Second College of Clinical Medicine, Nanjing Medical University, Nanjing, China.
Academy of Paediatrics, Nanjing Medical University, Nanjing, China.
Metab Syndr Relat Disord. 2024 Sep;22(7):525-550. doi: 10.1089/met.2024.0030. Epub 2024 May 14.
Chronic kidney disease (CKD) is associated with metabolic disorders. However, the evidence for the causality of circulating metabolites to promote or prevent CKD is still lacking. The two-sample Mendelian randomization (MR) analysis was conducted to evaluate the latent causal relationship between the genetically proxied 486 blood metabolites and CKD. Genome-wide association study (GWAS) data for exposures were derived from 7824 European GWAS on metabolite levels, which have been extensively utilized in the medical field to elucidate the mechanisms underlying disease onset and progression. The random inverse variance weighted (IVW) is the primary analysis for causality analysis while MR-Egger and weighted median as complementary analyses. For the further identification of metabolites, reverse MR and linkage disequilibrium score regression were performed for further evaluation. The drug target for -acetylornithine was subsequently supplemented into the analysis, with MR and colocalization analysis being utilized. Key metabolic pathways were identified via MetaboAnalyst 4.0 (https://www.metaboanalyst.ca/) online website. -acetylornithine was identified as a reliable metabolite that increases the susceptibility to estimated glomerular filtration rate (eGFR) decrease (β = 0.047; 95% confidence interval: -0.068 to -0.026; = 1.5E-5). The "glyoxylate and dicarboxylate metabolism" pathway showed significant relevance to CKD development ( = 6E-4), whereas the "glycine, serine, and threonine metabolism" pathway was also recognized as associated with CKD by general practitioners ( = 7E-4). Colocalization analysis revealed a robust genetic link between -acetylornithine and both CKD and eGFR, with 85.1% and 99.4% colocalization rates, respectively. IVW-MR analysis substantiated these findings with a significant positive association for CKD (odds ratio = 1.43, = 4.7E-5) and a negative correlation with eGFR ( = -0.04, = 1.13E-31). MR was utilized to explore the potential causal links between 61 genetic serum metabolites and CKD. -acetylornithine and were further explored as a potential therapeutic target for CKD treatment.
慢性肾脏病（CKD）与代谢紊乱有关。然而，循环代谢物促进或预防 CKD 的因果关系的证据仍然缺乏。本研究采用两样本孟德尔随机化（MR）分析来评估遗传相关的 486 种血液代谢物与 CKD 之间潜在的因果关系。暴露的全基因组关联研究（GWAS）数据来自于 7824 项欧洲关于代谢物水平的 GWAS，这些数据在医学领域被广泛用于阐明疾病发病和进展的机制。随机逆方差加权（IVW）是因果分析的主要分析方法，而 MR-Egger 和加权中位数则是补充分析方法。为了进一步确定代谢物，进行了反向 MR 和连锁不平衡得分回归分析进行进一步评估。随后，将靶向乙酰鸟氨酸的药物纳入分析，采用 MR 和共定位分析。通过在线网站 MetaboAnalyst 4.0（https://www.metaboanalyst.ca/）确定关键代谢途径。乙酰鸟氨酸被鉴定为一种可靠的代谢物，可增加估算肾小球滤过率（eGFR）下降的易感性（β=0.047；95%置信区间：-0.068 至-0.026；=1.5E-5）。“乙醛酸和二羧酸代谢”途径与 CKD 发展显著相关（=6E-4），而“甘氨酸、丝氨酸和苏氨酸代谢”途径也被全科医生认为与 CKD 相关（=7E-4）。共定位分析显示，乙酰鸟氨酸与 CKD 和 eGFR 之间存在强大的遗传联系，分别为 85.1%和 99.4%的共定位率。IVW-MR 分析证实了这些发现，CKD 的相关性呈显著正相关（比值比=1.43，=4.7E-5），与 eGFR 呈负相关（= -0.04，=1.13E-31）。MR 用于探索 61 种遗传血清代谢物与 CKD 之间的潜在因果关系。进一步探讨乙酰鸟氨酸和作为 CKD 治疗的潜在治疗靶点。
