背景:许多代谢组学研究证实了代谢异常在特发性肺纤维化(IPF)发展中的关键作用。然而,缺乏关于循环代谢物与IPF风险之间因果关系的证据.
方法:通过双向双样本孟德尔随机化(TSMR)分析确定了486种血液代谢物与IPF之间的潜在因果关系。进行了一项涉及7,824名参与者的全基因组关联研究(GWAS)来分析代谢物数据,进行了一项GWAS荟萃分析,该分析涉及6,257例IPF病例和947,616例欧洲对照受试者,以分析IPF数据。TSMR分析主要使用逆方差加权模型进行,辅以加权模式,MR-Egger回归,和加权中位数估计。进行了一系列的灵敏度分析,包括水平多效性评估,异质性检验,Steiger测试,和遗漏分析。此外,对另一个IPFGWAS数据集进行复制分析和荟萃分析,该数据集包含4,125例IPF病例和20,464例对照受试者.中介分析用于确定混杂因素在代谢物对IPF的影响中的中介作用。
结果:有四种代谢物与IPF风险升高相关,即葡萄糖(比值比[OR]=2.49,95%置信区间[95CI]=1.13-5.49,P=0.024),尿素(OR=6.24,95%CI=1.77-22.02,P=0.004),鸟苷(OR=1.57,95CI=1.07-2.30,P=0.021),ADpSGEGDFXAEGGGVR(OR=1.70,95CI=1.00-2.88,P=0.0496)。值得注意的是,发现鸟苷对IPF的作用是由胃食管反流病介导的.反向孟德尔随机化分析表明,IPF可能会略微升高血液中的鸟苷水平。
结论:最后,高血糖可能对IPF有促进作用,强调应注意糖尿病与IPF之间的关系,不仅仅是糖尿病的诊断。此外,尿素,鸟苷,ADpSGEGDFXAEGGGVR也促进了IPF的发展。本研究可为分析IPF的潜在发病机制提供参考,并对IPF的防治具有一定的指导意义。
BACKGROUND: Numerous metabolomic studies have confirmed the pivotal role of metabolic abnormalities in the development of idiopathic pulmonary fibrosis (IPF). Nevertheless, there is a lack of evidence on the causal relationship between circulating metabolites and the risk of IPF.
METHODS: The potential causality between 486 blood metabolites and IPF was determined through a bidirectional two-sample Mendelian randomization (TSMR) analysis. A genome-wide association
study (GWAS) involving 7,824 participants was performed to analyze metabolite data, and a GWAS meta-analysis involving 6,257 IPF cases and 947,616 control European subjects was conducted to analyze IPF data. The TSMR analysis was performed primarily with the inverse variance weighted model, supplemented by weighted mode, MR-Egger regression, and weighted median estimators. A battery of sensitivity analyses was performed, including horizontal pleiotropy assessment, heterogeneity test, Steiger test, and leave-one-out analysis. Furthermore, replication analysis and meta-analysis were conducted with another GWAS dataset of IPF containing 4,125 IPF cases and 20,464 control subjects. Mediation analyses were used to identify the mediating role of confounders in the effect of metabolites on IPF.
RESULTS: There were four metabolites associated with the elevated risk of IPF, namely glucose (odds ratio [OR] = 2.49, 95% confidence interval [95%CI] = 1.13-5.49, P = 0.024),
urea (OR = 6.24, 95% CI = 1.77-22.02, P = 0.004), guanosine (OR = 1.57, 95%CI = 1.07-2.30, P = 0.021), and ADpSGEGDFXAEGGGVR (OR = 1.70, 95%CI = 1.00-2.88, P = 0.0496). Of note, the effect of guanosine on IPF was found to be mediated by gastroesophageal reflux disease. Reverse Mendelian randomization analysis displayed that IPF might slightly elevate guanosine levels in the blood.
CONCLUSIONS: Conclusively, hyperglycemia may confer a promoting effect on IPF, highlighting that attention should be paid to the relationship between diabetes and IPF, not solely to the diagnosis of diabetes. Additionally,
urea, guanosine, and ADpSGEGDFXAEGGGVR also facilitate the development of IPF. This
study may provide a reference for analyzing the potential mechanism of IPF and carry implications for the prevention and treatment of IPF.