Many thanks to our wonderful co-authors, many of whom are members of the MVP Cardiometabolic Working Group. 7/n @marijana.bsky.social

Overall, we used a multi-modal approach which demonstrated that contextualizing genetic signals through causal inference methods and protein folding experiments can elucidate potential drug repurposing targets and novel therapeutic discoveries for MASLD. 6/n

Structural analysis involved creating, to our knowledge, the first computational model of IPE bound to FADS1. We also generated molecular dynamic simulations which showed IPE remains in the binding pocket for >300 ns. These models suggest stable binding modes of IPE to FADS1. 5/n

Next, we used two-sample Mendelian randomization to proxy the therapeutic effects of these medications on MASLD risk. We found that icosapent ethyl (IPE), proxied by FADS1/FADS2 expression, and fingolimod, proxied by S1PR2 expression, have protective effects against MASLD.

We performed TWAS with previously published MVP sumstats, providing us with genetically predicted gene expression associated with MASLD risk. These genes were mapped to drug targets, refined by direction of effect & drug mechanism, and taken forward for casual analysis. 3/n

Millions of Americans have MASLD, but there are currently a limited number of treatment options. We developed a genome-informed drug repurposing approach, which integrates genetic, molecular, and pharmacological data, to identify new treatments for MASLD. 2/n