背景:最近的研究报告说,在临床试验中,患有慢性肾脏病(CKD)的成年人普遍存在虚弱,和单核细胞在这两种疾病中显示出与正常疾病相似的差异。然而,缺乏这两种疾病之间因果关系的科学证据,进一步探索单核细胞是否共同调节它们。
方法:我们旨在整合大规模孟德尔随机化(MR)和单细胞转录组分析,以确定虚弱与CKD之间是否存在因果关系(双向双样本孟德尔确定因果方向),单核细胞是否影响了它们,以及这两种疾病是否共有遗传变异位点。基于441个全基因组关联研究数据集,这项研究使用了五种MR方法,多敏感性分析,和相应的单细胞转录组数据集作为证据。
结果:虚弱与CKD之间存在显著的因果关系,虚弱会增加患者CKD的风险(OR(95CI):3.5597(1.8369-6.8982),p=0.000168909)。单核细胞暴露可增加患者衰弱和CKD的风险,特别是在这些细胞中HLA基因的高表达。现有的双样本MR结果不能拒绝单核细胞通过诱导虚弱增加CKD风险的假设。rs9275271\'1mb以上和以下的遗传位置已被证明是脆弱和CKD的有效遗传空间。
结论:我们进行了迄今为止最大的关于虚弱的MR,单核细胞,CKD,并发现虚弱与CKD之间存在显著的因果关系,单细胞分析证实。单核细胞暴露增加了虚弱和CKD的风险,特别是在这些细胞中HLA基因的高表达。我们发现了一个潜在的共同遗传变异空间,rs9275271,与虚弱和CKD相关,提供对这些条件的遗传基础的见解。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.