Genetic Risk Factors for Idiopathic Urolithiasis: A Systematic Review of the Literature and Causal Network Analysis

Context Urolithiasis has a high prevalence and recurrence rate. Prevention is key to patient management, but risk stratification is challenging. In particular, genetic predisposition for urinary stones is not fully understood. Objective To review current evidence of potential causative genes for idiopathic urolithiasis and map their relationships to one another. This evidence is essential for future establishment of molecular targeted therapy. Evidence acquisition A systematic literature review from 2007 to 2017 was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. The search was restricted to human studies conducted as either case–control or genome-wide association studies, and published in English. We also performed a causal network analysis of candidate genes gained from the systematic review using Ingenuity Pathway Analysis (IPA). Evidence synthesis During the systematic screening of literature, 30 papers were selected for the review. A total of 20 genes with 42 polymorphisms/variants were found to be associated with urolithiasis risk. Their functional roles were mainly categorized as stone matrix, calcium and phosphate regulation, urinary concentration and constitution, and inflammation/oxidative stress. IPA network analysis revealed that these genes connected via signaling pathways and a proinflammatory/oxidative environment. Conclusions This systematic review provides an updated gene list and novel causal networks for idiopathic urolithiasis risk. Although some genes such as SPP1, CASR, VDR, CLDN14, and SLC34A1 were identified by several studies and recognized by prior reviews, further investigation elucidating their roles in stone formation will be essential for future studies. Patient summary In this review, we summarized recent literature regarding genes responsible for kidney stone risk. Based on a detailed review of 30 articles and computational network analysis, we concluded that disorder of mineral regulation with local inflammation in the kidney may cause kidney stone disease.