PCSK9 inhibitors and the risk of vitiligo: a Mendelian randomization study

Lipid-lowering agents have been suggested as a therapeutic option for vitiligo based on 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. Genome-wide association study summary statistics for European ancestry were extracted from the largest available meta-analysis for vitiligo, the Global Lipids Genetics Consortium for seven lipid profiles, and two large biobanks, UKB and deCODE, for 4,719 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 two-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%CI] = 0.71[0.52-0.95]), which was replicated in PCSK9-inhibition MR analyses across two separate biobanks (UKB: OR[95%CI]=0.82[0.71-0.96]; deCODE: OR[95%CI]=0.78[0.67-0.91]). Multivariable MR suggested that well-known lipid profiles do not mediate the relationship between PCSK9 and vitiligo, while two-step MR analyses identified five potential protein mediators (CCN5, CXCL12, FCRL1, LGMN, 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.