Elevated PCSK9 Levels Associated With Psoriasis Suggest New Treatment Target

A Mendelian randomization study employing data from nearly 300,000 individuals has linked elevated levels of the PCSK9 enzyme with an increased risk of psoriasis, suggesting it might be targetable as an intervention.

Independent of low-density lipoprotein cholesterol (LDL-C), which is reduced when PCSK9 is inhibited, a reduction in PCSK9 levels appears to have a direct impact on lowering psoriasis risk. Conversely, psoriasis risk did not appear to be affected when LDL-C was reduced by other pathways of lipid control.

This study "suggests that PCSK9 inhibition is causally associated with reduced risk of psoriasis," reported a team of investigators led by Sizheng Steven Zhao, MD, PhD, of the division of musculoskeletal and dermatological sciences, University of Manchester (England). "Existing PCSK9 inhibitors hold potential as therapeutic targets for prevention, and possibly treatment, of psoriasis, although further clinical studies are needed," they concluded.

In an interview, Dr. Zhao also noted that it will be interesting to look at psoriasis susceptibility in post hoc analyses of large randomized controlled trials of PCSK9 inhibitors for cardiovascular disease.

"Genetically proxied" inhibition of HMG-CoA reductase, which is targeted by statins, and NPC1L1 which is targeted by ezetimibe, "were not associated with psoriasis risk," the investigators reported in the study, published in JAMA Dermatology.

Abnormal lipid metabolism is sufficiently common among people with psoriasis that screening in patients with moderate to severe disease is recommended in 2019 psoriasis guidelines from the American Academy of Dermatology and the National Psoriasis Foundation. However, the link between these diseases is unclear. This study was launched to explore genetically proxied relationships between psoriasis and LDL-C reductions as well as specific treatments for elevated LDL-C.

Mendelian randomizations were applied to deidentified data from two sources, a UK biobank and FinnGen, a Finnish-based project for identifying genotype-to-phenotype correlations. Genetic proxies for these variables were established on the basis of genomewide association studies on large population samples.

Ultimately, 34 genetic variants were selected to proxy for lipid lowering by PCSK9, 19 were selected to proxy for HMG-CoA reductase, and 9 for NPC1L1. In the Mendelian analyses performed on the two sources, genetically proxied PCSK9 inhibition was associated with about a 30% reduction in the odds ratio of psoriasis (OR, 0.69; P = .003). There were no robust associations with proxies for reductions in either HMG-CoA reductase or NPC1L1.

In sensitivity analyses, there was no evidence of bias from pleiotropy or genetic confounding, according to Dr. Zhao and his coauthors, who noted that the relationship between reductions in PCSK9 and reduced risk of psoriasis appeared to be independent of change in circulating LDL-C.