, Volume 42, Issue 1, pp 45–52 | Cite as

Vitamin D receptor gene (VDR) polymorphisms and the urolithiasis risk: an updated meta-analysis based on 20 case–control studies

  • Wentao Liu
  • Minfeng Chen
  • Mengjun Li
  • Hong Ma
  • Shiyu Tong
  • Ye Lei
  • Lin Qi
Original Paper


Vitamin D receptor (VDR) plays a key role in calcium metabolism, and is closely related to urinary stone formation (urolithiasis). Previous studies have investigated the associations between VDR single nucleotide polymorphisms (SNPs) (polymorphisms at BsmI, ApaI, FokI, or TaqI cutting sites) and urolithiasis in different populations. However, the results remain inconsistent and controversial. Therefore, meta-analysis was performed to evaluate these associations. Twenty studies that investigated the associations between VDR SNPs and urolithiasis were retrieved. Odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated under the most appropriate genetic model. The TaqI polymorphism was associated with an increased risk of urolithiasis (tt + Tt vs. TT: OR = 1.253; 95 % CI = 1.033–1.520, p = 0.022, I 2 = 0), whereas the ApaI, BsmI, and FokI polymorphisms were not. Stratifying for ethnicity, a slightly increased risk was found among Asians as compared to Whites (OR 1.263, 1.232, respectively, p < 0.01). Deviation from Hardy–Weinberg equilibrium (HWE) was the major source of heterogeneity. In summary, this updated meta-analysis suggests the TaqI polymorphism is associated with urolithiasis risk, whereas BsmI, ApaI, and FokI polymorphisms are not.


Vitamin D receptor Polymorphisms Urolithiasis Meta-analysis 


Conflict of interest

The authors have no financial and non-financial conflicts of interest to declare.

Supplementary material

240_2013_619_MOESM1_ESM.tif (345 kb)
Figure S1 Begg’s funnel plots of TaqI polymorphism and the risk of urinary stones. (TIFF 345 kb)
240_2013_619_MOESM2_ESM.docx (13 kb)
Table S1 The refined criteria for quality assessment. (DOCX 13 kb)
240_2013_619_MOESM3_ESM.docx (14 kb)
Table S2 Summary of meta-analysis results for ApaI polymorphisms. (DOCX 14 kb)
240_2013_619_MOESM4_ESM.docx (14 kb)
Table S3 Summary of meta-analysis results for FokI polymorphism. (DOCX 14 kb)
240_2013_619_MOESM5_ESM.docx (14 kb)
Table S4 Summary of meta-analysis results for TaqI and BsmI polymorphisms. (DOCX 14 kb)


  1. 1.
    Aji K, Song G, Yasen A, Azad B, Tursun H (2012) Association of vitamin D receptor gene polymorphisms with urolithiasis in Uyghur children from southern Xinjiang, China. Zhongguo dang dai er ke za zhi 14:956–959PubMedGoogle Scholar
  2. 2.
    Anderson RA (2002) A complementary approach to urolithiasis prevention. World J Urol 20:294–301PubMedGoogle Scholar
  3. 3.
    Arai H, Miyamoto KI, Taketani Y, Yamamoto H, Iemori Y, Morita K, Tonai T, Nishisho T, Mori S, Takeda E (1997) A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res 12:915–921PubMedCrossRefGoogle Scholar
  4. 4.
    Attia J, Thakkinstian A, D’Este C (2003) Meta-analyses of molecular association studies: methodologic lessons for genetic epidemiology. J Clin Epidemiol 56:297–303PubMedCrossRefGoogle Scholar
  5. 5.
    Basiri A, Shakhssalim N, Houshmand M, Kashi AH, Azadvari M, Golestan B, Pargoo EM, Pakmanesh H (2012) Coding region analysis of vitamin D receptor gene and its association with active calcium stone disease. Urol Res 40:35–40PubMedCrossRefGoogle Scholar
  6. 6.
    Bid HK, Chaudhary H, Mittal RD (2005) Association of vitamin-D and calcitonin receptor gene polymorphism in paediatric nephrolithiasis. Pediatr Nephrol 20:773–776PubMedCrossRefGoogle Scholar
  7. 7.
    Bid HK, Kumar A, Kapoor R, Mittal RD (2005) Association of vitamin D receptor-gene (FokI) polymorphism with calcium oxalate nephrolithiasis. J Endourol 19:111–115PubMedCrossRefGoogle Scholar
  8. 8.
    Bland JM, Altman DG (1995) Multiple significance tests: the Bonferroni method BMJ. Br Med J 310:170CrossRefGoogle Scholar
  9. 9.
    Chen W-C, Chen H-Y, Hsu C-D, Wu J-Y, Tsai F-J (2001) No association of vitamin D receptor gene Bsm I polymorphisms with calcium oxalate stone formation. Mol Urol 5:7–10PubMedCrossRefGoogle Scholar
  10. 10.
    Chen WC, Chen HY, Lu HF, Hsu CD, Tsai FJ (2001) Association of the vitamin D receptor gene start codon Fok I polymorphism with calcium oxalate stone disease. BJU Int 87:168–171PubMedCrossRefGoogle Scholar
  11. 11.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188PubMedCrossRefGoogle Scholar
  12. 12.
    Gao B, Yasui T, Okada A, Tozawa K, Hayashi Y, Kohri K (2005) A polymorphism of the osteopontin gene is related to urinary calcium stones. J Urol 174:1472–1476PubMedCrossRefGoogle Scholar
  13. 13.
    Goldfarb DS, Fischer ME, Keich Y, Goldberg J (2005) A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry. Kidney Int 67:1053–1061PubMedCrossRefGoogle Scholar
  14. 14.
    Goodman HO, Holmes RP, Assimos DG (1995) Genetic factors in calcium oxalate stone disease. J Urol 153:301–307PubMedCrossRefGoogle Scholar
  15. 15.
    Gunes S, Bilen CY, Kara N, Asci R, Bagci H, Yilmaz AF (2006) Vitamin D receptor gene polymorphisms in patients with urolithiasis. Urol Res 34:47–52PubMedCrossRefGoogle Scholar
  16. 16.
    Holick MF (1994) McCollum Award Lecture, 1994: vitamin D–new horizons for the 21st century. Am J Clin Nutr 60:619–630PubMedGoogle Scholar
  17. 17.
    Hosking L, Lumsden S, Lewis K, Yeo A, McCarthy L, Bansal A, Riley J, Purvis I, Xu C-F (2004) Detection of genotyping errors by Hardy–Weinberg equilibrium testing. Eur J Hum Genet 12:395–399PubMedCrossRefGoogle Scholar
  18. 18.
    Jackman SV, Kibel AS, Ovuworie CA, Moore RG, Kavoussi LR, Jarrett TW (1999) Familial calcium stone disease: Taq I polymorphism and the vitamin D receptor. J Endourol 13:313–316PubMedCrossRefGoogle Scholar
  19. 19.
    Lin Y, Mao Q, Zheng X, Chen H, Yang K, Xie L (2011) Vitamin D receptor genetic polymorphisms and the risk of urolithiasis: a meta-analysis. Urol Int 86:249–255PubMedCrossRefGoogle Scholar
  20. 20.
    Liu CC, Huang CH, Wu WJ, Huang SP, Chou YH, Li CC, Chai CY, Wu MT (2007) Association of vitamin D receptor (Fok-I) polymorphism with the clinical presentation of calcium urolithiasis. BJU Int 99:1534–1538PubMedCrossRefGoogle Scholar
  21. 21.
    Mantel N, Haenszel W (2004) Statistical aspects of the analysis of data from retrospective studies of disease. Chall Epidemiol Issues Sel Read 1:533–553Google Scholar
  22. 22.
    Mittal RD, Mishra D, Srivastava P, Manchanda P, Bid H, Kapoor R (2010) Polymorphisms in the vitamin D receptor and the androgen receptor gene associated with the risk of urolithiasis. Indian J Clin Biochem 25:119–126PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287PubMedCrossRefGoogle Scholar
  24. 24.
    Mossetti G, Vuotto P, Rendina D, Numis F, Viceconti R, Giordano F, Cioffi M, Scopacasa F, Nunziata V (2003) Association between vitamin D receptor gene polymorphisms and tubular citrate handling in calcium nephrolithiasis. J Intern Med 253:194–200PubMedCrossRefGoogle Scholar
  25. 25.
    Nishijima S, Sugaya K, Naito A, Morozumi M, Hatano T, Ogawa Y (2002) Association of vitamin D receptor gene polymorphism with urolithiasis. J Urol 167:2188–2191PubMedCrossRefGoogle Scholar
  26. 26.
    Özkaya O, Söylemezoğlu O, Mısırlıoğlu M, Gönen S, Buyan N, Hasanoğlu E (2003) Polymorphisms in the vitamin D receptor gene and the risk of calcium nephrolithiasis in children. Eur Urol 44:150–154PubMedCrossRefGoogle Scholar
  27. 27.
    Relan V, Khullar M, Singh S, Sharma S (2004) Association of vitamin D receptor genotypes with calcium excretion in nephrolithiatic subjects in northern India. Urol Res 32:236–240PubMedCrossRefGoogle Scholar
  28. 28.
    Rendina D, Mossetti G, Viceconti R, Sorrentino M, Castaldo R, Manno G, Guadagno V, Strazzullo P, Nunziata V (2004) Association between vitamin D receptor gene polymorphisms and fasting idiopathic hypercalciuria in recurrent stone-forming patients. Urology 64:833–838PubMedCrossRefGoogle Scholar
  29. 29.
    Roy C, Gies H, Toomey S (1995) The solar UV radiation environment: measurement techniques and results. J Photochem Photobiol B Biol 31:21–27CrossRefGoogle Scholar
  30. 30.
    Ruggiero M, Pacini S, Amato M, Aterini S, Chiarugi V (1999) Association between vitamin D receptor gene polymorphism and nephrolithiasis. Miner Electrolyte Metab 25:185–190PubMedCrossRefGoogle Scholar
  31. 31.
    Schaid DJ, Jacobsen SJ (1999) Blased Tests of Association: comparisons of allele frequencies when departing from Hardy-Weinberg proportions. Am J Epidemiol 149:706–711PubMedCrossRefGoogle Scholar
  32. 32.
    Seo IY, Kang I-H, Chae S-C, Park SC, Lee Y-J, Yang YS, Ryu SB, Rim JS (2010) Vitamin D Receptor Gene AlwI FokI ApaI and TaqI polymorphisms in patients with urinary stone. Urology 75:923–927PubMedCrossRefGoogle Scholar
  33. 33.
    Seyhan S, Yavascaoglu I, Kilicarslan H, Dogan HS, Kordan Y (2007) Association of vitamin D receptor gene Taq I polymorphism with recurrent urolithiasis in children. Int J Urol 14:1060–1062PubMedCrossRefGoogle Scholar
  34. 34.
    Shaogang W, Jihong L, Shaoqun H, Zhangqun Y (2003) Association of vitamin D receptor gene polymorphisms with calcium oxalate calculus disease. J Huazhong Univ Sci Technol 23:38–41CrossRefGoogle Scholar
  35. 35.
    Simpson D (1983) Citrate excretion: a window on renal metabolism. Am J Physiol 244:F223–F234PubMedGoogle Scholar
  36. 36.
    Snellman G, Melhus H, Gedeborg R, Olofsson S, Wolk A, Pedersen NL, Michaelsson K (2009) Seasonal genetic influence on serum 25-hydroxyvitamin D levels: a twin study. PLoS ONE 4:e7747PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC (2003) Time trends in reported prevalence of kidney stones in the United States: 1976–19941. Kidney Int 63:1817–1823PubMedCrossRefGoogle Scholar
  38. 38.
    Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J (2005) A method for meta-analysis of molecular association studies. Stat Med 24:1291–1306PubMedCrossRefGoogle Scholar
  39. 39.
    Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, Duffy D, Thompson J, Hall I, Kaufman J, Leung TF, Helms PJ, Hakonarson H, Halpi E, Navon R, Attia J (2005) Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol 162:201–211PubMedCrossRefGoogle Scholar
  40. 40.
    Thorleifsson G, Holm H, Edvardsson V, Walters GB, Styrkarsdottir U, Gudbjartsson DF, Sulem P, Halldorsson BV, de Vegt F, d’Ancona FC, den Heijer M, Franzson L, Christiansen C, Alexandersen P, Rafnar T, Kristjansson K, Sigurdsson G, Kiemeney LA, Bodvarsson M, Indridason OS, Palsson R, Kong A, Thorsteinsdottir U, Stefansson K (2009) Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density. Nat Genet 41:926–930PubMedCrossRefGoogle Scholar
  41. 41.
    Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP (2006) Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol 163:300–309PubMedCrossRefGoogle Scholar
  42. 42.
    Urabe Y, Tanikawa C, Takahashi A, Okada Y, Morizono T, Tsunoda T, Kamatani N, Kohri K, Chayama K, Kubo M, Nakamura Y, Matsuda K (2012) A genome-wide association study of nephrolithiasis in the Japanese population identifies novel susceptible Loci at 5q35.3, 7p14.3, and 13q14.1. PLoS Genet 8:e1002541PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Vezzoli G, Terranegra A, Arcidiacono T, Gambaro G, Milanesi L, Mosca E, Soldati L (2010) Calcium kidney stones are associated with a haplotype of the calcium-sensing receptor gene regulatory region. Nephrol Dial Transplant 25:2245–2252PubMedCrossRefGoogle Scholar
  44. 44.
    Wang S, Wang X, Wu J, Lin Y, Chen H, Zheng X, Zhou C, Xie L (2012) Association of vitamin D receptor gene polymorphism and calcium urolithiasis in the Chinese Han population. Urol Res 40:277–284PubMedCrossRefGoogle Scholar
  45. 45.
    Whitehead A, Whitehead J (1991) A general parametric approach to the meta-analysis of randomized clinical trials. Stat Med 10:1665–1677PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Wentao Liu
    • 1
  • Minfeng Chen
    • 1
  • Mengjun Li
    • 2
  • Hong Ma
    • 3
  • Shiyu Tong
    • 1
  • Ye Lei
    • 1
  • Lin Qi
    • 1
  1. 1.Department of UrologyXiangya Hospital of Central South UniversityChangshaChina
  2. 2.Department of NeurosurgeryThe Second Xiangya Hospital of Central South UniversityChangshaChina
  3. 3.Department of Spine SurgeryThe Second Xiangya Hospital of Central South UniversityChangshaChina

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