Abstract
Polymorphisms of vitamin D receptor (VDR) gene have been associated with risk of urolithiasis, but, with inconsistent results and lack data from Pakistani population. Therefore, after including our indigenous study data, a comprehensive meta-analysis was performed to provide an evidence-based estimate of any association between VDR polymorphisms and urolithiasis risk. A total of 483 Pakistani subjects, comprising 235 urolithiasis patients and 248 healthy controls, were genotyped for 6 VDR polymorphisms. Additionally, a systematic literature search with subsequent meta-analysis was conducted and pooled odds ratios (ORs) were used to determine the strength of any existent associations. Trial sequential analysis (TSA) was also performed. Results revealed no significant association of any VDR polymorphism and urolithiasis risk in indigenous Pakistani patients. However, meta-analysis of 29 relevant studies indicated that VDR FokI polymorphism significantly increased the risk of urolithiasis in allelic (f vs. F: OR = 1.13; 95% CI = 1.05–1.22; p ≤ 0.01) and recessive (ff vs. FF + Ff: OR = 1.20; 95% CI = 1.05–1.38; p = 0.01) models with no significant heterogeneity. No associations were evident for VDR ApaI, BsmI and TaqI polymorphic variants and urolithiasis risk after correction for multiple testing. Subgroup analysis by ethnicity suggested significant association for FokI variant among Asians. The TSA results demonstrated that the evidence reflecting association of FokI polymorphism and urolithiasis risk was sufficient and conclusive. In conclusion, this meta-analysis suggests that VDR FokI polymorphism is significantly associated with urolithiasis risk, especially in Asians, whereas ApaI, BsmI and TaqI polymorphisms are not associated.
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References
Pritchard JK, Cox NJ (2002) The allelic architecture of human disease genes: common disease-common variant or not? Hum Mol Genet 11(20):2417–2423
Foulkes AS (2009) Applied statistical genetics with R: for population-based association studies. Use R!. Springer, New York
Dampf Stone A, Batie SF, Sabir MS, Jacobs ET, Lee JH, Whitfield GK, Haussler MR, Jurutka PW (2015) Resveratrol potentiates vitamin D and nuclear receptor signaling. J Cell Biochem 116(6):1130–1143. https://doi.org/10.1002/jcb.25070
Haussler MR, Jurutka PW, Mizwicki M, Norman AW (2011) Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)2vitamin D3: genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab 25(4):543–559. https://doi.org/10.1016/j.beem.2011.05.010
Jacobs TP, Kaufman M, Jones G, Kumar R, Schlingmann K-P, Shapses S, Bilezikian JP (2014) A lifetime of hypercalcemia and hypercalciuria, finally explained. J Clin Endocrinol Metab 99(3):708–712. https://doi.org/10.1210/jc.2013-3802
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(6460):284–287. https://doi.org/10.1038/367284a0
Arai H, Miyamoto K, 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(6):915–921. https://doi.org/10.1359/jbmr.1997.12.6.915
Uitterlinden AG, Fang Y, Van Meurs JBJ, Pols HAP, Van Leeuwen JPTM (2004) Genetics and biology of vitamin D receptor polymorphisms. Gene 338(2):143–156. https://doi.org/10.1016/j.gene.2004.05.014
Li XQ, Tembe V, Horwitz GM, Bushinsky DA, Favus MJ (1993) Increased intestinal vitamin D receptor in genetic hypercalciuric rats. A cause of intestinal calcium hyperabsorption. J Clin Investig 91(2):661–667. https://doi.org/10.1172/jci116246
Scott P, Ouimet D, Valiquette L, Guay G, Proulx Y, Trouvé ML, Gagnon B, Bonnardeaux A (1999) Suggestive evidence for a susceptibility gene near the vitamin D receptor locus in idiopathic calcium stone formation. J Am Soc Nephrol 10(5):1007–1013
Rule AD, Bergstralh EJ, Melton LJ, Li X, Weaver AL, Lieske JC (2009) Kidney stones and the risk for chronic kidney disease. Clin J Am Soc Nephrol 4(4):804–811. https://doi.org/10.2215/CJN.05811108
Scales CD, Smith AC, Hanley JM, Saigal CS, Urologic Diseases in America P (2012) Prevalence of kidney stones in the United States. Eur Urol 62(1):160–165. https://doi.org/10.1016/j.eururo.2012.03.052
Germino G, Kirkali Z (2015) Urinary stone disease research challenges and opportunities meeting minutes. National Institute of Diabetes and Digestive and Kidney Diseases, NIH Campus, Bethesda, USA
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(3):1053–1061. https://doi.org/10.1111/j.1523-1755.2005.00170.x
Goldfarb DS, Avery AR, Beara-Lasic L, Duncan GE, Goldberg J (2019) A twin study of genetic influences on nephrolithiasis in women and men. Kidney Int Rep 4(4):535–540. https://doi.org/10.1016/j.ekir.2018.11.017
Halbritter J, Baum M, Hynes AM, Rice SJ, Thwaites DT, Gucev ZS, Fisher B, Spaneas L, Porath JD, Braun DA, Wassner AJ, Nelson CP, Tasic V, Sayer JA, Hildebrandt F (2015) Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J Am Soc Nephrol 26(3):543–551. https://doi.org/10.1681/ASN.2014040388
Braun DA, Lawson JA, Gee HY, Halbritter J, Shril S, Tan W, Stein D, Wassner AJ, Ferguson MA, Gucev Z, Fisher B, Spaneas L, Varner J, Sayer JA, Milosevic D, Baum M, Tasic V, Hildebrandt F (2016) Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. Clin J Am Soc Nephrol 11(4):664–672. https://doi.org/10.2215/CJN.07540715
Daga A, Majmundar AJ, Braun DA, Gee HY, Lawson JA, Shril S, Jobst-Schwan T, Vivante A, Schapiro D, Tan W, Warejko JK, Widmeier E, Nelson CP, Fathy HM, Gucev Z, Soliman NA, Hashmi S, Halbritter J, Halty M, Kari JA, El-Desoky S, Ferguson MA, Somers MJG, Traum AZ, Stein DR, Daouk GH, Rodig NM, Katz A, Hanna C, Schwaderer AL, Sayer JA, Wassner AJ, Mane S, Lifton RP, Milosevic D, Tasic V, Baum MA, Hildebrandt F (2018) Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney Int 93(1):204–213. https://doi.org/10.1016/j.kint.2017.06.025
Amar A, Majmundar AJ, Ullah I, Afzal A, Braun DA, Shril S, Daga A, Jobst-Schwan T, Ahmad M, Sayer JA, Gee HY, Halbritter J, Knöpfel T, Hernando N, Werner A, Wagner C, Khaliq S, Hildebrandt F (2019) Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis. Hum Genet. https://doi.org/10.1007/s00439-019-01978-x
Sayer JA (2017) Progress in understanding the genetics of calcium-containing nephrolithiasis. J Am Soc Nephrol 28(3):748–759. https://doi.org/10.1681/ASN.2016050576
Civelek M, Lusis AJ (2014) Systems genetics approaches to understand complex traits. Nat Rev Genet 15(1):34–48. https://doi.org/10.1038/nrg3575
Lieske JC, Turner ST, Edeh SN, Smith JA, Kardia SLR (2014) Heritability of urinary traits that contribute to nephrolithiasis. Clin J Am Soc Nephrol 9(5):943–950. https://doi.org/10.2215/CJN.08210813
Talati J, Khan F, Drago H, Lall E, Khan NZ, Talati A, Noordzij J (1997) Epidemiology of urolithiasis in Pakistan. The management of lithiasis. Developments in nephrology. Springer, Dordrecht, pp 21–33
SaH Rizvi, SaA Naqvi, Hussain Z, Hashmi A, Hussain M, Zafar MN, Mehdi H, Khalid R (2002) The management of stone disease. BJU Int 89(s1):62–68. https://doi.org/10.1046/j.1465-5101.2001.134.x
Solé X, Guinó E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22(15):1928–1929. https://doi.org/10.1093/bioinformatics/btl268
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinform (Oxf, Engl) 21(2):263–265. https://doi.org/10.1093/bioinformatics/bth457
Abid A, Ajaz S, Khan AR, Zehra F, Hasan AS, Sultan G, Mohsin R, Hashmi A, Niamatullah N, Rizvi SA-U-H, Mehdi SQ, Khaliq S (2016) Analysis of the glutathione S-transferase genes polymorphisms in the risk and prognosis of renal cell carcinomas. Case-control and meta-analysis. Urol Oncol 34(9):419.e411–419.e412. https://doi.org/10.1016/j.urolonc.2016.04.005
Deeks JJ, Higgins JPT (2010) Statistical algorithms in review manager 5. In: Statistical methods group of the Cochrane collaboration, pp 1–11
Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634
R Core Team (2014) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.R-project.org/
Relan V, Khullar M, Singh SK, Sharma SK (2004) Association of vitamin D receptor genotypes with calcium excretion in nephrolithiatic subjects in northern India. Urol Res 32(3):236–240. https://doi.org/10.1007/s00240-004-0414-x
Bid HK, Chaudhary H, Mittal RD (2005) Association of vitamin-D and calcitonin receptor gene polymorphism in paediatric nephrolithiasis. Pediatr Nephrol 20(6):773–776. https://doi.org/10.1007/s00467-005-1846-4
Bid HK, Kumar A, Kapoor R, Mittal RD (2005) Association of vitamin D receptor-gene (FokI) polymorphism with calcium oxalate nephrolithiasis. J Endourol 19(1):111–115. https://doi.org/10.1089/end.2005.19.111
Mittal RD, Mishra DK, Srivastava P, Manchanda P, Bid HK, 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(2):119–126. https://doi.org/10.1007/s12291-010-0023-0
Jackman SV, Kibel AS, Ovuworie CA, Moore RG, Kavoussi LR, Jarrett TW (1999) Familial calcium stone disease: TaqI polymorphism and the vitamin D receptor. J Endourol 13(4):313–316. https://doi.org/10.1089/end.1999.13.313
Ruggiero M, Pacini S, Amato M, Aterini S, Chiarugi V (1999) Association between vitamin D receptor gene polymorphism and nephrolithiasis. Miner Electrolyte Metab 25(3):185–190. https://doi.org/10.1159/000057443
Mª Jesús Moyano Franco MJGdTR (2007) Changes in bone mineral metabolism in patients with recurrent urolithiasis and vitamin D receptor gene polymorphisms. Preliminary results. Nefrol (Engl Ed) 27(6):694–703
Mossetti G, Rendina D, Viceconti R, Manno G, Guadagno V, Strazzullo P, Nunziata V (2004) The relationship of 3′ vitamin D receptor haplotypes to urinary supersaturation of calcium oxalate salts and to age at onset and familial prevalence of nephrolithiasis. Nephrol Dial Transplant 19(9):2259–2265. https://doi.org/10.1093/ndt/gfh273
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(4):833–838. https://doi.org/10.1016/j.urology.2004.05.013
Mossetti G, Vuotto P, Rendina D, Numis FG, 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(2):194–200
Rendina D, De Filippo G, Gianfrancesco F, Muscariello R, Schiano di Cola M, Strazzullo P, Esposito T (2017) Evidence for epistatic interaction between VDR and SLC13A2 genes in the pathogenesis of hypocitraturia in recurrent calcium oxalate stone formers. J Nephrol 30(3):411–418. https://doi.org/10.1007/s40620-016-0348-8
Ozkaya O, Söylemezoğlu O, Misirlioğlu 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(1):150–154
Seyhan S, Yavascaoglu I, Kilicarslan H, Dogan HS, Kordan Y (2007) Association of vitamin D receptor gene TaqI polymorphism with recurrent urolithiasis in children. Int J Urol 14(12):1060–1062. https://doi.org/10.1111/j.1442-2042.2007.01899.x
Aykan S, Tuken M, Gunes S, Akin Y, Ozturk M, Seyhan S, Yuruk E, Temiz MZ, Yılmaz AF, Nguyen DP (2016) ApaL1 urokinase and Taq1 vitamin D receptor gene polymorphisms in first-stone formers, recurrent stone formers, and controls in a Caucasian population. Urolithiasis 44(2):109–115. https://doi.org/10.1007/s00240-015-0813-1
Cakir OO, Yilmaz A, Demir E, Incekara K, Kose MO, Ersoy N (2016) Association of the BsmI, ApaI, TaqI, Tru9I and FokI polymorphisms of the vitamin D receptor gene with nephrolithiasis in the Turkish population. Urol J 13(1):2509–2518
Goknar N, Öktem F, Torun E, Gok O, Demir AD, Kucukkoc M, Kilic U (2016) The role of vitamin D receptor gene polymorphisms in Turkish infants with urolithiasis. Ren Fail 38(4):545–551. https://doi.org/10.3109/0886022X.2016.1148557
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(1):47–52. https://doi.org/10.1007/s00240-005-0033-1
Subaşı B, Gökçe İ, Delil K, Alpay H (2017) Vitamin D receptor gene polymorphisms in children with kidney stone disease. Turk J Pediatr 59(4):404–409. https://doi.org/10.24953/turkjped.2017.04.006
Chen WC, Chen HY, Lu HF, Hsu CD, Tsai FJ (2001) Association of the vitamin D receptor gene start codon FokI polymorphism with calcium oxalate stone disease. BJU Int 87(3):168–171
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 [Med Sci] 23(1):38–41. https://doi.org/10.1007/BF02829458
Seo IY, Park KW, Park SC, Lee SJ, Kim MS, Kim JJ, Rim JS (2004) Vitamin D receptor gene BsaM I polymorphism as genetic marker in patients with calcium stone. Korean J Urol 45(11):1143–1147
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(5):2188–2191
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(4):277–284. https://doi.org/10.1007/s00240-011-0438-y
Chen WC, Chen HY, Hsu CD, Wu JY, Tsai FJ (2001) No association of vitamin D receptor gene BsmI polymorphisms with calcium oxalate stone formation. Mol Urol 5(1):7–10. https://doi.org/10.1089/109153601750124203
Liu C-C, Huang C-H, Wu W-J, Huang S-P, Chou Y-H, Li C-C, Chai C-Y, Wu M-T (2007) Association of vitamin D receptor (Fok-I) polymorphism with the clinical presentation of calcium urolithiasis. BJU Int 99(6):1534–1538. https://doi.org/10.1111/j.1464-410X.2007.06792.x
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(4):923–927. https://doi.org/10.1016/j.urology.2009.10.006
Yang Z, Wang Q, Zhong JF, Li L (2018) Polymorphisms of the VDR gene in patients with nephrolithiasis in a Han Chinese population. Urolithiasis. https://doi.org/10.1007/s00240-018-1053-y
Sorokin I, Mamoulakis C, Miyazawa K, Rodgers A, Talati J, Lotan Y (2017) Epidemiology of stone disease across the world. World J Urol 35(9):1301–1320. https://doi.org/10.1007/s00345-017-2008-6
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(3):249–255. https://doi.org/10.1159/000323949
Zhang P, Nie W, Jiang H (2013) Effects of vitamin D receptor polymorphisms on urolithiasis risk: a meta-analysis. BMC Med Genet 14:104. https://doi.org/10.1186/1471-2350-14-104
Liu W, Chen M, Li M, Ma H, Tong S, Lei Y, Qi L (2014) Vitamin D receptor gene (VDR) polymorphisms and the urolithiasis risk: an updated meta-analysis based on 20 case-control studies. Urolithiasis 42(1):45–52. https://doi.org/10.1007/s00240-013-0619-y
Zhou T-B, Jiang Z-P, Li A-H, Ju L (2015) Association of vitamin D receptor BsmI (rs1544410), Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism with the nephrolithiasis susceptibility. J Recept Signal Transduct Res 35(2):107–114. https://doi.org/10.3109/10799893.2014.936459
Hu SQ, Liu JH, Wang SG, Cao ZG, Wu W (2004) Relationship between vitamin D receptor allele polymorphism and calcium oxalate stone disease. Chin J Urol 25(3):155–158
Wang Q, Qian B, Ding G, Zheng L (2009) Vitamin D receptor gene polymorphisms in Chinese uygur patients with urolithiasis in south Xinjian. J Pract Med 25(17):2805–2807
Ruan L, Li Z, Zheng R, Huang W, Shi G, Li G, Li S, Luo B (2012) Relationship between vitamin D receptor FokI polymorphism and calcium oxalate stone disease in Guangzhou Chinese patients. Guangdong Medical Journal 33(1):84–85
Aji K, Song G-L, 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(12):956–959
Basiri A, Shakhssalim N, Houshmand M, Kashi AH, Azadvari M, Golestan B, Mohammadi Pargoo E, Pakmanesh H (2012) Coding region analysis of vitamin D receptor gene and its association with active calcium stone disease. Urol Res 40(1):35–40. https://doi.org/10.1007/s00240-011-0399-1
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We thank patients who participated in the study and hospital staff who facilitated the research team in data and sample collection. We also acknowledge the facilities and support provided by university staff.
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This study was funded by Higher Education Commission, Pakistan (Grant no. NRPU#1987).
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Amar, A., Afzal, A., Hussain, S.A. et al. Association of vitamin D receptor gene polymorphisms and risk of urolithiasis: results of a genetic epidemiology study and comprehensive meta-analysis. Urolithiasis 48, 385–401 (2020). https://doi.org/10.1007/s00240-019-01157-7
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DOI: https://doi.org/10.1007/s00240-019-01157-7