Zhao Yaping, Liu Zehui, Feng Shiyu, Yang Rong, Ran Zhenqin, Zhu Rong, Ma Lijuan, Wang Zizhou, Chen Lixin, Han Rui
Department of International Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, 650000, China.
BMC Med Genomics. 2024 Dec 18;17(1):288. doi: 10.1186/s12920-024-02061-9.
The role of the vitamin D receptor single nucleotide polymorphism FOKI (VDR-FOKI) (rs2228570) in genetic susceptibility to type 2 diabetic kidney disease (T2DKD) remains uncertain. This study investigated the relationship between VDR-FOKI and T2DKD within the Chinese Plateau Han population and analyzed the underlying mechanisms.
A total of 316 subjects were enrolled, including 44 healthy adults, 114 individuals with type 2 diabetes mellitus (T2DM), and 158 patients with T2DKD. According to the 2023 American Diabetes Association Diabetes Guidelines, patients with T2DKD were categorized into low-medium-risk and high-risk groups based on estimates of glomerular filtration rate and urinary albumin-to-creatinine ratio. The VDR-FokI genotypes of all participants were identified using the Taqman probe and classified as homozygous mutant genotypes (C/C or FF), heterozygous mutant genotypes (C/T or Ff), and homozygous wild genotypes (T/T or ff). Plasma levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase activity (SOD) were assessed in T2DKD patients with FF and ff genotypes. Additionally, the levels of plasma VDR, GPX4, and P53 were determined using ELISA, while the relative expressions of VDR mRNA, GPX4 mRNA, and TP53 mRNA in whole blood were measured by RT-qPCR.
The T2DM patients with the ff genotype exhibited a 2.93-fold increased likelihood of developing T2DKD compared to those with the FF genotype (OR = 2.93; 95% CI: 1.142-7.513). Additionally, they were 2.01 times more likely to develop T2DKD than individuals with the FF and Ff genotypes (OR = 2.01; 95% CI: 1.008-4.006). However, no significant differences in VDR-FokI genotype distribution were observed between the healthy control group and the T2DM group, as well as between the low-medium-risk and high-risk groups of T2DKD. Furthermore, T2DKD patients with the ff genotype had significantly higher plasma levels of MDA compared to those with the FF genotype. In contrast, plasma GSH and SOD content was significantly lower in the ff genotype patients (P < 0.05). Additionally, the GPX4 concentration in ff genotype patients was significantly lower than in FF genotype patients [14.88 (11.32,22.39) vs. 12.76 (8.55,13.75), P = 0.037]. Nevertheless, no statistically significant difference was observed in the expression of VDRmRNA, GPX4mRNA, TP53mRNA, plasma VDR, and plasma P53.
The ff genotype of VDR-FokI is a risk factor for T2DKD, and the potential mechanism may be related to ferroptosis. However, It is not associated with T2DM or the progression of T2DKD.
维生素D受体单核苷酸多态性FOKI（VDR-FOKI）（rs2228570）在2型糖尿病肾病（T2DKD）遗传易感性中的作用尚不确定。本研究调查了中国高原汉族人群中VDR-FOKI与T2DKD的关系，并分析了其潜在机制。
共纳入316名受试者，包括44名健康成年人、114名2型糖尿病（T2DM）患者和158名T2DKD患者。根据2023年美国糖尿病协会糖尿病指南，T2DKD患者根据肾小球滤过率和尿白蛋白与肌酐比值的估计分为低中风险组和高风险组。使用Taqman探针鉴定所有参与者的VDR-FokI基因型，并分为纯合突变基因型（C/C或FF）、杂合突变基因型（C/T或Ff）和纯合野生基因型（T/T或ff）。评估了FF和ff基因型的T2DKD患者血浆丙二醛（MDA）、谷胱甘肽（GSH）水平和超氧化物歧化酶活性（SOD）。此外，使用酶联免疫吸附测定法测定血浆VDR、GPX4和P53水平，同时通过逆转录定量聚合酶链反应测量全血中VDR mRNA、GPX4 mRNA和TP53 mRNA的相对表达。
与FF基因型的T2DM患者相比，ff基因型的T2DM患者发生T2DKD的可能性增加了2.93倍（OR = 2.93；95%CI：1.142 - 7.513）。此外，与FF和Ff基因型的个体相比，他们发生T2DKD的可能性高2.01倍（OR = 2.01；95%CI：1.008 - 4.006）。然而，在健康对照组与T2DM组之间以及T2DKD的低中风险组与高风险组之间，未观察到VDR-FokI基因型分布的显著差异。此外，与FF基因型的T2DKD患者相比，ff基因型的患者血浆MDA水平显著更高。相比之下，ff基因型患者的血浆GSH和SOD含量显著更低（P < 0.05）。此外，ff基因型患者的GPX4浓度显著低于FF基因型患者[14.88（11.32，22.39）对12.76（8.55，13.75），P = 0.037]。然而，在VDRmRNA、GPX4mRNA、TP53mRNA的表达、血浆VDR和血浆P53方面未观察到统计学上的显著差异。
VDR-FokI的ff基因型是T2DKD的危险因素，其潜在机制可能与铁死亡有关。然而，它与T2DM或T2DKD的进展无关。
