估计的肾小球滤过率(eGFR)影响血浆生物标志物的浓度混淆了eGFR与反向因果关系的关联研究。为了确定与eGFR有因果关系的生物标志物,我们进行了一项全蛋白质组孟德尔随机化研究.在前瞻性城市和农村流行病学(PURE)研究的12,066名参与者的多血统样本中,测试了附近生物标志物编码基因的遗传变异与1,161种生物标志物的血浆浓度的关联。使用双样本孟德尔随机化,根据已发表的全基因组关联研究(GWAS),个体变异体对生物标志物浓度的影响与其对eGFR和肾脏特征的影响相关.22种生物标志物的遗传改变浓度与高于Bonferroni校正的显著性阈值的eGFR相关。GWAS先前鉴定了五种生物标志物(UMOD,FGF5、LGALS7、NINJ1、COL18A1)。九种生物标志物在前导GWAS变异体的1Mb内,但生物标志物的基因未被鉴定为GWAS信号的候选基因(INHBC,TNFRSF11A,TCN2,PXN1,PRTN3,PSMD9,TFPI,ITGB6、CA3)。单细胞转录组数据表明22个生物标志物在肾小管中表达,收集管道,成纤维细胞,和免疫细胞。路径分析显示细胞外肾实质中鉴定的生物标志物显著富集。因此,通过蛋白质组范围的孟德尔随机化使用生物标志物浓度的遗传调节剂,我们确定了22种生物标志物,这些生物标志物似乎以有益或不利的方式对eGFR有因果关系.当前的研究为eGFR的新型治疗靶标提供了理论基础,并强调了由管状细胞和成纤维细胞产生的细胞外蛋白对影响eGFR的作用。
Estimated glomerular filtration rate (eGFR) impacts the concentration of plasma biomarkers confounding biomarker association studies of eGFR with reverse causation. To identify biomarkers causally associated with eGFR, we performed a proteome-wide Mendelian randomization
study. Genetic variants nearby biomarker coding genes were tested for association with plasma concentration of 1,161 biomarkers in a multi-ancestry sample of 12,066 participants from the Prospective Urban and Rural Epidemiological (PURE)
study. Using two-sample Mendelian randomization, individual variants\' effects on biomarker concentration were correlated with their effects on eGFR and kidney traits from published genome-wide association studies (GWAS). Genetically altered concentrations of 22 biomarkers were associated with eGFR above a Bonferroni-corrected significance threshold. Five biomarkers were previously identified by GWAS (UMOD, FGF5, LGALS7, NINJ1, COL18A1). Nine biomarkers were within 1 Mb of the lead GWAS variant but the gene for the biomarker was unidentified as the candidate for the GWAS signal (INHBC, TNFRSF11A, TCN2, PXN1, PRTN3, PSMD9, TFPI, ITGB6, CA3). Single-cell transcriptomic data indicated the 22 biomarkers are expressed in kidney tubules, collecting duct, fibroblasts, and immune cells. Pathway analysis showed significant enrichment of identified biomarkers in the extracellular kidney parenchyma. Thus, using genetic regulators of biomarker concentration via proteome-wide Mendelian randomization, we identified 22 biomarkers that appear to causally impact eGFR in either a beneficial or adverse manner. The current
study provides rationale for novel therapeutic targets for eGFR and emphasized a role for extracellular proteins produced by tubular cells and fibroblasts for impacting eGFR.