Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China; and Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China.
J Am Soc Nephrol. 2024 Aug 1;35(8):1045-1057. doi: 10.1681/ASN.0000000000000379. Epub 2024 Apr 30.
A multiancestry proteome-wide Mendelian randomization analysis was conducted for IgA nephropathy. The findings from the study would help prioritize new drug targets and drug-repurposing opportunities.
The therapeutic options for IgA nephropathy are rapidly evolving, but early diagnosis and targeted treatment remain challenging. We aimed to identify circulating plasma proteins associated with IgA nephropathy by proteome-wide Mendelian randomization studies across multiple ancestry populations.
In this study, we applied Mendelian randomization and colocalization analyses to estimate the putative causal effects of 2615 proteins on IgA nephropathy in Europeans and 235 proteins in East Asians. Following two-stage network Mendelian randomization, multitrait colocalization analysis and protein-altering variant annotation were performed to strengthen the reliability of the results. A protein–protein interaction network was constructed to investigate the interactions between the identified proteins and the targets of existing medications.
Putative causal effects of 184 and 13 protein–disease pairs in European and East Asian ancestries were identified, respectively. Two protein–disease pairs showed shared causal effects across them (CFHR1 and FCRL2). Supported by the evidence from colocalization analysis, potential therapeutic targets were prioritized and four drug-repurposing opportunities were suggested. The protein–protein interaction network further provided strong evidence for existing medications and pathways that are known to be therapeutically important.
Our study identified a number of circulating proteins associated with IgA nephropathy and prioritized several potential drug targets that require further investigation.
对 IgA 肾病进行了多祖先蛋白质组全基因组 Mendelian 随机分析。该研究的结果将有助于确定新的药物靶点和药物再利用机会。
IgA 肾病的治疗选择正在迅速发展，但早期诊断和靶向治疗仍然具有挑战性。我们旨在通过对多个祖先人群的蛋白质组全基因组 Mendelian 随机研究来鉴定与 IgA 肾病相关的循环血浆蛋白。
在这项研究中，我们应用 Mendelian 随机和共定位分析来估计 2615 种蛋白质在欧洲人和 235 种蛋白质在东亚人中对 IgA 肾病的潜在因果作用。在两阶段网络 Mendelian 随机之后，进行多性状共定位分析和蛋白质改变变体注释，以加强结果的可靠性。构建蛋白质-蛋白质相互作用网络，以研究鉴定出的蛋白质与现有药物的靶标之间的相互作用。
在欧洲和东亚血统中分别鉴定出 184 种和 13 种蛋白质-疾病对的潜在因果作用。两个蛋白质-疾病对在两者之间显示出共同的因果作用（CFHR1 和 FCRL2）。共定位分析的证据支持下，优先考虑了潜在的治疗靶点，并提出了四种药物再利用的机会。蛋白质-蛋白质相互作用网络进一步为现有药物和已知具有治疗重要性的途径提供了有力证据。
我们的研究确定了一些与 IgA 肾病相关的循环蛋白，并确定了几个需要进一步研究的潜在药物靶点。
