PCSK9 Inhibitors and the Risk of Vitiligo: A Mendelian Randomization Study.

Lipid-lowering agents have been suggested as a therapeutic option for vitiligo on the basis of the potential pathogenic role of lipid metabolism abnormalities. We aimed to explore the impact of genetically proxied lipid-lowering agents on the risk of vitiligo and potentially associated mediators. GWAS summary statistics for European ancestry were extracted from the largest available meta-analysis for vitiligo: the Global Lipids Genetics Consortium for 7 lipid profiles and 2 large biobanks, UK Biobank and deCODE, for 4719 proteins. After identifying lipid-lowering agents with genetically proxied protective effects against vitiligo using lipid-lowering and protein-inhibition Mendelian randomization (MR) analyses, multivariable and 2-step MR analyses were conducted to identify potential mediators between lipid-lowering agents and vitiligo. Lipid-lowering MR indicated a potential role of PCSK9 in reducing the vitiligo risk (OR [95% confidence interval] = 0.71 [0.52-0.95]), which was replicated in PCSK9-inhibition MR analyses across 2 separate biobanks (UK Biobank: OR [95% confidence interval] = 0.82 [0.71-0.96]; deCODE: OR [95% confidence interval] = 0.78 [0.67-0.91]). Multivariable MR suggested that well-known lipid profiles do not mediate the relationship between PCSK9 and vitiligo, whereas 2-step MR analyses identified 5 potential protein mediators (CCN5, CXCL12, FCRL1, legumain, and FGF2). Hence, PCSK9 inhibitor may attenuate the vitiligo risk; PCSK9 and the potential protein mediators can serve as promising novel therapeutic targets for its effective treatment.