The gene proprotein convertase subtilisin/kexin type 9 (PCSK9) may be involved in the pathogenesis of psoriasis and its inhibition may prevent the development of psoriasis, according to study findings published in JAMA Dermatology.
Researchers in the United Kingdom (UK) sourced data for this study from prior genome wide association studies, the UK Biobank, and FinnGen. Using genetic data from 6495 psoriasis case participants and 25,980 controls, a Mendelian randomization analysis was performed to assess whether genetically proxied lipid-lowering medications demonstrate clinical utility in psoriasis. Data from the FinnGen study was used as the replication cohort.
In the primary analysis, 34 genetic variants were selected as proxies for inhibition of PCSK9 (F, 246); 19 variants as proxies for 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition (F, 187); and 9 for NPC1, such as intracellular cholesterol transporter 1 (NPC1L1) inhibition (F, 105).
For every standard deviation (SD) reduction in low-density lipoprotein cholesterol (LDL-C) levels by proxied inhibition of PCSK9, a significant association with decreased risk for psoriasis was observed (odds ratio [OR], 0.69; 95% CI, 0.55-0.88; P =.003). This association was replicated using the FinnGen data (OR, 0.77; 95% CI, 0.66-0.91 per SD reduction in LDL-C; P =.001). These comparisons showed no evidence of heterogeneity (I2, 0%; P =.46).
For the other genetic proxies, neither HMGCR (Biobank: OR, 0.55; 95% CI, 0.25-1.23; FinnGen: OR, 0.67; 95% CI, 0.32-1.40) nor NPC1L1 (Biobank: OR, 0.84; 95% CI, 0.64-1.09; FinnGen: OR, 0.98; 95% CI, 0.64-1.50) showed significant evidence supporting the relationship between inhibition per SD reduction in LDL-C and psoriasis risk.
In a supplementary positive control analysis, all genetic proxies for lipid-lowering activities were significantly associated with risk for coronary artery disease (OR range, 0.48-0.71 per SD reduction in LDL-C).
Limitations of the analysis include the fact that these results likely related to psoriasis prevention and not treatment of existing psoriasis.
Study authors conclude, “The results of this MR study suggest that PCSK9 inhibition is causally associated with reduced risk of psoriasis. Existing PCSK9 inhibitors hold potential as therapeutic targets for prevention, and possibly treatment, of psoriasis, although further clinical studies are needed.”
Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.
Zhao SS, Yiu ZZN, Barton A, Bowes J. Association of lipid-lowering drugs with risk of psoriasis: a Mendelian randomization study. JAMA Dermatol. 2023;e226051. doi:10.1001/jamadermatol.2022.6051