背景:特发性肺纤维化(IPF)是一种病因不明,治疗选择有限的呼吸系统疾病,可能与脂质代谢失调有关.虽然一些观察性研究表明,降脂药可以降低IPF的风险,证据不一致。本孟德尔随机化(MR)研究旨在确定循环脂质性状与IPF之间的关联,并评估调脂药物对IPF的潜在影响。
方法:5个脂质性状的汇总统计(高密度脂蛋白胆固醇,低密度脂蛋白胆固醇,甘油三酯,载脂蛋白A,和载脂蛋白B)和IPF来自英国生物银行和FinnGen项目第10轮。这项研究的重点是脂质调节基因包括PCSK9,NPC1L1,ABCG5,ABCG8,HMGCR,APOB,LDLR,CETP,ANGPTL3,APOC3,LPL,和PPARA。主要效果估计是使用逆方差加权法确定的,使用污染混合方法进行额外的分析,稳健的调整后的配置文件分数,加权中位数,加权模式方法,还有MR-Egger.基于汇总数据的孟德尔随机化(SMR)用于确认显著的调脂药物靶标,利用相关组织中表达数量性状基因座的数据。敏感性分析包括异质性评估,水平多效性,和遗漏的方法。
结果:血脂性状对IPF发病风险无显著影响(均P>0.05)。药物靶MR分析显示NPC1L1、PCSK9、ABCG5、ABCG8和APOC3抑制剂的基因模拟与IPF风险增加相关。比值比(OR)和95%置信区间(CI)如下:2.74(1.05-7.12,P=0.039),1.36(1.02-1.82,P=0.037),1.66(1.12-2.45,P=0.011),1.68(1.14-2.48,P=0.009),和1.42(1.20-1.67,P=3.17×10-5),分别。SMR方法确定了全血中PCSK9基因表达与降低IPF风险之间的显着关联(OR=0.71,95%CI:0.50-0.99,P=0.043)。敏感性分析显示没有偏倚的证据。
结论:血脂特征对特发性肺纤维化的发病风险无显著影响。对12种调脂药物的MR研究表明,PCSK9抑制剂可以显着增加IPF风险,这种机制可能不同于它们的降脂作用,因此需要进一步研究。
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder of obscure etiology and limited treatment options, possibly linked to dysregulation in lipid metabolism. While several observational studies suggest that lipid-lowering agents may decrease the risk of IPF, the evidence is inconsistent. The present Mendelian randomization (MR) study aims to determine the association between circulating lipid traits and IPF and to assess the potential influence of lipid-modifying medications for IPF.
METHODS: Summary statistics of 5 lipid traits (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apolipoprotein A, and apolipoprotein B) and IPF were sourced from the UK Biobank and FinnGen Project Round 10. The study\'s focus on lipid-regulatory genes encompassed PCSK9, NPC1L1, ABCG5, ABCG8, HMGCR, APOB, LDLR, CETP, ANGPTL3, APOC3, LPL, and PPARA. The primary effect estimates were determined using the inverse-variance-weighted method, with additional analyses employing the contamination mixture method, robust adjusted profile score, the weighted median, weighted mode methods, and MR-Egger. Summary-data-based Mendelian randomization (SMR) was used to confirm significant lipid-modifying drug targets, leveraging data on expressed quantitative trait loci in relevant tissues. Sensitivity analyses included assessments of heterogeneity, horizontal pleiotropy, and leave-one-out methods.
RESULTS: There was no significant effect of blood lipid traits on IPF risk (all P>0.05). Drug-target MR analysis indicated that genetic mimicry for inhibitor of NPC1L1, PCSK9, ABCG5, ABCG8, and APOC3 were associated with increased IPF risks, with odds ratios (ORs) and 95% confidence intervals (CIs) as follows: 2.74 (1.05-7.12, P = 0.039), 1.36 (1.02-1.82, P = 0.037), 1.66 (1.12-2.45, P = 0.011), 1.68 (1.14-2.48, P = 0.009), and 1.42 (1.20-1.67, P = 3.17×10-5), respectively. The SMR method identified a significant association between PCSK9 gene expression in whole blood and reduced IPF risk (OR = 0.71, 95% CI: 0.50-0.99, P = 0.043). Sensitivity analyses showed no evidence of bias.
CONCLUSIONS: Serum lipid traits did not significantly affect the risk of idiopathic pulmonary fibrosis. Drug targets MR studies examining 12 lipid-modifying drugs indicated that PCSK9 inhibitors could dramatically increase IPF risk, a mechanism that may differ from their lipid-lowering actions and thus warrants further investigation.