Abstract：
Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterised by the accumulation of lipoprotein material in the alveoli. Although dyslipidaemia is a prominet feature, the causal effect of lipid traits on PAP remains unclear. This study aimed to explore the role of lipid traits in PAP and evaluate the potential of lipid-lowering drug targets in PAP.
Clinical outcomes, lipid profiles and lung function tests were analysed in a clinical cohort of diagnosed PAP patients and propensity score-matched healthy controls. Genome-wide association study data on PAP, lipid metabolism, blood cells and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses.
Observational results showed that higher levels of total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) were associated with increased risks of PAP. Higher levels of TC and LDL were also associated with worse PAP severity. In MR analysis, elevated LDL was associated with an increased risk of PAP (OR: 4.32, 95% CI: 1.63 to 11.61, p=0.018). Elevated monocytes were associated with a lower risk of PAP (OR 0.34, 95% CI: 0.18 to 0.66, p=0.002) and mediated the risk impact of LDL on PAP. Genetic mimicry of PCSK9 inhibition was associated with a reduced risk of PAP (OR 0.03, p=0.007).
Our results support the crucial role of lipid and metabolism-related traits in PAP risk, emphasising the monocyte-mediated, causal effect of elevated LDL in PAP genetics. PCSK9 mediates the development of PAP by raising LDL. These finding provide evidence for lipid-related mechanisms and promising lipid-lowering drug target for PAP.
Clinical outcomes, lipid profiles and lung function tests were analysed in a clinical cohort of diagnosed PAP patients and propensity score-matched healthy controls. Genome-wide association study data on PAP, lipid metabolism, blood cells and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses.
Observational results showed that higher levels of total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) were associated with increased risks of PAP. Higher levels of TC and LDL were also associated with worse PAP severity. In MR analysis, elevated LDL was associated with an increased risk of PAP (OR: 4.32, 95% CI: 1.63 to 11.61, p=0.018). Elevated monocytes were associated with a lower risk of PAP (OR 0.34, 95% CI: 0.18 to 0.66, p=0.002) and mediated the risk impact of LDL on PAP. Genetic mimicry of PCSK9 inhibition was associated with a reduced risk of PAP (OR 0.03, p=0.007).
Our results support the crucial role of lipid and metabolism-related traits in PAP risk, emphasising the monocyte-mediated, causal effect of elevated LDL in PAP genetics. PCSK9 mediates the development of PAP by raising LDL. These finding provide evidence for lipid-related mechanisms and promising lipid-lowering drug target for PAP.
摘要：
背景：肺泡蛋白沉积症（PAP）是一种罕见的间质性肺病，其特征是肺泡中脂蛋白物质的积累。虽然血脂异常是一个突出的特征，脂质性状对PAP的因果效应尚不清楚。本研究旨在探讨脂质性状在PAP中的作用，并评估PAP中降脂药物靶标的潜力。
方法：临床结果，我们在诊断为PAP的患者和倾向评分匹配的健康对照的临床队列中分析了血脂谱和肺功能检查.PAP的全基因组关联研究数据，脂质代谢，我们获得了血细胞和编码潜在降脂药靶基因的变异体,用于孟德尔随机化(MR)和中介分析.
结果：观察结果表明，较高水平的总胆固醇（TC），甘油三酯和低密度脂蛋白(LDL)与PAP风险增加相关.较高的TC和LDL水平也与较差的PAP严重程度相关。在MR分析中，LDL升高与PAP风险增加相关(OR:4.32,95%CI:1.63~11.61,p=0.018).单核细胞升高与PAP的风险较低相关（OR0.34，95％CI：0.18至0.66，p=0.002），并介导LDL对PAP的风险影响。PCSK9抑制的遗传模拟与PAP风险降低相关(OR=0.03,p=0.007)。
结论：我们的结果支持脂质和代谢相关性状在PAP风险中的关键作用，强调单核细胞介导的，LDL升高在PAP遗传学中的因果效应。PCSK9通过提高LDL介导PAP的发展。这些发现为PAP的脂质相关机制和有希望的降脂药物靶标提供了证据。
方法：临床结果，我们在诊断为PAP的患者和倾向评分匹配的健康对照的临床队列中分析了血脂谱和肺功能检查.PAP的全基因组关联研究数据，脂质代谢，我们获得了血细胞和编码潜在降脂药靶基因的变异体,用于孟德尔随机化(MR)和中介分析.
结果：观察结果表明，较高水平的总胆固醇（TC），甘油三酯和低密度脂蛋白(LDL)与PAP风险增加相关.较高的TC和LDL水平也与较差的PAP严重程度相关。在MR分析中，LDL升高与PAP风险增加相关(OR:4.32,95%CI:1.63~11.61,p=0.018).单核细胞升高与PAP的风险较低相关（OR0.34，95％CI：0.18至0.66，p=0.002），并介导LDL对PAP的风险影响。PCSK9抑制的遗传模拟与PAP风险降低相关(OR=0.03,p=0.007)。
结论：我们的结果支持脂质和代谢相关性状在PAP风险中的关键作用，强调单核细胞介导的，LDL升高在PAP遗传学中的因果效应。PCSK9通过提高LDL介导PAP的发展。这些发现为PAP的脂质相关机制和有希望的降脂药物靶标提供了证据。
