一项新的多血统蛋白质组全基因组孟德尔随机化研究表明，细胞外蛋白、管状细胞和成纤维细胞参与了估算肾小球滤过率的调节。
A novel multi-ancestry proteome-wide Mendelian randomization study implicates extracellular proteins, tubular cells, and fibroblasts in estimated glomerular filtration rate regulation.
机构信息
Population Health Research Institute, Hamilton, Ontario, Canada; Division of Nephrology, St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Population Health Research Institute, Hamilton, Ontario, Canada.
出版信息
Kidney Int. 2023 Dec;104(6):1170-1184. doi: 10.1016/j.kint.2023.08.025. Epub 2023 Sep 27.
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.
肾小球滤过率（eGFR）会影响血浆生物标志物的浓度，从而干扰 eGFR 与反向因果关系的生物标志物关联研究。为了确定与 eGFR 因果相关的生物标志物，我们进行了一项蛋白质组范围的孟德尔随机化研究。在 Prospective Urban and Rural Epidemiological（PURE）研究的一个多血统样本中，对位于生物标志物编码基因附近的遗传变异与 12066 名参与者的血浆 1161 种生物标志物浓度进行关联测试。使用两样本孟德尔随机化，个体变异对生物标志物浓度的影响与已发表的全基因组关联研究（GWAS）中对 eGFR 和肾脏特征的影响相关联。22 种生物标志物的遗传改变浓度与 eGFR 相关，超过 Bonferroni 校正的显著性阈值。有 5 种生物标志物先前通过 GWAS 确定（UMOD、FGF5、LGALS7、NINJ1、COL18A1）。9 种生物标志物位于 GWAS 主要变异体的 1Mb 范围内，但候选基因尚未确定为 GWAS 信号（INHBC、TNFRSF11A、TCN2、PXN1、PRTN3、PSMD9、TFPI、ITGB6、CA3）。单细胞转录组数据表明，22 种生物标志物在肾小管、集合管、成纤维细胞和免疫细胞中表达。通路分析表明，鉴定出的生物标志物在外肾实质中显著富集。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，它们似乎以有益或不利的方式因果影响 eGFR。本研究为 eGFR 的新治疗靶点提供了依据，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。
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