SPP1 和 UMOD 基因变异与肾结石病的风险呈协同关联。

Department of Clinical Pharmacy, Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa, Anand, Gujarat 388421, India.

Department of Pharmaceutical Chemistry and Analysis, Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa, Anand, Gujarat 388421, India.

Gene. 2023 May 5;863:147264. doi: 10.1016/j.gene.2023.147264. Epub 2023 Feb 16.

OBJECTIVE

Calcium and oxalate are the most abundant metabolites present in the stone matrix. The SPP1 and UMOD gene has specific expression in kidneys and are involved in various stages of stone formation. Therefore, genetic variants in the SPP1 and UMOD genes may enhance the development of renal stone disease. This study has been designed to understand the association of genetic variants of SPP1 and UMOD genes with renal stone disease.

MATERIALS AND METHOD

A prospective study has been carried out, including 150 renal stone disease patients and 150 healthy individuals. Biochemical parameters were performed, including serum calcium levels, creatinine, parathyroid hormone, and 24-Hour urine metabolites. The genotyping of SPP1 (rs1126616) and UMOD (rs4293393) gene variants were performed using a customized TaqMan probe. T-test was used for continuous biochemical data analysis. The Chi-square test has been applied to assess the risk of a particular genotype associated with renal stone disease. In addition, correlation analysis for biochemical parameters and genetic variants with the renal stone disease has been performed using Shapley additive explanations (SHAP) values calculated with the help of the pycaret library.

RESULT

Renal stone patients had significantly higher levels of parathyroid hormone (93.37 ± 52.78 pg/ml vs 64.67 ± 31.50 pg/ml, P=<0.0001), serum creatinine (0.94 ± 0.38 mg/dl vs 0.77 ± 0.17 mg/dl, P=<0.0001) and 24hr urine metabolites in comparison to the healthy controls. Heterozygous (CT) variant of SPP1 and homozygous (GG) variant of UMOD genes were significantly associated with an increased risk of developing the renal stone disease (p = 0.0100, OR = 2.06, 95 %CI = 1.13-3.75; p=<0.0001, OR = 5.773, 95 % CI = 2.03-16.38, respectively). Individuals with hyperparathyroidism and CC (SPP1) and GG (UMOD) genotypes have a high risk (P = 0.0055, OR = 2.75, 95 %CI = 1.35-5.67; P = 0.0129, OR = 10.03, 95 %CI = 1.60-110.40, respectively) of developing a renal stone. In addition, individuals with hypercalciuria and TT genotype of SPP1 (P = 0.0112, OR = 2.92, 95 % CI = 1.33-6.35), AG genotype of UMOD (P=<0.0001, OR = 5.45, 95 %CI = 2.24-13.96) and GG genotype of UMOD (P=<0.0001, OR = 10.02, 95 %CI = 3.53-24.63) have high risk of developing renal stones. Moreover, Individuals with hyperoxaluria and AG + GG (UMOD) genotype have a greater risk (P=<0.0001, OR = 7.35, 95 % CI = 3.83-13.68) of developing a renal stone. The renal stone risk was persistent (P=<0.0002, OR = 2.44, 95 % CI = 1.52-3.86) when analyzed for the synergistic effect of risk genotypes of SPP1 (CT) and UMOD (GG) gene. Further, correlation analysis also confirmed the strong association between genetic variants and renal stone development.

CONCLUSION

Genetic variants of the SPP1 and UMOD genes were associated with renal stone disease. In the presence of risk genotype and hyperparathyroidism, hypercalciuria, and hyperoxaluria, the susceptibility to develop the renal stone disease risk gets modulated.

目的

钙和草酸盐是结石基质中含量最丰富的代谢物。 SPP1 和 UMOD 基因在肾脏中有特异性表达，并参与结石形成的各个阶段。因此，SPP1 和 UMOD 基因的遗传变异可能会增强肾结石病的发展。本研究旨在了解 SPP1 和 UMOD 基因的遗传变异与肾结石病的关系。

材料和方法

进行了一项前瞻性研究，包括 150 例肾结石病患者和 150 例健康个体。进行了生化参数检测，包括血清钙水平、肌酐、甲状旁腺激素和 24 小时尿液代谢物。使用定制的 TaqMan 探针进行了 SPP1(rs1126616)和 UMOD(rs4293393)基因变异的基因分型。使用 t 检验进行连续生化数据分析。使用卡方检验评估特定基因型与肾结石病相关的风险。此外，使用 pycaret 库中的 Shapley 加法解释（SHAP）值进行了生化参数和遗传变异与肾结石病的相关性分析。

结果

肾结石患者的甲状旁腺激素（93.37±52.78pg/ml 与 64.67±31.50pg/ml，P<0.0001）、血清肌酐（0.94±0.38mg/dl 与 0.77±0.17mg/dl，P<0.0001）和 24 小时尿液代谢物水平明显高于健康对照组。SPP1 的杂合子（CT）变体和 UMOD 基因的纯合子（GG）变体与肾结石病的发病风险增加显著相关（p=0.0100，OR=2.06，95%CI=1.13-3.75;p<0.0001，OR=5.773，95%CI=2.03-16.38，分别）。患有甲状旁腺功能亢进症和 CC（SPP1）和 GG（UMOD）基因型的个体患肾结石的风险很高（P=0.0055，OR=2.75，95%CI=1.35-5.67；P=0.0129，OR=10.03，95%CI=1.60-110.40，分别）。此外，患有高钙尿症和 SPP1 的 TT 基因型（P=0.0112，OR=2.92，95%CI=1.33-6.35）、UMOD 的 AG 基因型（P<0.0001，OR=5.45，95%CI=2.24-13.96）和 GG 基因型（P<0.0001，OR=10.02，95%CI=3.53-24.63）的个体患肾结石的风险很高。此外，患有高草酸尿症和 UMOD 的 AG+GG 基因型（P<0.0001，OR=7.35，95%CI=3.83-13.68）的个体患肾结石的风险更高。当分析 SPP1（CT）和 UMOD（GG）基因的风险基因型的协同作用时，肾结石的风险持续存在（P<0.0002，OR=2.44，95%CI=1.52-3.86）。此外，相关性分析也证实了遗传变异与肾结石发展之间的强烈关联。