Genetic Risk Scores from Multiple Single Nucleotide Polymorphisms Reveal Genetic Susceptibility and Recurrence Risk of Calcium Nephrolithiasis

Background : We aimed to evaluate susceptibility loci for nephrolithiasis in the Chinese Han population and assess validated loci’s contributions to genetic risk scores in predicting the incidence and recurrence risk of calcium nephrolithiasis. Methods : The association of each single nucleotide polymorphism (SNP) with incidence and recurrence of calcium nephrolithiasis was analyzed. We genotyped 54 SNPs in 1,157 patients with calcium nephrolithiasis between April 2011 and September 2021 at Huashan Hospital of Fudan University. Genetic scores were computed for each individual by incorporating odds ratios (ORs) and allele frequencies of SNPs associated with increased risk. Results : Nine loci were associated with the risk of calcium nephrolithiasis. Among them, rs17216707 at CYP24A1 (P=1.521×10^-4, OR=4.208), rs3760702 at GIPC1 (P=7.70×10^-5, OR=1.654), and rs755622 at MIF-AS (P=5.67×10^-5, OR=0.605) were significantly associated after Bonferroni correction. GRS1 was calculated based on 35 SNPs from GWAS, and GRS2 was based on 9 associated SNPs. The AUC of GRS1 (0.557, 95%CI: 0.523–0.591) and GRS2 (0.590, 95%CI: 0.557–0.624) were similar. Neither GRS1 nor GRS2 showed discrimination ability for recurrence risk. Significant associations of rs7057398 (OR=1.971, P=0.03681) and rs7652589 (P=0.6715, OR=0.03872) with recurrence risk were observed. GRS3 had an AUC of 0.552 (95%CI: 0.506 to 0.598), improved to 0.574 when combined with a clinical model. Conclusions : GRS based on significant SNPs could predict incidence risk but not recurrence of calcium nephrolithiasis. The weight GRS from two recurrence-associated SNPs significantly correlated with recurrence risk and could enhance predictive value for traditional clinical risk factors.