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.
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.
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.
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.
Gene. 2023 Feb 16 [Epub ahead of print]
Yash P Patel, Samir G Patel, Sandip B Patel, Aditya Parikh, Shailesh Soni, Ratika Srivastava, Chintal Raval, Manan A Raval, Sachchida Nand Pandey, Arvind P Ganpule, Mahesh R Desai
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., Department of Pharmacology, L.M. College of Pharmacy, Ahmedabad, Gujarat 380009, India., Department of Urology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat 387001, India., Department of Pathology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat 387001, India., School of Life Sciences, Department of Biotechnology, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, UP 226025, India., Department of Information Technology, Devang Patel Institute of Advance Technology and Research, Charotar University of Science and Technology, Changa, Anand, Gujarat 388421, India., Department of Pharmacognosy and Phytochemistry, Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa, Anand, Gujarat 388421, India., Department of Pathology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat 387001, India. Electronic address: .