Liu Yong, Liu Hui, Bian Queqiao
Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Department of Dermatology and STD, The Third Central Hospital of Tianjin, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China.
Tianjin Institute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin, China.
Front Med (Lausanne). 2024 Sep 25;11:1396036. doi: 10.3389/fmed.2024.1396036. eCollection 2024.
Although previous studies have indicated an association between low-density lipoprotein (LDL) and skin diseases, their causal effects remain inconclusive. This study aimed to assess the causal relationship between genetically proxied lipid-lowering drugs and skin cancers and psoriasis.
Two-sample Mendelian randomization (MR) analysis was performed using single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was used to determine causal relationships. The "leave-one-out" sensitivity test, Cochran's Q-statistic and MR-Egger intercept were used to assess heterogeneity and horizontal pleiotropy.
We identified 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and proprotein convertase subtilisin-kexin type 9 (PCSK9) as genetically proxied lipid-lowering drugs. Genetically proxied inhibition of HMGCR (stains) was causally associated with reduced risk of nonmelanoma skin cancer (OR 0.982, 95% CI 0.967-0.997, = 0.016 by weighted median; OR 0.977, 95% CI 0.966-0.989, < 0.001 by IVW) and psoriasis (OR 0.585, 95% CI 0.378-0.905, = 0.016 by IVW), while PCSK9 inhibition (alirocumab) was causally associated with reduced risk of psoriasis (OR 0.560, 95% CI 0.413-0.761 by weighted median; OR 0.564, 95% CI 0.447-0.712 by IVW; < 0.001) in the ieu-b-5089 dataset. Similar results were observed in the ieu-b-110 dataset for HMGCR and PCSK9. Sensitivity analysis revealed no evidence of heterogeneity or horizontal pleiotropy.
This study revealed the existing HMGCR inhibitors (stains) might be protective for reducing nonmelanoma skin cancer risk, and HMGCR inhibitors (stains) and PCSK9 inhibitor (alirocumab) might be promising for reducing psoriasis risk in the European population.
尽管先前的研究表明低密度脂蛋白（LDL）与皮肤疾病之间存在关联，但其因果效应仍不明确。本研究旨在评估基因代理的降脂药物与皮肤癌和银屑病之间的因果关系。
使用全基因组关联研究（GWAS）中的单核苷酸多态性（SNP）进行两样本孟德尔随机化（MR）分析。采用逆方差加权（IVW）方法确定因果关系。使用“留一法”敏感性检验、 Cochr an Q 统计量和 MR-Egger 截距来评估异质性和水平多效性。
我们确定 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGCR）和前蛋白转化酶枯草溶菌素 9 型（PCSK9）为基因代理的降脂药物。基因代理的 HMGCR 抑制（他汀类药物）与非黑色素瘤皮肤癌风险降低存在因果关系（加权中位数法 OR 为 0.982，95%CI 为 0.967 - 0.997，P = 0.016；IVW 法 OR 为 0.977，95%CI 为 0.966 - 0.989，P < 0.001）以及银屑病（IVW 法 OR 为 0.585，95%CI 为 0.378 - 0.905，P = 0.016），而在ieu-b-5089数据集中PCSK9抑制（阿利西尤单抗）与银屑病风险降低存在因果关系（加权中位数法 OR为0.560，95%CI为0.413 - 0.761；IVW法OR为0.564，95%CI为0.447 - 0.712；P < 0.001）。在ieu-b-110数据集中对HMGCR和PCSK9观察到类似结果。敏感性分析未发现异质性或水平多效性的证据。
本研究表明，现有的HMGCR抑制剂（他汀类药物）可能对降低非黑色素瘤皮肤癌风险具有保护作用，并且HMGCR抑制剂（他汀类药物）和PCSK9抑制剂（阿利西尤单抗）可能有望降低欧洲人群中的银屑病风险。
