Genetically Supported Therapeutic Targets for Coronary Artery Disease in Diabetes-Evidence from Proteome-Wide Mendelian Randomization

Coronary artery disease (CAD) remains a major burden in people with diabetes. Genome-wide association studies (GWASs) have identified multiple genetic loci, yet most have yet to translate to clinical applications. The aim of this study was to leverage on genetic data to identify novel drug targets for CAD in diabetes. We applied Mendelian randomization (MR) to investigate the causal association of 1677 plasma proteins from 6 large GWASs, and a recently published GWAS of 15,666 individuals with diabetes (including 3968 CAD cases and 11698 controls). 5 of the 6 proteomic studies were selected as discovery MR analysis, and the remaining one as replication MR to validate the top findings. We employed sensitivity analyses, Bayesian colocalization and transcriptome-wide association study (TWAS) to test the validity of MR assumptions and meanwhile prioritized candidates of drug targets using multi-omics layers. We further integrated phenome-wide MR using the summary data from UK Biobank (N≤408 961) studies and clinical evidence based on DrugBank database to detect potential side effects associated with hypothetical therapeutic agents for CAD in diabetes and prioritize them. Our primary discovery MR analysis identified 4 prioritized proteins (F5, LPA, NPPB and TNFRSF11B) with both MR and colocalization evidence. NPPB and TNFRSF11B could be verified by replication MR analysis. Multi-tissue TWAS analysis revealed all 4 targets whose imputed expression was associated with the outcome. No adverse side effects were found for LPA via phenome-wide MR. By combining the putative causal MR signals with clinical evidence, we suggested these 4 drug repurposing opportunities for the treatment of CAD with diabetes that warranted further investigation. In summary, we prioritized 4 potential drug targets for CAD in diabetes. In particular, LPA might represent a promising target for the treatment of CAD in diabetes, with no predicted adverse side effects. Disclosure C.Huang: None. M.Shi: None. G.Yu: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. R.C.Ma: Advisory Panel; AstraZeneca, Merck & Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. Funding Research Grants Council of the Hong Kong Special Administrative Region (CU R4012-18); Croucher Foundation