综合分析在糖代谢异常的参与者中发现与慢性肾脏疾病相关的新蛋白。

IF 7.4 3区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Ning Li , Jingyang Liu , Guangheng Wu , Jie Zhang , Long Liu , Manqi Zheng , Haibin Li , Changwei Li , Yalu Wen , Jianguang Ji , Yang Yu , Kun Zhao , Deqiang Zheng
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引用次数: 0

摘要

目的:慢性肾脏疾病(CKD)在糖代谢异常的个体中非常普遍。然而,在这一高危人群中,专门研究ckd相关蛋白的研究有限。为了弥补这一空白,我们的研究旨在识别与糖代谢异常的参与者中CKD相关的蛋白质,为早期发现和靶向治疗策略提供潜在的信息。方法:我们首先采用正交偏最小二乘法判别分析(OPLS-DA)来选择重要的蛋白质,并利用来自UK Biobank的蛋白质组学数据,进一步使用Cox比例风险模型来识别糖代谢异常参与者中与CKD相关的候选蛋白质。随后,我们采用两阶段最小二乘法,使用来自UK Biobank的个体水平基因组数据和UKB-PPP的pQTL汇总统计数据进行单样本孟德尔随机化(MR)。对于双样本MR,我们使用来自deCODE的pQTL数据和来自UK Biobank的CKD GWAS汇总统计数据,采用Wald比或逆方差加权(IVW)方法。观察性分析和至少一种MR方法支持的蛋白质使用公开可用的数据库进一步评估以确定其新颖性。最后,对于所有方法一致鉴定的蛋白质,我们评估了组织特异性、基因表达,并进行了敏感性分析,以加强我们发现的稳健性。结果:通过综合观察和MR分析,我们共鉴定出45种与糖代谢异常参与者的CKD显著相关的蛋白,其中11种为新发现:CD300C、CD300LG、CDNF、CDSN、CHRDL1、ENPP6、LEFTY2、MOG、RSPO3、TNFRSF13B和MYLPF。值得注意的是,ENPP6在所有分析方法中都有一致的证据。观察性分析表明,风险比(HR)为0.75 (95% CI: 0.63-0.89),而单样本MR显示的优势比(OR)为0.32 (95% CI: 0.14-0.73),双样本MR产生的OR为0.60 (95% CI: 0.37-0.98),支持ENPP6在CKD发展中的保护作用。此外,ENPP6表现出肾脏特异性表达,特别是在小管周围和近端小管细胞中。这些发现通过综合敏感性分析得到了有力的验证。结论:总之,我们在糖代谢异常的个体中发现了11种与CKD相关的新蛋白,其中ENPP6因其在多种分析方法中一致的保护性关联而成为特别引人注目的候选蛋白。这些发现为CKD病理生理学提供了有希望的见解,并突出了ENPP6作为潜在的生物标志物或治疗靶点。需要进一步的研究来阐明这些新蛋白在CKD发生和进展中的机制作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Integrative analysis identifies novel proteins associated with chronic kidney disease in participants with abnormal glucose metabolism

Integrative analysis identifies novel proteins associated with chronic kidney disease in participants with abnormal glucose metabolism

Aim

Chronic kidney disease (CKD) is highly prevalent among individuals with abnormal glucose metabolism. However, limited research has specifically investigated CKD-associated proteins within this high-risk population. To address this gap, our study aimed to identify proteins associated with CKD in participants with abnormal glucose metabolism, potentially informing early detection and targeted therapeutic strategies.

Methods

We first employed orthogonal partial least squares discriminant analysis (OPLS-DA) to select important proteins and further used Cox proportional hazards models using proteomic data from the UK Biobank to identify candidate proteins associated with CKD in participants with abnormal glucose metabolism. Subsequently, we performed one-sample Mendelian randomization (MR) using individual-level genomic data from the UK Biobank and pQTL summary statistics from the UKB-PPP, applying a two-stage least squares approach. For two-sample MR, we utilized pQTL data from deCODE and CKD GWAS summary statistics derived from the UK Biobank, applying either the Wald ratio or inverse variance weighted (IVW) method. Proteins supported by both observational analyses and at least one MR approach were further evaluated using publicly available databases to determine their novelty. Finally, for proteins consistently identified across all approaches, we assessed tissue specificity, gene expression, and conducted sensitivity analyses to strengthen the robustness of our findings.

Results

Through integrated observational and MR analyses, we identified a total of 45 proteins significantly associated with CKD in participants with abnormal glucose metabolism, among which 11 represent novel discoveries: CD300C, CD300LG, CDNF, CDSN, CHRDL1, ENPP6, LEFTY2, MOG, RSPO3, TNFRSF13B, and MYLPF. Notably, ENPP6 emerged with consistent evidence across all analytic approaches. Observational analyses demonstrated a hazard ratio (HR) of 0.75 (95% CI: 0.63–0.89), while one-sample MR revealed an odds ratio (OR) of 0.32 (95% CI: 0.14–0.73), and two-sample MR produced an OR of 0.60 (95% CI: 0.37–0.98), supporting a protective role of ENPP6 in CKD development. Furthermore, ENPP6 displayed kidney-specific expression, particularly within peritubular and proximal tubular cells. These findings were robustly validated through comprehensive sensitivity analyses.

Conclusion

In conclusion, we identified 11 novel proteins associated with CKD in individuals with abnormal glucose metabolism, with ENPP6 emerging as a particularly compelling candidate due to its consistent protective association across multiple analytical approaches. These findings offer promising insights into CKD pathophysiology and highlight ENPP6 as a potential biomarker or therapeutic target. Further research is warranted to elucidate the mechanistic roles of these novel proteins in CKD development and progression.
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来源期刊
Diabetes research and clinical practice
Diabetes research and clinical practice 医学-内分泌学与代谢
CiteScore
10.30
自引率
3.90%
发文量
862
审稿时长
32 days
期刊介绍: Diabetes Research and Clinical Practice is an international journal for health-care providers and clinically oriented researchers that publishes high-quality original research articles and expert reviews in diabetes and related areas. The role of the journal is to provide a venue for dissemination of knowledge and discussion of topics related to diabetes clinical research and patient care. Topics of focus include translational science, genetics, immunology, nutrition, psychosocial research, epidemiology, prevention, socio-economic research, complications, new treatments, technologies and therapy.
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