Urolithiasis is a worldwide urological problem with significant contribution of genetic factors. Pakistan, which resides within the Afro-Asian stone belt, has a high reported prevalence (12%) of urolithiasis. Osteopontin (SPP1) is a urinary macromolecule with a suggested critical role in modulating renal stone formation, genetic polymorphisms of which may determine individual risk of developing urolithiasis. However, results of previous studies regarding SPP1 polymorphisms and susceptibility to urolithiasis have apparent inconsistencies with no data available for local population. A total of 235 urolithiasis patients and 243 healthy controls, all of Pakistani ancestry, underwent genotyping for six SPP1 genetic polymorphisms in an effort to investigate potential association with urolithiasis using indigenous candidate gene association study design. Further, a comprehensive meta-analysis following a systematic literature search was also done to ascertain an evidence based account of any existent association regarding SPP1 promoter polymorphisms and risk of developing urolithiasis. Three SPP1 promoter polymorphisms, rs2853744:G > T, rs11730582:T > C and rs11439060:delG>G, were found to be significantly associated with risk of urolithiasis in indigenous genetic association study (OR = 3.14; p = 0.006, OR = 1.78; p = 0.006 and OR = 1.60; p = 0.012, respectively). We also observed a 1.68-fold positive association of a tri-allelic haplotype of these SPP1 promoter polymorphisms (G-C-dG) with risk of urolithiasis (OR = 1.68; p = 0.0079). However, no association was evident when data were stratified according to gender, age at first presentation, stone recurrence, stone multiplicity, parental consanguinity and family history of urolithiasis. The overall results from meta-analysis, which included 4 studies, suggested a significant association of SPP1 rs2853744:G > T polymorphism with susceptibility of urolithiasis (OR = 1.37; p = 0.004), but not for other SPP1 polymorphic variants analyzed. In conclusion, we report significant association of 3 SPP1 polymorphisms with urolithiasis for the first time from South Asia, however, this association persisted only for SPP1 rs2853744:G > T polymorphism after meta-analysis of pooled studies. Further studies with a larger sample size will be required to validate this association and assess any potential usefulness in diagnosis and prognosis of renal stone disease.

中文翻译：

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骨桥蛋白启动子多态性和尿路结石的风险：候选基因关联和荟萃分析研究。

尿石症是世界范围内的泌尿科疾病，遗传因素的影响很大。巴基斯坦位于亚非石带内，据报道尿路结石患病率很高（12％）。骨桥蛋白（SPP1）是一种泌尿大分子，在调节肾结石形成中起关键作用，其遗传多态性可能决定了个体发展尿路结石的风险。但是，先前关于SPP1基因多态性和尿石症易感性的研究结果存在明显的矛盾，没有本地人群的可用数据。巴基斯坦全部血统的总共235名尿石症患者和243名健康对照者接受了6种SPP1基因多态性的基因分型，目的是使用本地候选基因关联研究设计调查与尿石症的潜在关联。此外，在进行系统的文献检索后，还进行了全面的荟萃分析，以确定与SPP1启动子多态性和发生尿路结石的风险有关的任何存在关联的证据。在本地遗传协会研究中，发现三个SPP1启动子多态性rs2853744：G> T，rs11730582：T> C和rs11439060：delG> G与尿石症风险显着相关（OR = 3.14； p = 0.006，OR = 1.78 ； p = 0.006和OR = 1.60； p = 0.012）。我们还观察到这些SPP1启动子多态性（GC-dG）的三等位基因单倍型的1.68倍正相关性具有尿路结石的风险（OR = 1.68; p = 0.0079）。但是，根据性别，初次出现的年龄，结石复发，结石多发性，父母血缘和尿石症家族史。荟萃分析的总体结果（包括4项研究）表明，SPP1 rs2853744：G> T多态性与尿石症易感性之间存在显着关联（OR = 1.37； p = 0.004），但与其他分析的SPP1多态性变异无关。总之，我们首次报告了来自南亚的3个SPP1多态性与尿石症的显着相关性，但是，对荟萃研究进行荟萃分析后，这种相关性仅在SPP1 rs2853744：G> T多态性中持续存在。将需要进行更大样本量的进一步研究，以验证这种关联并评估在肾结石疾病的诊断和预后中的任何潜在有用性。提示SPP1 rs2853744：G> T多态性与尿路结石易感性之间存在显着相关性（OR = 1.37； p = 0.004），但与其他分析的SPP1多态性变异无关。总之，我们首次报告了来自南亚的3个SPP1多态性与尿石症的显着相关性，但是，对荟萃研究进行荟萃分析后，这种相关性仅在SPP1 rs2853744：G> T多态性中持续存在。将需要进行更大样本量的进一步研究，以验证这种关联并评估在肾结石疾病的诊断和预后中的任何潜在有用性。提示SPP1 rs2853744：G> T多态性与尿路结石易感性之间存在显着相关性（OR = 1.37； p = 0.004），但与其他分析的SPP1多态性变异无关。总之，我们首次报告了来自南亚的3个SPP1多态性与尿石症的显着相关性，但是，对荟萃研究进行荟萃分析后，这种相关性仅在SPP1 rs2853744：G> T多态性中持续存在。将需要进行更大样本量的进一步研究，以验证这种关联并评估在肾结石疾病的诊断和预后中的任何潜在有用性。我们首次报告了来自南亚的3个SPP1多态性与尿路结石的显着相关性，但是，对汇总研究进行荟萃分析后，这种相关性仅在SPP1 rs2853744：G> T多态性中持续存在。将需要进行更大样本量的进一步研究，以验证这种关联并评估在肾结石疾病的诊断和预后中的任何潜在有用性。我们首次报告了来自南亚的3个SPP1多态性与尿路结石的显着相关性，但是，对汇总研究进行荟萃分析后，这种相关性仅在SPP1 rs2853744：G> T多态性中持续存在。将需要进行更大样本量的进一步研究，以验证这种关联并评估在肾结石疾病的诊断和预后中的任何潜在有用性。