Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Guangming District, The Seventh Affiliated Hospital, Sun Yat-Sen University, 66 Gongchang Road, Shenzhen, 518107, China.
Department of Orthopaedics and Trauma, The Affiliated Hospital of Yunnan University, Yunnan University, Kunming, 650091, China.
Inflamm Res. 2024 Mar;73(3):475-484. doi: 10.1007/s00011-024-01850-3. Epub 2024 Feb 11.
Lipid pathways play a crucial role in psoriatic arthritis development, and some lipid-lowering drugs are believed to have therapeutic benefits due to their anti-inflammatory properties. Traditional observational studies face issues with confounding factors, complicating the interpretation of causality. This study seeks to determine the genetic link between these medications and the risk of psoriatic arthritis.
This drug target study utilized the Mendelian randomization strategy. We harnessed high-quality data from population-level genome-wide association studies sourced from the UK Biobank and FinnGen databases. The inverse variance-weighted method, complemented by robust pleiotropy methods, was employed. We examined the causal relationships between three lipid-lowering agents and psoriatic arthritis to unveil the underlying mechanisms.
A significant association was observed between genetically represented proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and a decreased risk of psoriatic arthritis (odds ratio [OR]: 0.51; 95% CI 0.14-0.88; P < 0.01). This association was further corroborated in an independent dataset (OR 0.60; 95% CI 0.25-0.94; P = 0.03). Sensitivity analyses affirmed the absence of statistical evidence for pleiotropic or genetic confounding biases. However, no substantial associations were identified for either 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or Niemann-Pick C1-like 1 inhibitors.
This Mendelian randomization analysis underscores the pivotal role of PCSK9 in the etiology of psoriatic arthritis. Inhibition of PCSK9 is associated with reduced psoriatic arthritis risk, highlighting the potential therapeutic benefits of existing PCSK9 inhibitors.
脂质代谢途径在银屑病关节炎的发生发展中起着至关重要的作用，一些降脂药物因其抗炎特性而被认为具有治疗益处。传统的观察性研究面临混杂因素的问题，使得因果关系的解释变得复杂。本研究旨在确定这些药物与银屑病关节炎风险之间的遗传联系。
本药物靶点研究采用孟德尔随机化策略。我们利用来自英国生物库和芬兰遗传数据库的人群水平全基因组关联研究的高质量数据。采用逆方差加权法，并辅以稳健的多效性方法。我们检查了三种降脂药物与银屑病关节炎之间的因果关系，以揭示潜在的机制。
遗传代表的前蛋白转化酶枯草溶菌素/糜蛋白酶 9（PCSK9）抑制与银屑病关节炎风险降低之间存在显著关联（比值比 [OR]：0.51；95%置信区间 0.14-0.88；P<0.01）。在独立数据集（OR 0.60；95%置信区间 0.25-0.94；P=0.03）中进一步证实了这一关联。敏感性分析证实不存在多效性或遗传混杂偏倚的统计学证据。然而，对于 3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂或尼曼-匹克 C1 样 1 抑制剂，均未发现与银屑病关节炎有实质性关联。
这项孟德尔随机化分析强调了 PCSK9 在银屑病关节炎发病机制中的关键作用。PCSK9 的抑制与银屑病关节炎风险降低相关，这突出了现有 PCSK9 抑制剂的潜在治疗益处。
