Tosedostat

Inflammatory bowel disease (IBD) with the two predominant endophenotypes—Crohn's disease (CD) and ulcerative colitis (UC)—represents a group of chronic gastrointestinal inflammatory conditions. Since most genetic associations with IBD are often limited to independent subtypes, we reported a genome‐wide association study (GWAS) cross‐trait analysis combined with CD and UC to enhance statistical power. Initially, we detected 256 association signals at 54 genomic susceptibility loci and further characterized the functionality of variants within these regions. Subsequently, we revealed tissue and cell‐specific heritability enrichment, particularly in whole blood, small intestine terminal ileum, spleen, lung, and colon transverse. Leveraging multi‐omics datasets, we adopted a two‐pronged approach comprising summary data‐based Mendelian randomization (SMR) and transcriptome‐wide association study (TWAS) to pinpoint likely causal genes and variants. Further, RNA‐seq analysis facilitated the evaluation of differential expression and co‐expression in intestinal tissues. Through a multi‐stage prioritization strategy, compelling evidence for putative targets was nominated; notably highlighting several potential susceptibility genes such as IL27 and SBNO2 . Finally, we utilized Mendelian randomization (MR) analysis with diverse datasets to verify the convergence of these two endophenotype‐driven genes. Our investigation yields valuable insights to inform genetic mechanisms in IBD and reveal potential causal gene targets.

Drug development for atrial fibrillation (AF) has failed to yield new approved compounds. We sought to identify and prioritise potential druggable targets with support from human genetics, by integrating the available evidence with bioinformatics sources relevant for AF drug development.

Genetic hits for AF and related traits were identified through structured search of MEDLINE. Genes derived from each paper were cross-referenced with the OpenTargets platform for drug interactions. Confirmation/validation was demonstrated through structured searches and review of evidence on MEDLINE and ClinialTrials.gov for each drug and its association with AF.

613 unique drugs were identified, with 21 already included in AF Guidelines. Cardiovascular drugs from classes not currently used for AF (e.g. ranolazine and carperitide) and anti-inflammatory drugs (e.g. dexamethasone and mehylprednisolone) had evidence of potential benefit. Further targets were considered druggable but remain open for drug development.

Our systematic approach, combining evidence from different bioinformatics platforms, identified drug repurposing opportunities and druggable targets for AF.

KK is supported by Barts Charity grant G-002089 and is mentored on the AFGen 2023-24 Fellowship funded by the AFGen NIH/NHLBI grant R01HL092577. RP is supported by the UCL BHF Research Accelerator AA/18/6/34223 and NIHR grant NIHR129463. AFS is supported by the BHF grants PG/18/5033837, PG/22/10989 and UCL BHF Accelerator AA/18/6/34223 as well as the UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee EP/Z000211/1 and by the UKRI-NIHR grant MR/V033867/1 for the Multimorbidity Mechanism and Therapeutics Research Collaboration. AF is supported by UCL BHF Accelerator AA/18/6/34223. CF is supported by UCL BHF Accelerator AA/18/6/34223.