Genetic Polymorphisms and Kidney Stones Around the Globe: A Systematic Review and Meta-Analysis

Abstract

Objective: This study explores associations between recurrent kidney stones and genetic polymorphisms.Methods: Meta-analysis of polymorphisms in renal stone cases versus control groups. Four electronic databases (PubMed, SCOPUS, EMBASE, and Web of Science) were searched up to 30 May 2021, using the keywords: “kidney stone” or “kidney calculi,” or “urolithiasis” or “nephrolithiasis” or “urinary calculi” and “genome” or “genetic” or “mutation” or “single nucleotide polymorphism.” Forrest plots, ORs, 95% CI, Chi-square (χ2)-test, and index of heterogeneity (I2) were calculated. Only studies with Newcastle–Ottawa scale (NOS) ≥ 6 were included for quality control, and Funnel, Begg’s, and Eager’s plots assessed publication bias. PROSPERO: CRD42022250427.Results: Among 7,671 searched articles, 72 were included. Polymorphisms in VDR (OR: 1.20; 95% CI: 1.06–1.36), CASR (OR = 1.24; 95% CI: 1.01–1.52), Osteopontin (OR = 1.38; 95% CI: 1.09–1.74), and Urokinase genes (OR = 1.52; 95% CI: 1.02–2.28) showed a significant association with risk of urinary stone formation, while Klotho gene showed a protective effect (OR = 0.75; 95% CI: 0.57–0.99). The VDR gene polymorphism was frequent in Asians, whereas CASR polymorphism was frequent in European and North American populations.Conclusion: Multifactorial nature of the stone formation, emphasizing the role of environmental factors, might explain contradictory results in the literature. While polymorphisms in VDR, CASR, Osteopontin, and Urokinase genes were associated with urinary stone formation, the Klotho gene showed a protective effect.

Association between Serum Klotho and Kidney Stones in US Middle-Aged and Older Individuals with Diabetes Mellitus: Results from 2007 to 2016 National Health and Nutrition Survey

“…Klotho gene G395A single-nucleotide polymorphisms were linked to the formation of renal stones among North Indian patients with KS [ 28 ]. Moreover, a meta-analysis involving five distinct research studies revealed that Klotho prevented the development of urinary stones [ 20 ]. All studies were conducted in Asian countries, and only a small number focused on the US population, which lessens their external validity.…”

“…In addition, in vitro CaOx KS model, Klotho overexpression prevented the CaOx-induced enhancement of crystal cell adhesion and apoptosis in HKC cells, whereas in vivo assays revealed that Klotho overexpression reduced renal oxidative injury, renal apoptosis, and crystal deposition that were caused by glyoxylate administration in mouse kidneys [ 18 ]. The Klotho gene demonstrated a protective effect, with multiple studies demonstrating a strong correlation between Klotho gene variations and urolithiasis susceptibility [ 19 , 20 ]. However, most studies on the relationships between Klotho gene polymorphisms and KS were conducted in Asia and lacked information on multiethnicity, which might be considered a confounding factor.…”

Methylation of the Vitamin D Receptor (VDR) gene in human disorders

“…Published data reported a negative correlation between seminal methylation status of CGI2, located in the VDR promoter region, and both sperm concentration and progressive motility, strengthening the potential role of this epigenetic mechanism in male infertility [39]. Methylation of VDR has also recently been investigated in the pathological state of recurrent kidney stone formation, given the significant association between the genetic variability of VDR and urinary stone formation risk [40,72]. In the study from Khatami et al, VDR methylation analysis was performed in 30 consecutive recurrent kidney stone formers and 30 age and gender-matched CTRs, revealing a hypermethylation pattern of two VDR promoter regions, including 5 and 11 CpG sites, in cases respect to CTRs [40].…”

Methylation of the Vitamin D Receptor Gene in Human Disorders

“…Published data reported a negative correlation between the seminal methylation status of CGI2, located in the VDR promoter region, and both sperm concentration and progressive motility, strengthening the potential role of this epigenetic mechanism in male infertility [ 42 ] ( Figure 2 ). The methylation of the VDR has also recently been investigated in the pathological state of recurrent kidney stone formation, given the significant association between the genetic variability of VDR and urinary stone formation risks [ 43 , 75 ] ( Table 1 ). In the study conducted by Khatami et al VDR methylation analysis was performed in 30 consecutive recurrent kidney stone formers and 30 age and gender-matched CTRs, revealing a hypermethylation pattern of two VDR promoter regions, including 5 and 11 CpG sites, in cases related to CTRs [ 43 ] ( Figure 2 ).…”