Association of vitamin D receptor gene polymorphisms and risk of urolithiasis: results of a genetic epidemiology study and comprehensive meta-analysis
- 1 Downloads
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.
KeywordsVDR Renal stones SNP Case–control Pakistan
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.
This study was funded by Higher Education Commission, Pakistan (Grant no. NRPU#1987).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All the procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethical Review Committee for Medical and Biomedical Research, University of Health Sciences, Lahore) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 1.Pritchard JK, Cox NJ (2002) The allelic architecture of human disease genes: common disease-common variant or not? Hum Mol Genet 11(20):2417–2423Google Scholar
- 2.Foulkes AS (2009) Applied statistical genetics with R: for population-based association studies. Use R!. Springer, New YorkGoogle Scholar
- 7.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.1922.214.171.1245 Google Scholar
- 10.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):1007–1013Google Scholar
- 13.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, USAGoogle Scholar
- 16.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 Google Scholar
- 17.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 Google Scholar
- 18.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 Google Scholar
- 19.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 Google Scholar
- 23.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 21–33Google Scholar
- 27.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 Google Scholar
- 28.Deeks JJ, Higgins JPT (2010) Statistical algorithms in review manager 5. In: Statistical methods group of the Cochrane collaboration, pp 1–11Google Scholar
- 29.Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101Google Scholar
- 30.Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634Google Scholar
- 38.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):694–703Google Scholar
- 39.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 Google Scholar
- 40.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 Google Scholar
- 41.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):194–200Google Scholar
- 42.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 Google Scholar
- 43.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):150–154Google Scholar
- 45.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 Google Scholar
- 46.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):2509–2518Google Scholar
- 50.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):168–171Google Scholar
- 52.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):1143–1147Google Scholar
- 53.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):2188–2191Google Scholar
- 63.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 Google Scholar
- 64.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):155–158Google Scholar
- 65.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):2805–2807Google Scholar
- 66.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):84–85Google Scholar
- 67.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):956–959Google Scholar