Wang Kunying, Ye Shuo, Feng Hongliang, Liang Yannis Yan, Guo Sheng, Zheng Rui, Zhou Yujing, Jia Guangbo, Qi Lu, Zhao Guoan, Zhang Jihui, Ai Sizhi
Department of Cardiology, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China; Department of Endocrinology, Nan'an Hospital, Quanzhou, Fujian, China.
Department of Cardiology, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China.
Mayo Clin Proc. 2025 Jul;100(7):1127-1141. doi: 10.1016/j.mayocp.2024.12.020. Epub 2025 Mar 31.
To investigate the causal association between insomnia and chronic kidney disease (CKD) and to explore the underlying protein pathways.
In primary analyses, multivariate regression and 1-sample mendelian randomization (1SMR) analyses were performed to estimate the associations between insomnia and CKD in the UK Biobank cohort. The study was conducted from March 13, 2006, to November 12, 2021. Thereafter, a 2-sample MR (2SMR) analysis was used to validate the findings from primary analyses. Finally, proteome-wide MR analysis was conducted to pinpoint CKD-associated blood proteins, supplemented by the colocalization analysis. In addition, the potential mediation effects of blood proteins on the pathway of insomnia giving rise to CKD were explored through a 2-step MR design.
Across the multivariate regression, 1SMR, and their sensitivity analyses, we found consistent evidence suggesting that more frequent insomnia was associated with a higher risk of CKD (multivariate regression: hazard ratio, 1.21 [95% CI, 1.17 to 1.25; P<.001]; 1SMR: odds ratio, 1.35 [95% CI, 1.02 to 1.79; P=.04]). Consistent evidence was obtained by using 2SMR (odds ratio,1.06; 95% CI, 1.02 to 1.11; P=.009). Genetically predicted 124 circulating proteins were associated with CKD in proteome-wide MR analysis. ENPP5 is a promising novel target that mediates the association between insomnia and CKD.
More frequent insomnia is causally associated with increased risk of CKD, and ENPP5 as a potential blood protein mediates the association between insomnia and CKD. These findings indicate that addressing insomnia could serve as a viable and valid intervention to mitigate CKD risk.
探讨失眠与慢性肾脏病（CKD）之间的因果关系，并探索潜在的蛋白质通路。
在初步分析中，进行了多变量回归分析和单样本孟德尔随机化（1SMR）分析，以估计英国生物银行队列中失眠与CKD之间的关联。该研究于2006年3月13日至2021年11月12日进行。此后，采用两样本孟德尔随机化（2SMR）分析来验证初步分析的结果。最后，进行全蛋白质组孟德尔随机化分析以确定与CKD相关的血液蛋白质，并辅以共定位分析。此外，通过两步孟德尔随机化设计探索血液蛋白质在失眠引发CKD途径中的潜在中介作用。
在多变量回归、1SMR及其敏感性分析中，我们发现一致的证据表明，更频繁的失眠与更高的CKD风险相关（多变量回归：风险比，1.21[95%CI，1.17至1.25；P<0.001]；1SMR：优势比，1.35[95%CI，1.02至1.79；P=0.04]）。使用2SMR也获得了一致的证据（优势比，1.06；95%CI，1.02至1.11；P=0.009）。在全蛋白质组孟德尔随机化分析中，124种遗传预测的循环蛋白与CKD相关。ENPP5是介导失眠与CKD之间关联的一个有前景的新靶点。
更频繁的失眠与CKD风险增加存在因果关系，ENPP5作为一种潜在的血液蛋白质介导了失眠与CKD之间的关联。这些发现表明，解决失眠问题可能是减轻CKD风险的一种可行且有效的干预措施。
