Wang Zhe, Gao Bingjun, Liu Xiao, Li Aiwu
Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China.
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.
Front Pediatr. 2024 Aug 27;12:1371933. doi: 10.3389/fped.2024.1371933. eCollection 2024.
Gut microbiome (GM) was observed to be associated with the incidence of Hirschsprung disease (HD). However, the effect and mechanism of GM in HD is still unclear. To investigate the relationship between GM and HD and the effect of metabolites as mediators, a bidirectional two-step Mendelian randomization (MR) study was conducted.
The study selected instrument variables (IVs) from summary-level genome-wide association studies (GWAS). The MiBioGen consortium provided the GWAS data for GM, while the GWAS data for metabolites and HD were obtained from the GWAS Catalog consortium. Two-sample MR analyses were performed to estimate bidirectional correlations between IVs associated with GM and HD. Then, genetic variants related to 1,400 metabolite traits were selected for further mediation analyses using the Product method.
This study found that seven genus bacteria had a significant causal relationship with the incidence of HD but not vice versa. 27 metabolite traits were significantly correlated with HD. After combining the significant results, three significant GM-metabolites-HD lines have been identified. In the -Stearoyl sphingomyelin (d18:1/18:0)-HD line, the Stearoyl sphingomyelin (d18:1/18:0) levels showed a mediation proportion of 14.5%, while in the -lysine-HD line, the lysine levels had a mediation proportion of 12.9%. Additionally, in the -X-21733-HD line, the X-21733 levels played a mediation proportion of 23.5%.
Our MR study indicates a protective effect of on HD risk that is partially mediated through serum levels of stearoyl sphingomyelin (d18:1/18:0) and lysine, and a risk effect of on HD that is partially mediated by X-21733 levels. These findings could serve as novel biomarkers and therapeutic targets for HD.
观察到肠道微生物群（GM）与先天性巨结肠病（HD）的发病率相关。然而，GM在HD中的作用及机制仍不清楚。为了研究GM与HD之间的关系以及代谢产物作为中介的作用，进行了一项双向两步孟德尔随机化（MR）研究。
该研究从汇总水平的全基因组关联研究（GWAS）中选择工具变量（IVs）。MiBioGen联盟提供了GM的GWAS数据，而代谢产物和HD的GWAS数据则从GWAS Catalog联盟获得。进行两样本MR分析以估计与GM和HD相关的IVs之间的双向相关性。然后，使用乘积法选择与1400种代谢产物性状相关的遗传变异进行进一步的中介分析。
本研究发现7种属细菌与HD的发病率存在显著因果关系，反之则不然。27种代谢产物性状与HD显著相关。综合显著结果后，确定了三条显著的GM-代谢产物-HD线。在硬脂酰鞘磷脂（d18:1/18:0）-HD线中，硬脂酰鞘磷脂（d18:1/18:0）水平的中介比例为14.5%，而在赖氨酸-HD线中，赖氨酸水平的中介比例为12.9%。此外，在X-21733-HD线中，X-21733水平的中介比例为23.5%。
我们的MR研究表明，[此处原文可能有缺失内容]对HD风险具有保护作用，部分通过硬脂酰鞘磷脂（d18:1/18:0）和赖氨酸的血清水平介导，而[此处原文可能有缺失内容]对HD具有风险作用，部分由X-21733水平介导。这些发现可为HD提供新的生物标志物和治疗靶点。
