Association of Lipid-Lowering Drugs With Risk of Psoriasis

Abstract

ImportanceLipid pathways have been implicated in the pathogenesis of psoriasis, and some lipid-lowering drugs, such as statins, are hypothesized to have disease-modifying properties. However, large population-level studies are scarce, and causal interpretation of results from traditional observational designs is limited by confounding.ObjectiveTo investigate the causal association between genetically proxied lipid-lowering drugs and psoriasis risk.Design, Setting, and ParticipantsThis 2-sample mendelian randomization study was performed from August to October 2022 and included population-level genome-wide association studies of psoriasis in the UK Biobank and FinnGen studies and low-density lipoprotein (LDL) by the Global Lipids Genetics Consortium. The inverse variance–weighted method was used with pleiotropy robust methods and colocalization as sensitivity analyses.ExposuresGenetically 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.Main Outcomes and MeasuresRisk of psoriasis.ResultsData from 12 116 patients with psoriasis and approximately 1.3 million individuals with LDL measurement were analyzed. Genetically proxied PCSK9 inhibition was associated with reduced risk of psoriasis (odds ratio, 0.69 per standard deviation reduction in LDL; 95% CI, 0.55-0.88; P = .003), which was replicated in FinnGen (odds ratio, 0.71; 95% CI, 0.57-0.88; P = .002). Sensitivity analyses did not provide statistical evidence of bias from pleiotropy or genetic confounding. No robust association was found for HMGCR or NPC1L1 inhibition.Conclusions and RelevanceThis mendelian randomization study suggests that PCSK9 is implicated in psoriasis pathogenesis, and its inhibition is associated with reduced psoriasis risk. These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of psoriasis.

Assessment of relationships between bullous pemphigoid and neurological diseases: A bidirectional two‐sample Mendelian randomization study

“…After the Bonferroni correction, p < 0.0125 (0.05/4) was identified as significant, while associations with p ≥ 0.0125 and <0.05 were considered as suggesting significance 17 . Besides, we used odds ratios (ORs) with 95% confidence intervals (CIs) to present the effect estimates, which can be explained as the average variation in the outcome per log‐odds increase in the genetically predicted risk of the respective binary exposure 18 . Furthermore, comprehensive sensitivity analyses with several complementary MR methods, including weighted median estimator, MR‐Egger regression, and MR‐PRESSO were conducted to appreciate the stability of the outcome 19 .…”

“…17 Besides, we used odds ratios (ORs) with 95% confidence intervals (CIs) to present the effect estimates, which can be explained as the average variation in the outcome per log-odds increase in the genetically predicted risk of the respective binary exposure. 18 Furthermore, comprehensive sensitivity analyses with several complementary MR methods, including weighted median estimator, MR-Egger regression, and MR-PRESSO were conducted to appreciate the stability of the outcome. 19 Additionally, MR-PRESSO was employed to detect potential outlier instrument (p < 0.05), which was removed stepwise to decrease the horizontal pleiotropy effect.…”

Association between genetically proxied PCSK9 inhibition and systemic lupus erythematosus risk: A mendelian randomization study

“…13 The association between lipid-lowering drug targets and autoimmune diseases has been investigated using MR approaches, and Zhao et al found that PCSK9 is associated with the pathogenesis of psoriasis and its inhibition is associated with a reduced risk of psoriasis. 14 However, less has yet investigated the potential association between PCSK9 and SLE. Therefore, the present study used the MR method to try to determine whether there is genetic evidence for an effect of PCSK9 inhibition on SLE.…”

Acne and COVID‐19 susceptibility, hospitalization, and severity: A genetic correlation study

“…To preclude genetic confounders, we sought corroboration of the genetic link via Bayesian colocalization analysis. 5 MR results indicated no causal link between acne and COVID-19 susceptibility or severity but a significant association with increased COVID-19 hospitalization risk (odds ratio = 1.09, 95% confidence interval: 1.02-1.16, p = 0.017) without heterogeneity and pleiotropy (Supporting Information S1: Tables 2 and 3). Reverse MR analyses revealed no causal connection between COVID-19 factors and acne (Figure 2).…”