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Background 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. Methods 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. Results 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. Conclusions 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.

Additional file 3. Basic information and HWE analysis for SPP1 gene polymorphisms analyzed in this study.

Additional file 7. Meta-analysis of SPP1 rs11730582:T > C polymorphism with risk of urolithiasis. a) and b) Forest plots of urolithiasis association with rs11730582 polymorphism using dominant and recessive model, respectively. c) and d) Funnel plots of rs11730582 polymorphism assuming dominant and recessive inheritance, respectively, using fixed effect model.

Additional file 1. Oligonucleotide sequences, PCR conditions and restriction enzyme used for the genotyping of SPP1 gene polymorphisms.

Additional file 8. Meta-analysis of SPP1 rs11439060:delG>G polymorphism with susceptibility of urolithiasis. a) and b) Forest plots of urolithiasis association with rs11439060 polymorphism following dominant and recessive model, respectively. c) and d) Funnel plots of rs11439060 polymorphism using dominant and recessive inheritance, respectively, by random effect model.

Additional file 6. A Association of SPP1 rs2853744:G > T with different clinical characteristics of urolithiasis. B Association of SPP1 rs11730582:T > C with different clinical characteristics of urolithiasis. C Association of SPP1 rs11439060:delG>G with different clinical characteristics of urolithiasis.

Additional file 5. Pairwise linkage disequilibrium (LD) map, based on D´ values, of SPP1 polymorphic markers analyzed in the present study. No significant LD was apparent in any of the SPP1 polymorphic pairs analyzed.

Additional file 2. Basic characteristics of the study participants in the case-control part of the study.

Additional file 4. Representative electropherograms for each genotype of three SPP1 polymorphisms. (A) rs11730582:T > C, (B) rs2853744:G > T and (C) rs11439060:delG>G.