PCSK9 may be ‘implicated’ in psoriasis risk
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The lipid-lowering drug proprotein convertase subtilisin/kexin type 9 was associated with an increase in psoriasis risk, according to a study.
“Previous research showed that people with psoriasis have abnormal lipid profiles, and that some lipid-lowering drugs, such as statins, may reduce skin inflammation,” Sizheng Steven Zhao, MD, PhD, of the Centre for Epidemiology Versus Arthritis at the University of Manchester and Manchester Academic Health Science Centre in England, told Healio. “The potential to repurpose these drugs to treat psoriasis is appealing, particularly since many people with psoriasis will be prescribed lipid lowering medication anyway.”
In the current two-sample mendelian randomization study, Zhao and colleagues explored causal associations between genetically proxied lipid-lowering drugs and psoriasis risk.
“A big part of our research is using real-world data to answer questions like this, but there are potential sources of bias that can lead to spurious findings, such as confounding and reverse causation,” Zhao said. “We are increasingly using Mendelian randomization because it is less susceptible to these biases and helps to support or refute findings from real-world data.”
Data from the UK Biobank and FinnGen studies, along with information from the Global Lipids Genetics Consortium, underwent analysis. The study was performed between August and October 2022.
Psoriasis risk associated with “genetically proxied inhibition of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR, targeted by statins), Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by, eg, alirocumab), using LDL as the biomarker” served as the primary outcome measure.
The analysis included data for 12,116 individuals with psoriasis and approximately 1.3 million individuals with LDL measurements.
Results showed that genetically proxied PCSK9 inhibition carried an association with reduction in psoriasis risk (OR = 0.69 per standard reduction in LDL; 95% CI, 0.55-0.88). This result was replicated in FinnGen (OR = 0.71; 95% CI, 0.57-0.88), according to the findings.
“We knew that other researchers before us have found PCSK9 to be important for psoriasis, but the unexpected finding was that drug target for ezetimibe NPC1L1 also showed potential as a drug target,” Zhao said. “This is a much more available and affordable medication than PCSK9 inhibitors, but these results will need to be confirmed in future studies.”
Conversely, HMGCR and NPC1L1 failed to demonstrate any associations with psoriasis risk.
Evidence of bias from pleiotropy or genetic confounding was not observed when the researchers conducted sensitivity analyses.
“PCSK9 is implicated in the psoriasis disease process and its inhibition may reduce psoriasis risk,” Zhao concluded. “These findings pave the way for personalised selection of lipid lowering drugs in those at risk of psoriasis.