest convincing evidence. In mediation analysis, we found four pathways, including F2-Triglycerides-DVT, LRP4-Triglycerides-DVT, MAP1LC3A-eGFR-DVT, and MAP1LC3A-Creatinine-DVT. In druggability evaluation, F11, F2, KLKB1, SYK, and VWF have been developed as drugs related to coagulation.ConclusionThis study identified 12 protein targets associated with DVT of the lower extremities and offered promising insights for developing therapeutic agents and biomarkers for DVT screening.