Valo Erkka, Richmond Anne, Mutter Stefan, Dahlström Emma H, Campbell Archie, Porteous David J, Wilson James F, Groop Per-Henrik, Hayward Caroline, Sandholm Niina
Folkhälsan Research Center, Helsinki, Finland.
Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Nat Commun. 2025 Jan 2;16(1):325. doi: 10.1038/s41467-024-55182-1.
Dissecting the genetic mechanisms underlying urinary metabolite concentrations can provide molecular insights into kidney function and open possibilities for causal assessment of urinary metabolites with risk factors and disease outcomes. Proton nuclear magnetic resonance metabolomics provides a high-throughput means for urinary metabolite profiling, as widely applied for blood biomarker studies. Here we report a genome-wide association study meta-analysed for 3 European cohorts comprising 8,011 individuals, covering both people with type 1 diabetes and general population settings. We identify 54 associations (p < 9.3 × 10) for 19 of 54 studied metabolite concentrations. Out of these, 33 were not reported previously for relevant urinary or blood metabolite traits. Subsequent two-sample Mendelian randomization analysis suggests that estimated glomerular filtration rate causally affects 13 urinary metabolite concentrations whereas urinary ethanolamine, an initial precursor for phosphatidylcholine and phosphatidylethanolamine, was associated with higher eGFR lending support for a potential protective role. Our study provides a catalogue of genetic associations for 53 metabolites, enabling further investigation on how urinary metabolites are linked to human health.
剖析尿液代谢物浓度背后的遗传机制，可以为肾功能提供分子层面的见解，并为评估尿液代谢物与风险因素及疾病结局之间的因果关系开辟可能性。质子核磁共振代谢组学为尿液代谢物谱分析提供了一种高通量方法，广泛应用于血液生物标志物研究。在此，我们报告了一项针对3个欧洲队列的全基因组关联研究的荟萃分析，该队列包括8011名个体，涵盖1型糖尿病患者和普通人群。我们确定了54种研究代谢物浓度中的19种存在54个关联（p < 9.3×10）。其中，33个关联此前未在相关尿液或血液代谢物特征中报道。随后的两样本孟德尔随机化分析表明，估计肾小球滤过率因果性地影响13种尿液代谢物浓度，而尿液乙醇胺（磷脂酰胆碱和磷脂酰乙醇胺的初始前体）与较高的估算肾小球滤过率相关，这支持了其潜在的保护作用。我们的研究提供了53种代谢物的遗传关联目录，有助于进一步研究尿液代谢物与人类健康的关联。
