Zhao Cong, Zhang Mingzhu, Zhao Leying, Sun Weiwei
Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China.
Int Immunopharmacol. 2024 May 10;132:112051. doi: 10.1016/j.intimp.2024.112051. Epub 2024 Apr 9.
IgA Nephropathy (IgAN), the primary form of glomerulonephritis, presents significant clinical challenges due to its obscure pathogenesis and lack of targeted treatments. We conducted a proteome-wide Mendelian randomization (MR) study to identify therapeutic targets for IgAN.
Utilizing a plasma proteome dataset comprising 4907 blood plasma proteins as the exposure variable, and renal biopsy-confirmed IgAN cases as the outcome, this study employed MR to pinpoint proteins potentially pathogenic to IgAN. The robustness of our findings was affirmed through external dataset validation, reverse causation testing, and Bayesian colocalization analysis. Additionally, we conducted phenotypic scanning and analyzed downstream metabolites to investigate candidate proteins's biological function.
In our study, a significant association was identified between an increase in neuraminidase 1 (NEU1) expression and the risk of IgAN. Specifically, a one standard deviation increase in NEU1 expression was associated with an odds ratio of 11.80 for the development of IgAN (95% confidence interval: 4.03-34.54). This association was substantiated across various statistical models and external validations. Colocalization analysis indicated a shared causal variant between NEU1 expression and IgAN. Furthermore, an increased influenza risk associated with NEU1 was observed, supporting the therapeutic potential of NEU1 inhibitors for IgAN. However, our study found no significant role for neuraminic acid-related metabolites in IgAN's development, suggesting an independent pathway for NEU1's influence.
This study identifies NEU1 as a promising therapeutic target for IgAN, backed by robust genetic evidence. Future research should explore NEU1's therapeutic potential in diverse populations and clinical scenarios, further establishing its role in IgAN.
IgA肾病（IgAN）是肾小球肾炎的主要形式，因其发病机制不明且缺乏靶向治疗方法，带来了重大的临床挑战。我们开展了一项全蛋白质组孟德尔随机化（MR）研究，以确定IgA肾病的治疗靶点。
本研究将包含4907种血浆蛋白的血浆蛋白质组数据集作为暴露变量，将经肾活检确诊的IgA肾病病例作为结局，采用孟德尔随机化方法来确定可能对IgA肾病具有致病性的蛋白质。我们通过外部数据集验证、反向因果关系检验和贝叶斯共定位分析，证实了研究结果的稳健性。此外，我们进行了表型扫描并分析了下游代谢产物，以研究候选蛋白质的生物学功能。
在我们的研究中，发现神经氨酸酶1（NEU1）表达增加与IgA肾病风险之间存在显著关联。具体而言，NEU1表达增加一个标准差与IgA肾病发生的比值比为11.80（95%置信区间：4.03 - 34.54）。这种关联在各种统计模型和外部验证中均得到证实。共定位分析表明NEU1表达与IgA肾病之间存在共同的因果变异。此外，观察到与NEU1相关的流感风险增加，这支持了NEU1抑制剂对IgA肾病的治疗潜力。然而，我们的研究发现神经氨酸相关代谢产物在IgA肾病发展中没有显著作用，这表明NEU1的影响存在独立途径。
本研究确定NEU1是IgA肾病一个有前景的治疗靶点，有强有力的遗传学证据支持。未来的研究应探索NEU1在不同人群和临床场景中的治疗潜力，进一步确立其在IgA肾病中的作用。
