Genetics

Recent genetic evidence is reshaping how we think about the relationship between statins, blood lipids, and multiple sclerosis (MS). In a large Mendelian randomization study, Almramhi et al. demonstrate that the potential protective effects of statins on MS risk are unlikely to be mediated by cholesterol lowering itself, as neither low-density lipoprotein cholesterol nor cholesterol biosynthesis genes showed causal associations with MS. Instead, the study highlights a cholesterol-independent immune mechanism involving RAC2, a Rho GTPase that regulates key inflammatory and tolerance pathways in immune cells, where higher genetically predicted expression was associated with reduced MS risk. Intriguingly, the authors also report that lifelong elevated high-density lipoprotein cholesterol increases MS risk, challenging the traditional view of HDL as uniformly protective. Together, these findings shift the focus from lipid levels to immunometabolic signaling pathways, offering new mechanistic insights and potential therapeutic directions for MS research.