■血液代谢异常显示与胆汁淤积性肝病(CLDs)有关,而潜在的代谢机制仍然缓慢。因此,本评估旨在调查血液代谢物与两种主要CLD风险之间的因果关系,包括原发性胆汁性胆管炎(PBC)和原发性硬化性胆管炎(PSC)。
■采用单变量和多变量孟德尔随机化(MR)方法来揭示血液代谢物和2个CLD之间的潜在因果关系,包括PBS和PSC,通过从对欧洲个体进行的全基因组关联研究(GWAS)中提取代谢物的工具变量(IVs)。PBC或PSC的GWAS汇总数据来自两个不同的数据集。初始分析采用逆方差加权(IVW)和一系列敏感性分析,其次是利用FinnGen联盟数据的复制和荟萃分析。最后,我们进行了多变量MR分析,以确定每种代谢物的独立效应.此外,我们使用基于网络的MetaboAnalyst5.0工具进行代谢途径检查.
■经过初步分析和错误发现率(FDR)校正后,认识到15种代谢物与CLD之间的遗传因果关系。随后,9种代谢物通过复制和荟萃分析一致地表示关联。此外,多变量MR分析证实了7种代谢物的独立因果效应.具体来说,代谢物异戊酰基肉碱(比值比[OR]=3.146,95%置信区间[CI]:1.471-6.726,p=0.003),缬氨酸(OR=192.44,95CI:4.949-7483.27,p=0.005),和甘露糖(OR=0.184,95CI:0.068-0.499,p<0.001)与PBC的发生有因果关系。此外,红细胞(OR=5.504,95CI:1.801-16.821,p=0.003),1-硬脂酰甘油磷酸胆碱(OR=6.753,95CI:2.621-17.399,p=7.64×10-5),X-11847(OR=0.478,95CI:0.352-0.650,p=2.28×10-6),X-12405(OR=3.765,95CI:1.771-8.005,p=5.71×10-4)与PSC的发生独立相关。此外,对代谢途径的分析在两个CLD中确定了7个重要途径。
■本研究的发现揭示了7种代谢物和2种CLD之间的强大因果关系,从而为这些疾病的代谢机制和治疗策略提供了新的见解。
UNASSIGNED: Blood metabolite abnormalities have revealed an association with cholestatic liver diseases (CLDs), while the underlying metabolic mechanisms have remained sluggish yet. Accordingly, the present evaluation aims to investigate the causal relationship between blood metabolites and the risk of two major CLDs, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).
UNASSIGNED: Univariable and multivariable Mendelian randomization (MR) approaches were employed to uncover potential causal associations between blood metabolites and 2 CLDs, including PBS and PSC, through extracting instrumental variables (IVs) for metabolites from genome-wide association studies (GWAS) conducted on European individuals. The GWAS summary data of PBC or PSC were sourced from two distinct datasets. The initial analysis employed inverse variance weighted (IVW) and an array of sensitivity analyses, followed by replication and meta-analysis utilizing FinnGen consortium data. Finally, a multivariable MR analysis was carried out to ascertain the independent effects of each metabolite. Furthermore, the web-based tool MetaboAnalyst 5.0 was used to perform metabolic pathway examination.
UNASSIGNED: A genetic causality between 15 metabolites and CLDs was recognized after preliminary analysis and false discovery rate (FDR) correction. Subsequently, 9 metabolites consistently represented an association through replication and meta-analysis. Additionally, the independent causal effects of 7 metabolites were corroborated by multivariable MR analysis. Specifically, the metabolites isovalerylcarnitine (odds ratio [OR] = 3.146, 95% confidence intervals [CI]: 1.471-6.726, p = 0.003), valine (OR = 192.44, 95%CI: 4.949-7483.27, p = 0.005), and mannose (OR = 0.184, 95%CI: 0.068-0.499, p < 0.001) were found to have a causal relationship with the occurrence of PBC. Furthermore, erythrose (OR = 5.504, 95%CI: 1.801-16.821, p = 0.003), 1-stearoylglycerophosphocholine (OR = 6.753, 95%CI: 2.621-17.399, p = 7.64 × 10-5), X-11847 (OR = 0.478, 95%CI: 0.352-0.650, p = 2.28 × 10-6), and X-12405 (OR = 3.765, 95%CI: 1.771-8.005, p = 5.71 × 10-4) were independently associated with the occurrence of PSC. Furthermore, the analysis of metabolic pathways identified seven significant pathways in two CLDs.
UNASSIGNED: The findings of the present
study have unveiled robust causal relationships between 7 metabolites and 2 CLDs, thereby providing novel insights into the metabolic mechanisms and therapeutic strategies for these disorders.