PCSK9 Inhibitors May Reduce Risk of Vitiligo,Promising New Therapeutic Approach, reports study

Vitiligo is a chronic, acquired skin disorder characterized by the loss of pigmenting agents in the skin and results in white patches of skin. The exact cause of vitiligo remains obscure, although several recent studies have suggested that lipid metabolism abnormalities may link with the state of the disease. Lipid-lowering agents have been proposed as potential therapeutic options, mainly PCSK9 inhibitors modulating the lipid profiles. The researchers investigated, in this paper, the genetically proxied effects of lipid-lowering agents on the risk of vitiligo and identified associated protein mediators that might further explain the protective effects observed.

In this study, genome-wide association study (GWAS) summary statistics were used for a large meta-analysis of vitiligo, along with data from the Global Lipids Genetics Consortium, the UK Biobank, and deCODE Genetics. These data were used to estimate the association of genetically proxied lipid-lowering agents with the risk of vitiligo. The MR analysis was performed to identify which lipid-lowering agents exerted protective effects against vitiligo, and multivariable and two-step MR analyses to explore the potential mediators between the lipid-lowering agents and the risk of vitiligo.

Key Findings

• MR analysis found out genetic inhibition of PCSK9, a protein involved in cholesterol metabolism, was associated with a significantly reduced risk of developing vitiligo. The odds ratio was 0.71, which represented a 29 percent reduced risk of vitiligo with PCSK9 inhibition.

• This protective effect was replicated in two independent biobank datasets: the UK Biobank (OR, 0.82; 95% CI, 0.71-0.96) and deCODE Genetics (OR, 0.78; 95% CI, 0.67-0.91).

• These consistent results across the different populations further strengthen the evidence for the role of PCSK9 inhibitors in reducing the risk of vitiligo.

• Further analysis was done to test whether the relationship between PCSK9 inhibition and vitiligo is driven by known lipid profiles.

• We found no evidence for these lipid profiles mediating this protective effect in multivariable MR analyses. Two-step MR analyses identified five potential protein mediators—CCN5, CXCL12, FCRL1, LGMN, and FGF2—that may play a role in the link of PCSK9 inhibition with reduced vitiligo risk.

These findings suggest that PCSK9 inhibitors already licensed for the lowering of cholesterol levels could be repurposed as a new vitiligo treatment. The identification of possible protein mediators supplies additional objectives for the development of drugs in the future. The researchers and clinicians can target PCSK9 and these mediators in an effort to develop more effective therapies for vitiligo and give some hope to the patients who are living with this rather serious condition.

This research provides evidence based on data that PCSK9 inhibitors could be a new avenue of treatment against vitiligo, wherein multiple data sets showed reduced risk. The identification of protein mediators raises comprehension of how lipid-lowering agents would affect vitiligo, further opening up avenues for targeted and more effective treatments.

Reference:

Kang, T.-J., Lee, S. Y., Yoon, S., Kim, E. G., Kim, J. O., Kim, J.-S., Park, J., & Nam, K.-H. (2024). PCSK9 inhibitors and the risk of vitiligo: a Mendelian randomization study. The Journal of Investigative Dermatology. https://doi.org/10.1016/j.jid.2024.07.021