E113 Prioritising drug targets for idiopathic inflammatory myopathies via QTL-based Mendelian randomisation and colocalisation

Background/Aims Idiopathic inflammatory myopathies (IIM) are rare autoimmune disorders with incompletely defined genetic mechanisms. Identifying causal genes and proteins may accelerate therapeutic target discovery. Methods We performed two-sample Mendelian randomisation (MR) with molecular quantitative trait loci (QTLs) and colocalisation to evaluate the causal effects of 1,064 proteins and 8,415 genes on overall IIM and clinical subtypes, including polymyositis (PM), dermatomyositis (DM), juvenile DM and anti-Jo-1. cis-protein QTLs (pQTLs) from Fenland serum protein study and cis-expression QTLs (eQTLs) from GTEx skeletal muscle and eQTLGen whole blood were used in two-sample MR. Bonferroni correction accounted for multiple testing. Significant MR signals after correction were assessed by colocalization to confirm shared causal variants (PP4>0.8). Drug target tractability was assessed via the Open Targets Platform. Results Four targets emerged after MR significance correction and colocalisation. pQTL-based MR implicated TLR1 (OR = 0.21, 95% CI: 0.10-0.44, P = 3.17 × 10-5) and NFKB1 (OR = 3.19, CI: 1.96-5.21, P = 3.37 × 10-6), with concordant eQTL-based MR in whole blood. eQTL-based MR additionally identified DCAKD (skeletal muscle; IIM: OR = 0.57, CI: 0.46-0.70, P = 1.22 × 10-7) and PTPN22 (whole blood; PM: OR = 3.43, CI: 2.14-5.48, P = 2.63 × 10-7). No significant signals were observed for DM, juvenile DM, or anti-Jo-1. Colocalisation confirmed shared causal variants for: (i) IIM with serum levels of TLR1 and NFKB1, and expression levels in skeletal muscle of DCAKD; and (ii) PM with expression levels in whole blood of PTPN22. Drug target assessment indicated tractability for TLR1, NFKB1, and PTPN22 with varying clinical readiness, while DCAKD emerged as a novel target with limited tractability. Conclusion Integrating QTL-based MR with colocalisation highlights TLR1, NFKB1, DCAKD, and PTPN22 as candidate regulators in IIM and PM, implicating innate immune sensing, NF-κB signalling, and proteostasis pathways. These findings nominate tractable therapeutic targets and demonstrate a scalable framework for causal drug target prioritisation in rare autoimmune disease. Disclosure G. Chen: None. H. Chinoy: None. S.S. Zhao: None. A.S. Morris: None. J.A. Lamb: None.