Exploring the causal role of plasma metabolites in pediatric asthma: a Mendelian randomization study

Pediatric asthma (PA) is the prevailing chronic respiratory ailment in childhood. A better understanding of plasma metabolites is the goal for elucidating the molecular pathological mechanisms of PA and investigating novel therapeutic approaches. Data for PA from Genome-Wide Association Studies (GWAS) was derived from the IEU-OpenGWAS project, featuring a collection of 1400 plasma metabolites. The inverse-variance weighting (IVW) method assessed causal relationships between plasma metabolites and PA, with measures taken to mitigate horizontal pleiotropy and heterogeneity. To select instrumental variables, a genome-wide significance threshold (<i>p</i> &lt; 5 × 10–8) was applied to ensure robust genetic instruments. A Bonferroni correction controlled for multiple testing, with statistical significance defined as <i>p</i> &lt; 3.57 × 10–5) (0.05/1400). To further substantiate outcomes, a reverse Mendelian randomization analysis was conducted. Research found 91 plasma metabolites linked to PA, ten of which showed significant associations. Of note, 20:4n6 levels (IVW: OR (95% CI) = 1.062 (1.030 to 1.094) and G/C16 (IVW: OR (95% CI) = 0.886 (0.832 to 0.943) were identified as pivotal exposure factors for PA. This study highlights 10 plasma metabolites that may have significant associations with PA incidence, with 20:4n6 levels and G/C16 potentially serving as valuable biomarkers for the early detection and management of PA.

小儿哮喘（Pediatric asthma, PA）是儿童群体中最为常见的慢性呼吸道疾病。深入解析血浆代谢物，旨在阐明小儿哮喘的分子病理机制并探索全新治疗策略。本研究的小儿哮喘全基因组关联研究（Genome-Wide Association Studies, GWAS）数据源自IEU-OpenGWAS项目，该项目收录了1400种血浆代谢物。研究采用逆方差加权（inverse-variance weighting, IVW）法评估血浆代谢物与小儿哮喘之间的因果关联，并采取措施以减轻水平多效性与异质性偏倚。为筛选工具变量（instrumental variables），本研究采用全基因组显著性阈值（p＜5×10^-8）以确保遗传工具变量的有效性。采用邦费罗尼校正（Bonferroni correction）对多重检验进行控制，将统计学显著性阈值设定为p＜3.57×10^-5（即0.05/1400）。为进一步验证研究结果，本研究还开展了反向孟德尔随机化（Mendelian randomization）分析。研究共筛选出91种与小儿哮喘存在关联的血浆代谢物，其中10种具有显著统计学关联。值得注意的是，20:4n6水平（IVW：比值比（95% CI）=1.062（1.030~1.094））与G/C16（IVW：比值比（95% CI）=0.886（0.832~0.943））被确定为小儿哮喘的关键暴露因素。本研究明确了10种与小儿哮喘发病存在显著关联的血浆代谢物，其中20:4n6水平与G/C16有望成为小儿哮喘早期检测与临床管理的潜在生物标志物。