Chen Zijin, Xu Lin-Lin, Du Wen, Ouyang Yan, Gu Xiangchen, Fang Zhengying, Yu Xialian, Li Junru, Xie Lin, Jin Yuanmeng, Ma Jun, Wang Zhaohui, Pan Xiaoxia, Zhang Wen, Ren Hong, Wang Weiming, Chen Xiaonong, Zhou Xu-Jie, Zhang Hong, Chen Nan, Xie Jingyuan
Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.
Clin Kidney J. 2024 Jul 15;17(8):sfae209. doi: 10.1093/ckj/sfae209. eCollection 2024 Aug.
This study investigates the link between genetic variants associated with kidney function and immunoglobulin A (IgA) nephropathy (IgAN) progression.
We recruited 961 biopsy-proven IgAN patients and 651 non-IgAN end-stage renal disease (ESRD) patients from Ruijin Hospital. Clinical and renal pathological data were collected. The primary outcome was the time to ESRD. A healthy population was defined as estimated glomerular filtration rate >60 mL/min/1.73 m without albuminuria or hematuria. Fifteen single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of kidney function and genotyped by the SNaPshot. Immunohistochemistry in renal tissue and ELISA in urine samples were performed to explore the potential functions of genetic variations.
The rs77924615-G was independently associated with an increased risk for ESRD in IgAN patients after adjustments for clinical and pathologic indices, and treatment (adjusted hazard ratio 2.10; 95% confidence interval 1.14-3.88). No significant differences in ESRD-free survival time were found among different genotypes in non-IgAN ESRD patients (log-rank, = .480). Moreover, rs77924615 exhibited allele-specific enhancer activity by dual-luciferase reporter assay. Accordingly, the urinary uromodulin-creatinine ratio (uUCR) was significantly higher in healthy individuals with rs77924615 AG or GG than in individuals with AA. Furthermore, uromodulin expression in tubular epithelial cells was higher in patients with rs77924615 AG or GG. Finally, we confirmed that an increased uUCR (= .009) was associated with faster IgAN progression.
The SNP rs77924615, which modulates the enhancer activity of the gene, is associated with renal function deterioration in IgAN patients by increasing uromodulin levels in both the renal tubular epithelium and urine.
本研究调查与肾功能相关的基因变异和免疫球蛋白A（IgA）肾病（IgAN）进展之间的联系。
我们从瑞金医院招募了961例经活检证实的IgAN患者和651例非IgAN终末期肾病（ESRD）患者。收集临床和肾脏病理数据。主要结局是进入ESRD的时间。健康人群定义为估算肾小球滤过率>60 mL/min/1.73 m²且无蛋白尿或血尿。从一项关于肾功能的全基因组关联研究中选择了15个单核苷酸多态性（SNP），并通过SNaPshot进行基因分型。在肾组织中进行免疫组织化学检测，在尿液样本中进行酶联免疫吸附测定（ELISA），以探索基因变异的潜在功能。
在对临床和病理指标以及治疗进行调整后，rs77924615 - G与IgAN患者进入ESRD的风险增加独立相关（调整后风险比为2.10；95%置信区间为1.14 - 3.88）。在非IgAN ESRD患者中，不同基因型之间的无ESRD生存时间未发现显著差异（对数秩检验，P = 0.480）。此外，通过双荧光素酶报告基因检测，rs77924615表现出等位基因特异性增强子活性。因此，rs77924615为AG或GG的健康个体的尿调节素 - 肌酐比值（uUCR）显著高于AA个体。此外，rs77924615为AG或GG的患者肾小管上皮细胞中的尿调节素表达更高。最后，我们证实uUCR升高（P = 0.009）与IgAN进展更快相关。
SNP rs77924615通过增加肾小管上皮细胞和尿液中的尿调节素水平，调节 基因的增强子活性，与IgAN患者的肾功能恶化相关。
