JAMA Dermatology

<jats:sec id="ab-doi220068-4"><jats:title>Importance</jats:title><jats:p>Lipid 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.</jats:p></jats:sec><jats:sec id="ab-doi220068-5"><jats:title>Objective</jats:title><jats:p>To investigate the causal association between genetically proxied lipid-lowering drugs and psoriasis risk.</jats:p></jats:sec><jats:sec id="ab-doi220068-6"><jats:title>Design, Setting, and Participants</jats:title><jats:p>This 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.</jats:p></jats:sec><jats:sec id="ab-doi220068-7"><jats:title>Exposures</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="ab-doi220068-8"><jats:title>Main Outcomes and Measures</jats:title><jats:p>Risk of psoriasis.</jats:p></jats:sec><jats:sec id="ab-doi220068-9"><jats:title>Results</jats:title><jats:p>Data 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; <jats:italic>P</jats:italic> = .003), which was replicated in FinnGen (odds ratio, 0.71; 95% CI, 0.57-0.88; <jats:italic>P</jats:italic> = .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.</jats:p></jats:sec><jats:sec id="ab-doi220068-10"><jats:title>Conclusions and Relevance</jats:title><jats:p>This 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.</jats:p></jats:sec>

Meta-analysis of psoriasis, cardiovascular disease, and associated risk factors.

J Am Acad Dermatol

AJC editor’s consensus: psoriasis and coronary artery disease.

Am J Cardiol

Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities.

The effect of statins on psoriasis severity: a meta-analysis of randomized clinical trials.

Arch Med Sci

Potentiation of psoriasis-like inflammation by PCSK9.

J Invest Dermatol

Global gene expression analysis reveals evidence for decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin.

Mendelian randomization for studying the effects of perturbing drug targets.

Wellcome Open Res

Mendelian randomization: genetic anchors for causal inference in epidemiological studies.

Hum Mol Genet

Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis.

Nat Genet

Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

The UK Biobank resource with deep phenotyping and genomic data.

Nature

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.

The power of genetic diversity in genome-wide association studies of lipids.

Mendelian randomization analysis with multiple genetic variants using summarized data.

Genet Epidemiol

Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians.

An approximation to the F distribution using the chi-square distribution.

Comput Stat Data Anal

Avoiding bias from weak instruments in Mendelian randomization studies.

Int J Epidemiol

Combining evidence from Mendelian randomization and colocalization: review and comparison of approaches.

Am J Hum Genet

Bayesian test for colocalisation between pairs of genetic association studies using summary statistics.

PLoS Genet

Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.

Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator.

Robust inference in summary data mendelian randomization via the zero modal pleiotropy assumption.

PhenoScanner: a database of human genotype-phenotype associations.

Bioinformatics

PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations.

Association between psoriatic disease and lifestyle factors and comorbidities: cross-sectional analysis and Mendelian randomisation.

Rheumatology (Oxford)

A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.

Large-scale integration of the plasma proteome with genetics and disease.

The MR-Base platform supports systematic causal inference across the human phenome.

Elife

Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) predicts future risk of cardiovascular events independently of established risk factors.

Circulation

Characterization of PCSK9 in the blood and skin of psoriasis.

A critical role of PCSK9 in mediating IL-17–producing T cell responses in hyperlipidemia.

Immune Netw

PCSK9 induces a pro-inflammatory response in macrophages.

Sci Rep

Suppressor of cytokine signaling-3 (SOCS-3) induces proprotein convertase subtilisin kexin type 9 (PCSK9) expression in hepatic hepG2 cell line.

J Biol Chem

Lipid 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.
To investigate the causal association between genetically proxied lipid-lowering drugs and psoriasis risk.
This 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.
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.
Risk of psoriasis.
Data 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.
This 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.

Association of Lipid-Lowering Drugs With Risk of Psoriasis: A Mendelian Randomization Study.

Association of Lipid-Lowering Drugs With Risk of Psoriasis

Papers