Causal association of monocytes with chronic kidney disease and the mediation role of frailty: A study integrating large-scale two-sample Mendelian randomization and single-cell analysis

孟德尔随机化 全基因组关联研究 调解 医学 遗传关联 转录组 肾脏疾病 疾病 生物信息学 单核苷酸多态性 内科学 生物 遗传学 遗传变异 基因表达 法学 基因型 基因 政治学
作者
Cong Zhang,Jielian Deng,Kangjie Li,Guichuan Lai,Hui Liu,Yuan Zhang,Haijiao Zeng,Wenlong Li,Xiaoni Zhong,Yao Wang,Biao Xie
出处
期刊:Archives of Gerontology and Geriatrics [Elsevier BV]
卷期号:123: 105435-105435 被引量:2
标识
DOI:10.1016/j.archger.2024.105435
摘要

Recent research reported that frailty was prevalent among adults with chronic kidney disease (CKD) in clinical trials, and monocytes illustrated a similar difference in these two diseases compared to the normal. However, the scientific evidence for a causal relationship between these two diseases was lacking, with further exploration into whether monocytes co-regulate them. We aimed to integrate large-scale Mendelian randomization (MR) and single-cell transcriptome analysis to determine whether there was a causal relationship between frailty and CKD (Bidirectional two-sample Mendelian determined the causal direction), whether monocytes impacted them, and whether the two diseases shared genetic variation sites. Based on 441 Genome-wide association study datasets, this study utilized five MR methods, multiple sensitivity analysis, and corresponding single-cell transcriptome datasets as proof. The association between frailty and CKD was significantly causal, and frailty increased the risk of CKD in patients (OR (95%CI): 3.5597 (1.8369 - 6.8982), p = 0.000168909). The exposure monocyte can increase the risk of frailty and CKD in patients, especially with high expression of HLA genes in these cells. The existing two-sample MR results cannot reject the hypothesis that monocytes increase the risk of CKD by inducing frailty. rs9275271' 1mb genetic location above and below had been proven to be an effective genetic space for both frailty and CKD. We conducted the largest MR to date on frailty, monocyte, and CKD, and found a significant causal association between frailty and CKD, with the single-cell analysis confirmed. The exposure monocytes increased the risk of frailty and CKD, particularly with high expression of HLA genes in these cells. We identified a potential common genetic variant space, rs9275271, associated with frailty and CKD, providing insights into the genetic basis of these conditions.
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