Association between genetically proxied PPARG activation and psoriasis vulgaris: a Mendelian randomization study

Psoriasis is a common autoimmune disease in clinical practice, and previous observational studies have suggested that PPARG agonists such as Pioglitazone may be potential therapeutic agents. However, due to interference from various confounding factors, different observational studies have not reached a unified conclusion. We aim to evaluate the potential use of PPARG agonists for treating psoriasis from a new perspective through drug-targeted Mendelian randomization (MR) analysis.
This study includes data on 8,876 individuals for acute myocardial infarction from GWAS, and LDL cholesterol data from 343,621 Europeans. FinnGen contributed psoriasis vulgaris data for 403,972 individuals. The DrugBank10 databases function to identify genes encoding protein products targeted by active constituents of lipid-modifying targets. A two-sample MR analysis and summary-data-based MR (SMR) analysis estimated the associations between expressions of drug target genes and symptoms of psoriasis vulgaris. A multivariable MR study was further conducted to examine if the observed association was direct association.
SMR analysis revealed that enhanced PPARG gene expression in the blood (equivalent to a one standard deviation increase) was a protective factor for psoriasis vulgaris (beta = −0.2017, se = 0.0723, p = 0.0053). Besides, there exists an MR association between LDL mediated by PPARG and psoriasis vulgaris outcomes (beta = −3.9169, se = 0.5676, p = 5.17E-12). These results indicate that PPARG is a therapeutic target for psoriasis, suggesting that psoriasis may be a potential indication for PPARG agonists.
This study confirms that therapeutic activation of PPARG helps suppress the development of psoriasis. Psoriasis may be a new indication for PPARG agonists, such as Pioglitazone. In the future, new anti-psoriatic drugs could be developed targeting PPARG.

银屑病（Psoriasis）是临床常见的自身免疫性疾病，既往观察性研究提示，吡格列酮（Pioglitazone）等PPARG激动剂或许是潜在治疗药物。但受各类混杂因素干扰，不同观察性研究尚未达成统一结论。本研究旨在通过药物靶向孟德尔随机化（Mendelian randomization, MR）分析，从全新视角评估PPARG激动剂治疗银屑病的潜在价值。
本研究纳入了来自全基因组关联研究（Genome-Wide Association Study, GWAS）的8876名急性心肌梗死患者数据，以及343621名欧洲裔人群的低密度脂蛋白胆固醇（LDL cholesterol）数据；FinnGen数据库提供了403972名个体的寻常型银屑病（psoriasis vulgaris）数据。DrugBank10数据库用于识别编码脂质修饰靶点活性成分所靶向蛋白产物的基因。本研究采用双样本孟德尔随机化分析及基于汇总数据的孟德尔随机化（summary-data-based MR, SMR）分析，评估药物靶点基因表达与寻常型银屑病症状间的关联；进一步开展多变量孟德尔随机化研究，以探究观察到的关联是否为直接关联。
SMR分析显示，血液中PPARG基因表达上调（相当于1个标准差的升高）是寻常型银屑病的保护因素（β = −0.2017, se = 0.0723, p = 0.0053）。此外，PPARG介导的低密度脂蛋白胆固醇与寻常型银屑病转归间存在孟德尔随机化关联（β = −3.9169, se = 0.5676, p = 5.17×10⁻¹²）。上述结果表明，PPARG是银屑病的治疗靶点，提示银屑病或可成为PPARG激动剂的潜在适应症。
本研究证实，治疗性激活PPARG有助于抑制银屑病的发生发展。银屑病或可成为吡格列酮等PPARG激动剂的全新适应症，未来可针对PPARG开发新型抗银屑病药物。