Targeting Specific Lipid Metabolic Pathway Linked to Reduced Psoriasis Risk

Inhibition of the PCSK9 pathway, best known for its links with dyslipidemia, had a significant association with a reduced risk of psoriasis, irrespective of lipid levels, according to a study focused on genetic variants.

Genetically proxied inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) significantly reduced the odds ratio for psoriasis in separate analyses of two large databases. In contrast, targeting two other well-known pathways associated with lipid metabolism did not influence psoriasis risk.

The findings suggest PCSK9 has a role in the pathogenesis of psoriasis and its inhibition "is causally associated with reduced risk of psoriasis," reported Sizheng Steven Zhao, MD, PhD, of the University of Manchester in England, and colleagues, in JAMA Dermatology.

"This association appeared to be independent of circulating LDL levels, since we did not observe an overall association of LDL with psoriasis risk," the authors concluded.

The lack of association with 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and Niemann-Pick C1-like 1 (NPC1L1) reinforced the specificity of the association with PCSK9.

"These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of psoriasis," they added.

The study is an example of mendelian randomization, which employs patients' genetic variation as a proxy for the true clinical state, noted Joel Gelfand, MD, of the University of Pennsylvania in Philadelphia.

"Since people inherit their genes randomly, this technique is thought to mimic a randomized controlled trial and thus relationships identified with this technique are often interpreted as causal," he told MedPage Today via email.

Dyslipidemia has been implicated as a factor in the pathogenesis of psoriasis for almost 2 decades, Gelfand continued. The current study adds to the hypothesis by showing an association between genetically proxied PCSK9 and development of psoriasis but not the other two genetic proxies they studied, suggesting a specific relationship that is independent of lipid levels.

"The authors suggest that existing PCSK9 inhibitors hold potential as therapeutic targets for prevention," said Gelfand. "Unfortunately, these drugs are very expensive, and the measure of association that they observed was modest, making it impractical to study these drugs in a rigorous manner for the prevention of psoriasis."

According to the CDC, mendelian randomization "is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies." Zhao and colleagues used mendelian randomization to examine the association between the risk of plaque psoriasis and three types of genetically proxied lipid-lowering drugs:

• HMGCR inhibitors (statins)
• NPC1L1 inhibitors, such as ezetimibe
• PCSK9 inhibitors, such as alirocumab (Praluent) and evolocumab (Repatha)

Investigators obtained genetic associations for psoriasis by performing genome-wide association studies of 6,495 patients with psoriasis and 25,980 randomly selected individuals without psoriasis from the U.K. Biobank, which maintains genetic and health information on more than 500,000 people. To replicate the analysis, they obtained genetic associations from 5,621 patients with psoriasis and a control group of 252,323 in the Finnish FinnGen database.

Investigators chose LDL as the biomarker for the study because all three classes of drugs are known to reduce LDL cholesterol. Genetic associations with LDL were obtained from the Global Lipids Genetics Consortium, which has data on 1.3 million people.

For the primary analysis, Zhao and colleagues selected variants associated with the genetic pathways targeted by the three types of drugs. They identified 19 variants to proxy lipid lowering by HMGCR inhibition, nine for NPC1L1 inhibition, and 34 for PCSK9. Analysis of U.K. Biobank data yielded an odds ratio of 0.69 for psoriasis risk in association with inhibition of PCSK9 (95% CI 0.55-0.88, P=0.003). Replication analyses with the FinnGen dataset produced an OR of 0.77 (95% CI 0.66-0.91, P=0.001).

For the other two genetic proxies, they found little evidence of an association with psoriasis. Some HMGCR variants had associations with body composition. Exclusion of those did not change the overall results. For NPC1L1, point estimates suggested a possible association with reduced psoriasis risk, but confidence intervals crossed the line of no effect.

Genetically proxied LDL lowering that included 320 genetic variants had no association with psoriasis when applied to either the U.K. Biobank or FinnGen database. Genetically proxied inhibition of all three drug targets was associated with a reduced risk of coronary artery disease.

Beyond possible implications for psoriasis, the study adds to suggestive evidence linking the PCSK9 pathway and its inhibition to a reduced risk of prostate cancer and severe COVID-19, possibly by anti-inflammatory effects.

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