TY  - EJOU
AU  - Lin, Jinglai 
AU  - Lin, Dengqiang 
AU  - Wu, Zhun 
AU  - Huang, Chao 
AU  - Xing, Jinchun 
AU  - Chen, Bin 
AU  - Zheng, Jiaxin 

TI  - Genetic variants in the STIM1–ORAI1 calcium entry pathway and susceptibility to calcium urolithiasis
T2  - Canadian Journal of Urology

PY  - 
VL  - 
IS  - 
SN  - 1488-5581

AB  -  <b>Objectives:</b> Calcium-containing stones account for the majority of urinary calculi, and genetic variation in calcium-signaling pathways may influence disease susceptibility. This study aims to determine whether common variants in STIM1, ORAI1, and TRPC1 are associated with susceptibility to calcium urolithiasis and to assess their clinical relevance. <b>Methods:</b> This single-center retrospective case-control study included 326 patients with calcium-containing urolithiasis and 198 controls. Thirteen tagSNPs in STIM1, ORAI1, and TRPC1 were genotyped using the Sequenom MassARRAY platform. Hardy–Weinberg equilibrium, allele- and genotype-based association analyses, logistic regression, exploratory genetic model analyses, linkage disequilibrium, haplotype analyses, and genotype–phenotype analyses were performed. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for sex, age, and body mass index (BMI). False discovery rate correction was applied to primary allele-level, retained common haplotype, and exploratory genotype–phenotype analyses. Subgroup analyses in overweight participants (BMI &gt; 24 kg/m²) were prespecified as exploratory and were not used to infer gene–BMI interaction. <b>Results:</b> In the overall cohort, the T allele of STIM1 rs10835206 and the C allele of ORAI1 rs12313273 showed allele-level associations with susceptibility to calcium urolithiasis after FDR correction (rs10835206: OR = 1.40, 95% CI 1.09–1.81; FDR-adjusted <i>p</i> = 0.046; rs12313273: OR = 1.53, 95% CI 1.17–2.00; FDR-adjusted <i>p</i> = 0.03). Exploratory analyses in overweight participants showed larger effect estimates (rs10835206: OR = 1.81, 95% CI 1.26–2.61; FDR-adjusted <i>p</i> = 0.007; rs12313273: OR = 2.09, 95% CI 1.43–3.05; FDR-adjusted <i>p</i> = 0.001), but these subgroup observations do not establish a formal interaction effect. Secondary genotype-based analyses provided supportive evidence of higher risk for rs10835206 TT and rs12313273 CC genotypes after adjustment for sex, age, and BMI. The ORAI1 GTTTA haplotype showed an exploratory protective signal (OR = 0.62, 95% CI 0.47–0.82; FDR-adjusted <i>p</i> = 0.003). In unadjusted exploratory genotype–phenotype analyses, rs10835206 showed a signal for higher BMI across CC, CT, and TT genotypes (22.9, 23.8, and 24.5 kg/m²; FDR-adjusted <i>p</i> = 0.04), whereas rs12313273 was associated with higher BMI (23.1, 23.9, and 26.8 kg/m<sup>2</sup>; FDR-adjusted <i>p</i> = 0.006), recurrence (26.1%, 34.5%, and 58.6%; FDR-adjusted <i>p</i> = 0.02), and stone size (9.8, 12.8, and 14.9 mm; FDR-adjusted <i>p</i> = 0.006). These effect sizes suggest modest genetic susceptibility signals with possible relevance to risk stratification, but not immediate clinical implementation. <b>Conclusions:</b> STIM1 rs10835206 and ORAI1 rs12313273 showed associations with susceptibility to calcium urolithiasis in this Han Chinese cohort. These findings are hypothesis-generating and warrant validation in multicenter cohorts and functional studies.
KW  - STIM1; ORAI1; TRPC1; polymorphism; calcium urolithiasis; recurrence; risk stratification

DO  - 10.32604/cju.2026.081735