http://informahealthcare.com/rst ISSN: 1079-9893 (print), 1532-4281 (electronic) J Recept Signal Transduct Res, Early Online: 1–8 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10799893.2014.936459
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RESEARCH ARTICLE
Association of vitamin D receptor BsmI (rs1544410), Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism with the nephrolithiasis susceptibility Tian-Biao Zhou, Zong-Pei Jiang, Ai-Hua Li, and Lang Ju Department of Nephrology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
Abstract
Keywords
Association of vitamin D receptor (VDR) gene polymorphism with the risk of nephrolithiasis from the published reports is still conflicting. This study was conducted to evaluate the relationship between VDR BsmI (rs1544410), Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism and the risk of nephrolithiasis using meta-analysis method. The association studies were identified from PubMed, and Cochrane Library on 1 April 2014, and eligible investigations were included and synthesized using meta-analysis method. Six reports were recruited into this meta-analysis for the association of VDR BsmI, Fok1, TaqI and ApaI gene polymorphism with nephrolithiasis susceptibility. In this meta-analysis, VDR BsmI, Fok1, TaqI and ApaI gene polymorphism were not associated with nephrolithiasis susceptibility for overall populations and in Caucasians. However, the Fok1 f allele and ff genotype were associated with the risk of nephrolithiasis in Asians, but the FF genotype not. Furthermore, TaqI TT genotype was associated with the risk of nephrolithiasis in Asians, but the t allele and tt genotype not. However, ApaI gene polymorphism was not associated with nephrolithiasis susceptibility in Asians. In conclusion, VDR BsmI, Fok1, TaqI and ApaI gene polymorphism were not associated with nephrolithiasis risk in overall populations and in Caucasians. But, the Fok1 f allele and ff genotype, TaqI TT genotype, ApaI gene polymorphism were associated with the risk of nephrolithiasis in Asians. However, more studies should be conducted to confirm it.
ApaI, BsmI, Fok1, gene polymorphism, meta-analysis, Nephrolithiasis, TaqI, vitamin D receptor
Introduction The vitamin D receptor (VDR) is an endocrine nuclear receptor for 1a,25-dihydroxyvitamin D3 (1). There have been several polymorphisms named according to the restriction sites, such as VDR BsmI (rs1544410), Fok1 (rs2228570), ApaI (rs7975232) and TaqI (rs731236). BsmI, FokI, ApaI and TaqI gene polymorphisms of VDR gene are regarded as reliable markers of disturbed vitamin D signaling pathway (2). VDR gene polymorphisms have been reported to influence susceptibility to some diseases (3–5). Nephrolithiasis is a multifactorial disease caused by environmental, hormonal and genetic factors (6). Nephrolithiasis is a significant clinical problem in everyday practice with a subsequent burden for the health system, and it remains a chronic disease and our fundamental understanding of the pathogenesis of stones as well as their prevention and cure still remains rudimentary (7). There lacks a welldocumented diagnostic approach for the nephrolithiasis risk,
Address for correspondence: Tian-Biao Zhou, Department of Nephrology, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China. Tel: +8613602424386. E-mail: [email protected], [email protected]
History Received 21 May 2014 Accepted 8 June 2014 Published online 22 July 2014
and the etiology of nephrolithiasis is not clear. Current evidence indicates that gene polymorphism of some genes are associated with the susceptibility of nephrolithiasis. Gene polymorphism factor has been reported to be an important factor which increases the susceptibility of nephrolithiasis. Most of the epidemiologic investigations studying the relationship between VDR gene polymorphism and the nephrolithiasis risk were conducted in the past decades. However, the available evidence is weak due to sparseness of data or disagreements among the reported investigations. The evidence from meta-analysis might be powerful compared with the individual investigation. This meta-analysis was performed to investigate whether the VDR gene polymorphism was associated with the risk of nephrolithiasis, by widely collect the reported studies.
Materials and methods Search strategy for the relationship between vitamin D receptor BsmI (rs1544410), Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism and the risk of nephrolithiasis The relevant studies were searched from the electronic databases of PubMed, and Cochrane Library on 1 April
2
T.-B. Zhou et al.
J Recept Signal Transduct Res, Early Online: 1–8
2014. The retrieval strategy of ‘‘(vitamin D receptor OR VDR) AND (nephrolithiasis OR calcium kidney stones OR urolithiasis OR stone-forming)’’ was entered into these databases. The additional reports were identified through references cited in recruited articles. Inclusion and exclusion criteria Inclusion criteria
Results
(1) The outcome had to be nephrolithiasis, (2) there had to be at least two comparison groups (case group versus control group) and (3) investigation should provide the data of VDR BsmI, Fok1, TaqI and ApaI genotype distribution. Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by Dokuz Eylul Univ. on 11/07/14 For personal use only.
effects model, but a random effects model was conducted when the p value of heterogeneity test was less than 0.1 (8,9). Results were expressed with odds ratios (OR) for dichotomous data, and 95% confidence intervals (CI) were also calculated. p50.05 was required for the pooled OR to be statistically significant (10,11). I2 was used to test the heterogeneity among the included studies.
Exclusion criteria (1) Review articles and editorials, (2) case reports, (3) preliminary result not on VDR BsmI, Fok1, TaqI and ApaI gene polymorphism or outcome, (4) investigating the role VDR gene expression to disease and (5) if multiple publications for the same data from the same study group occurred, we only recruited the later paper into our final analysis.
Study characteristics Six studies (12–17) reporting the relationship between VDR BsmI, Fok1, TaqI or ApaI gene polymorphism and nephrolithiasis susceptibility were recruited into this meta-analysis (Table 1). The data of our interest were extracted (Table 1). Four studies (12–15) were for BsmI (rs1544410) gene polymorphism, three studies (14,15,17) were for Fok1 (rs2228570) gene polymorphism, four studies (13,15–17) were for VDR TaqI (rs731236) gene polymorphism, and four study (13,14,16,17) were for ApaI (rs7975232) gene polymorphism. Association of VDR BsmI gene polymorphism with nephrolithiasis susceptibility
Data extraction and synthesis The following information from each eligible study was extracted independently by two investigators: first author’s surname, year of publication, location of the study performed, control source of the control group and the number of cases and controls for VDR genotypes. The results were compared and disagreement was resolved by discussion. Statistical analysis Cochrane Review Manager Version 5 (RevMan, Version 5, Oxford, UK) was used to calculate the available data from each study. The pooled statistic was counted using the fixed
In this meta-analysis, we found that VDR BsmI B allele, BB genotype and bb genotype were not associated with nephrolithiasis risk in overall populations (B allele: OR ¼ 0.91, 95% CI: 0.74–1.12, p ¼ 0.36; BB genotype: OR ¼ 0.99, 95% CI: 0.71–1.39, p ¼ 0.96; bb genotype: OR ¼ 1.37, 95% CI: 0.83– 2.27, p ¼ 0.22; Figure 1 and Table 2). Interestingly, all the included studies for the meta-analysis of were conducted in Caucasian population, and the results for association of VDR BsmI gene polymorphism with nephrolithiasis susceptibility were the same as those in overall populations (Table 2).
Table 1. Characteristics of the studies evaluating the effects of VDR BsmI, Fok1, TaqI and ApaI gene polymorphism on nephrolithiasis risk. Case Gene sites BsmI
Fok1
TaqI
ApaI
Control
Author, Year
Ethnicity
Country/subgroup
Source of control
BB
Bb
bb
Total
BB
Bb
bb
Total
Ruggiero, 1999 Ozkaya, 2003 Rendina, 2004 Mossetti, 2004
Caucasian Caucasian Caucasian Caucasian
Italy Turkey Turkey Italy
Population Population Population Population
4 5 47 40
12 36 69 46
11 23 43 24
27 64 159 110
18 13 39 40
108 49 56 56
24 28 29 31
150 90 124 127
ff
Ff
FF
Total
ff
Ff
FF
Total
22 20 2
68 47 98
69 43 25
159 110 125
16 19 5
55 55 76
53 53 69
124 127 150
tt
Tt
TT
Total
tt
Tt
TT
Total
4 4 36 8
27 30 53 61
33 49 21 56
64 83 110 125
10 1 38 16
30 22 68 50
50 60 21 84
90 83 127 150
AA
Aa
aa
Total
AA
Aa
aa
Total
13 14 43 43
30 34 87 70
21 35 29 12
64 83 159 125
4 9 37 57
50 37 68 71
36 37 19 22
90 83 124 150
Rendina, 2004 Mossetti, 2004 Mittal, 2010
Ozkaya, 2003 Nishijima, 2002 Mossetti, 2004 Mittal, 2010
Ozkaya, 2003 Nishijima, 2002 Rendina, 2004 Mittal, 2010
Caucasian Caucasian Asian
Caucasian Asian Caucasian Asian
Caucasian Asian Caucasian Asian
Turkey Italy India
Turkey Japan Italy India
Turkey Japan Turkey India
Population Population Population
Population Population Population Population
Population Population Population Population
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by Dokuz Eylul Univ. on 11/07/14 For personal use only.
DOI: 10.3109/10799893.2014.936459
Association of VDR with nephrolithiasis
3
Figure 1. Association of VDR BsmI gene polymorphism with nephrolithiasis susceptibility in overall populations.
Association of VDR Fok1 gene polymorphism with nephrolithiasis susceptibility
Association of VDR TaqI gene polymorphism with nephrolithiasis susceptibility
In this meta-analysis, we found that VDR Fok1 f allele, ff genotype and FF genotype were not associated with nephrolithiasis risk in overall populations (f allele: OR ¼ 1.09, 95% CI: 0.90–1.32, p ¼ 0.37; ff genotype: OR ¼ 1.36, 95% CI: 0.72–2.56, p ¼ 0.35; FF genotype: OR ¼ 0.87, 95% CI: 0.63–1.20, p ¼ 0.39; Figure 2 and Table 2). In Caucasian population, VDR Fok1 f allele, ff genotype and FF genotype were also not associated with nephrolithiasis risk (Table 2). However, f allele and FF genotype were associated with nephrolithiasis risk in Asian population, but the ff genotype not (Table 2).
In this meta-analysis, VDR TaqI t allele, tt genotype and TT genotype were not associated with nephrolithiasis risk in overall populations (t allele: OR ¼ 1.15, 95% CI: 0.93–1.42, p ¼ 0.21; tt genotype: OR ¼ 0.93, 95% CI: 0.61–1.41, p ¼ 0.74; TT genotype: OR ¼ 0.74, 95% CI: 0.55–1.00, p ¼ 0.05; Figure 3 and Table 2). In Caucasian population, the association of VDR TaqI gene polymorphism with nephrolithiasis susceptibility was also not found (Table 2). However, VDR TaqI TT genotype was associated with nephrolithiasis risk in Asians, but the t allele and tt genotype were not (Table 2).
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T.-B. Zhou et al.
J Recept Signal Transduct Res, Early Online: 1–8
Table 2. Meta analysis of the association of VDR BsmI, Fok1, TaqI and ApaI gene polymorphism with nephrolithiasis risk. Genetic contrasts BsmI B vs b BB vs Bb + bb bb vs BB + Bb Fok1 f vs F
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ff vs Ff + FF FF vs Ff + ff TaqI t vs T tt vs Tt + TT TT vs Tt + tt ApaI A vs a AA vs Aa + aa aa vs AA + Aa
Group and subgroups
Studies number
Q test p value
Model selected
Overall Caucasian Overall Caucasian Overall Caucasian
4 4 4 4 4 4
0.32 0.32 0.48 0.48 0.07 0.07
Fixed Fixed Fixed Fixed Random Random
0.91 0.91 0.99 0.99 1.37 1.37
(0.74,1.12) (0.74,1.12) (0.71,1.39) (0.71,1.39) (0.83,2.27) (0.83,2.27)
Overall Asian Caucasian Overall Asian Caucasian Overall Asian Caucasian
3 1 2 3 1 2 3 1 2
0.21 – 0.65 0.02 – 0.76 0.52 – 0.84
Fixed Fixed Fixed Random Fixed Fixed Fixed Fixed Fixed
1.09 1.71 1.06 1.36 0.47 1.17 0.87 0.29 0.97
(0.90,1.32) (1.20,2.45) (0.82,1.37) (0.72,2.56) (0.09,2.47) (0.72,1.91) (0.63,1.20) (0.17,0.51) (0.68,1.37)
Overall Asian Caucasian Overall Asian Caucasian Overall Asian Caucasian
4 2 2 4 2 2 4 2 2
0.38 0.25 0.93 0.24 0.10 0.26 0.35 0.73 0.48
Fixed Fixed Fixed Fixed Fixed Fixed Fixed Fixed Fixed
1.15 1.33 1.00 0.93 0.81 0.99 0.74 0.61 1.00
(0.93,1.42) (0.98,1.82) (0.74,1.34) (0.61,1.41) (0.37,1.74) (0.60,1.62) (0.55,1.00) (0.41,0.89) (0.63,1.59)
0.21 0.07 0.98 0.74 0.58 0.97 0.05 0.01 1.00
Overall Asian Caucasian Overall Asian Caucasian Overall Asian Caucasian
4 2 2 4 2 2 4 2 2
0.09 0.60 0.04 0.56 0.20 0.005 0.001 0.44 0.27
Random Fixed Random Fixed Fixed Random Random Fixed Fixed
1.25 1.09 1.18 1.08 1.00 2.02 0.65 0.77 0.97
(0.91,1.72) (0.83,1.44) (0.65,2.14) (0.68,1.72) (0.65,1.54) (0.33,12.24) (0.30,1.39) (0.48,1.24) (0.61,1.52)
0.17 0.53 0.59 0.75 0.99 0.44 0.27 0.29 0.88
Association of VDR ApaI gene polymorphism with nephrolithiasis susceptibility In this meta-analysis, the association of VDR ApaI gene polymorphism with nephrolithiasis susceptibility was not found in overall populations (A allele: OR ¼ 1.25, 95% CI: 0.91–1.72, p ¼ 0.17; AA genotype: OR ¼ 1.08, 95% CI: 0.68–1.72, p ¼ 0.75; aa genotype: OR ¼ 0.65, 95% CI: 0.30–1.39, p ¼ 0.27; Figure 4 and Table 2). In Caucasian population and Asian population, we found that VDR ApaI A allele, AA genotype and aa genotype were not associated with nephrolithiasis risk (Table 2).
Discussion In this meta-analysis for VDR BsmI B allele, BB genotype and bb genotype were not associated with nephrolithiasis risk in overall populations and in Caucasian population. Only four studies were included for this meta-analysis, and the results for overall populations might be less robust to some extent. More studies for the association between VDR BsmI gene polymorphism and nephrolithiasis risk should be performed in the future. In this meta-analysis, there were three included studies for this meta-analysis and the results for overall populations
OR (95% CI)
p Value 0.36 0.36 0.96 0.96 0.22 0.22 0.37 0.003 0.64 0.35 0.37 0.53 0.39 50.00001 0.84
might be slightly robust to some extent. VDR Fok1 f allele, ff genotype and FF genotype were not associated with nephrolithiasis risk in overall populations, and VDR Fok1 f allele, ff genotype and FF genotype were also not associated with nephrolithiasis risk in Caucasian population. However, f allele and FF genotype were associated with nephrolithiasis risk in Asian population, but the ff genotype not. However, there was only one report from Asian population, and the results for Asian population were less robust. More studies for the association between VDR Fok1 gene polymorphism and nephrolithiasis risk should be performed in the future. In this meta-analysis, VDR TaqI t allele, tt genotype and TT genotype were not associated with nephrolithiasis risk in overall populations, and the association of VDR TaqI gene polymorphism with nephrolithiasis susceptibility was also not found in Caucasian population. However, VDR TaqI TT genotype was associated with nephrolithiasis risk in Asians, but the t allele and tt genotype were not. There were two studies for Caucasian population and two studies for Asian population. The results from this meta-analysis should be confirmed in the future. In this meta-analysis, VDR ApaI A allele, AA genotype and aa genotype were not associated with nephrolithiasis risk in Caucasian population, Asians and overall populations.
Association of VDR with nephrolithiasis
Figure 2. Association of VDR Fok1 gene polymorphism with nephrolithiasis susceptibility in overall populations.
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DOI: 10.3109/10799893.2014.936459
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T.-B. Zhou et al.
Figure 3. Association of VDR TaqI gene polymorphism with nephrolithiasis susceptibility in overall populations.
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6 J Recept Signal Transduct Res, Early Online: 1–8
Association of VDR with nephrolithiasis
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DOI: 10.3109/10799893.2014.936459
7
Figure 4. Association of VDR ApaI gene polymorphism with nephrolithiasis susceptibility in overall populations.
There were two recruited studies for Caucasian population, and two recruited studies for Asians in this meta-analysis. More studies should be conducted in the future. There was no any meta-analysis to study the association of VDR BsmI (rs1544410), Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism with the risk of nephrolithiasis using meta-analysis method. In our metaanalysis, VDR BsmI, Fok1, TaqI and ApaI gene polymorphism were not associated with nephrolithiasis susceptibility for overall populations and in Caucasians. However, the Fok1 f allele and ff genotype, TaqI TT genotype, ApaI gene polymorphism were associated with the risk of nephrolithiasis in Asians. However, the number of included studies was small. The conclusion might be less robust, and more studies should be performed in the future.
In conclusion, VDR BsmI, Fok1, TaqI and ApaI gene polymorphism were not associated with nephrolithiasis risk in overall populations and in Caucasians. But, the Fok1 f allele and ff genotype, TaqI TT genotype, ApaI gene polymorphism were associated with the risk of nephrolithiasis in Asians. However, more studies should be conducted to confirm it.
Declaration of interest The authors declare no competing interests. This study was supported by the sub-item of 985 Project Foundation of Sun Yat-Sen (The Hundred Talents Program Foundation; No. 88000-3311300).
References 1. Belorusova AY, Eberhardt J, Potier N, et al. Structural insights into the molecular mechanism of Vitamin D Receptor activation by
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2. 3.
4.
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by Dokuz Eylul Univ. on 11/07/14 For personal use only.
5.
6. 7. 8. 9.
T.-B. Zhou et al. lithocholic acid involving a new mode of ligand recognition. J Med Chem 2014;57:4710–9. Santoro D, Gagliostro G, Alibrandi A, et al. Vitamin D receptor gene polymorphism and left ventricular hypertrophy in chronic kidney disease. Nutrients 2014;6:1029–37. Qin WH, Wang HX, Qiu JL, et al. A meta-analysis of association of vitamin D receptor BsmI gene polymorphism with the risk of type 1 diabetes mellitus. J Recept Signal Transduct Res 2014. (Epub ahead of print). Ou C, Zhao HL, Zhu B, et al. Association of vitamin D receptor gene polymorphism with the risk of renal cell carcinoma: a metaanalysis. J Recept Signal Transduct Res 2014. (Epub ahead of print). Colombini A, Brayda-Bruno M, Lombardi G, et al. FokI polymorphism in the vitamin D receptor gene (VDR) and its association with lumbar spine pathologies in the Italian population: a casecontrol study. PLoS One 2014;9:e97027. Kan WC, Chou YH, Chiu SJ, et al. Study of the Association between ITPKC Genetic Polymorphisms and Calcium Nephrolithiasis. Biomed Res Int 2014;2014:397826. Aggarwal KP, Narula S, Kakkar M, Tandon C. Nephrolithiasis: molecular mechanism of renal stone formation and the critical role played by modulators. Biomed Res Int 2013;2013:292953. Zhou TB, Yin SS. Association of matrix metalloproteinase-9 level with the risk of renal involvement for Henoch–Schonlein purpura in children. Ren Fail 2013;35:425–9. Zhou TB, Yin SS, Jiang ZP. Association of angiotensin II type-1 receptor A1166C gene polymorphism with the susceptibility of end-stage renal disease. J Recept Signal Transduct Res 2013;33: 325–31.
J Recept Signal Transduct Res, Early Online: 1–8
10. Liu G, Zhou TB, Jiang Z, et al. Relationship between PPARgamma Pro12Ala gene polymorphism and type 2 diabetic nephropathy risk in Asian population: results from a meta-analysis. J Recept Signal Transduct Res 2014;34:131–6. 11. Zhou TB, Guo XF, Yin SS. Association of peroxisome proliferatoractivated receptor gamma Pro12Ala gene polymorphism with type 2 diabetic nephropathy risk in Caucasian population. J Recept Signal Transduct Res 2014;34:180–4. 12. Ruggiero M, Pacini S, Amato M, et al. Association between vitamin D receptor gene polymorphism and nephrolithiasis. Miner Electrolyte Metab 1999;25:185–90. 13. Ozkaya O, Soylemezoglu O, Misirlioglu M, et al. Polymorphisms in the vitamin D receptor gene and the risk of calcium nephrolithiasis in children. Eur Urol 2003;44:150–4. 14. Rendina D, Mossetti G, Viceconti R, et al. Association between vitamin D receptor gene polymorphisms and fasting idiopathic hypercalciuria in recurrent stone-forming patients. Urology 2004; 64:833–8. 15. Mossetti G, Rendina D, Viceconti R, et al. The relationship of 30 vitamin D receptor haplotypes to urinary supersaturation of calcium oxalate salts and to age at onset and familial prevalence of nephrolithiasis. Nephrol Dial Transplant 2004;19:2259–65. 16. Nishijima S, Sugaya K, Naito A, et al. Association of vitamin D receptor gene polymorphism with urolithiasis. J Urol 2002;167: 2188–91. 17. Mittal RD, Mishra DK, Srivastava P, et al. Polymorphisms in the vitamin D receptor and the androgen receptor gene associated with the risk of urolithiasis. Indian J Clin Biochem 2010;25: 119–26.
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by Dokuz Eylul Univ. on 11/07/14 For personal use only.
RESEARCH ARTICLE
Association of vitamin D receptor BsmI (rs1544410), Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism with the nephrolithiasis susceptibility Tian-Biao Zhou, Zong-Pei Jiang, Ai-Hua Li, and Lang Ju Department of Nephrology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
Abstract
Keywords
Association of vitamin D receptor (VDR) gene polymorphism with the risk of nephrolithiasis from the published reports is still conflicting. This study was conducted to evaluate the relationship between VDR BsmI (rs1544410), Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism and the risk of nephrolithiasis using meta-analysis method. The association studies were identified from PubMed, and Cochrane Library on 1 April 2014, and eligible investigations were included and synthesized using meta-analysis method. Six reports were recruited into this meta-analysis for the association of VDR BsmI, Fok1, TaqI and ApaI gene polymorphism with nephrolithiasis susceptibility. In this meta-analysis, VDR BsmI, Fok1, TaqI and ApaI gene polymorphism were not associated with nephrolithiasis susceptibility for overall populations and in Caucasians. However, the Fok1 f allele and ff genotype were associated with the risk of nephrolithiasis in Asians, but the FF genotype not. Furthermore, TaqI TT genotype was associated with the risk of nephrolithiasis in Asians, but the t allele and tt genotype not. However, ApaI gene polymorphism was not associated with nephrolithiasis susceptibility in Asians. In conclusion, VDR BsmI, Fok1, TaqI and ApaI gene polymorphism were not associated with nephrolithiasis risk in overall populations and in Caucasians. But, the Fok1 f allele and ff genotype, TaqI TT genotype, ApaI gene polymorphism were associated with the risk of nephrolithiasis in Asians. However, more studies should be conducted to confirm it.
ApaI, BsmI, Fok1, gene polymorphism, meta-analysis, Nephrolithiasis, TaqI, vitamin D receptor
Introduction The vitamin D receptor (VDR) is an endocrine nuclear receptor for 1a,25-dihydroxyvitamin D3 (1). There have been several polymorphisms named according to the restriction sites, such as VDR BsmI (rs1544410), Fok1 (rs2228570), ApaI (rs7975232) and TaqI (rs731236). BsmI, FokI, ApaI and TaqI gene polymorphisms of VDR gene are regarded as reliable markers of disturbed vitamin D signaling pathway (2). VDR gene polymorphisms have been reported to influence susceptibility to some diseases (3–5). Nephrolithiasis is a multifactorial disease caused by environmental, hormonal and genetic factors (6). Nephrolithiasis is a significant clinical problem in everyday practice with a subsequent burden for the health system, and it remains a chronic disease and our fundamental understanding of the pathogenesis of stones as well as their prevention and cure still remains rudimentary (7). There lacks a welldocumented diagnostic approach for the nephrolithiasis risk,
Address for correspondence: Tian-Biao Zhou, Department of Nephrology, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China. Tel: +8613602424386. E-mail: [email protected], [email protected]
History Received 21 May 2014 Accepted 8 June 2014 Published online 22 July 2014
and the etiology of nephrolithiasis is not clear. Current evidence indicates that gene polymorphism of some genes are associated with the susceptibility of nephrolithiasis. Gene polymorphism factor has been reported to be an important factor which increases the susceptibility of nephrolithiasis. Most of the epidemiologic investigations studying the relationship between VDR gene polymorphism and the nephrolithiasis risk were conducted in the past decades. However, the available evidence is weak due to sparseness of data or disagreements among the reported investigations. The evidence from meta-analysis might be powerful compared with the individual investigation. This meta-analysis was performed to investigate whether the VDR gene polymorphism was associated with the risk of nephrolithiasis, by widely collect the reported studies.
Materials and methods Search strategy for the relationship between vitamin D receptor BsmI (rs1544410), Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism and the risk of nephrolithiasis The relevant studies were searched from the electronic databases of PubMed, and Cochrane Library on 1 April
2
T.-B. Zhou et al.
J Recept Signal Transduct Res, Early Online: 1–8
2014. The retrieval strategy of ‘‘(vitamin D receptor OR VDR) AND (nephrolithiasis OR calcium kidney stones OR urolithiasis OR stone-forming)’’ was entered into these databases. The additional reports were identified through references cited in recruited articles. Inclusion and exclusion criteria Inclusion criteria
Results
(1) The outcome had to be nephrolithiasis, (2) there had to be at least two comparison groups (case group versus control group) and (3) investigation should provide the data of VDR BsmI, Fok1, TaqI and ApaI genotype distribution. Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by Dokuz Eylul Univ. on 11/07/14 For personal use only.
effects model, but a random effects model was conducted when the p value of heterogeneity test was less than 0.1 (8,9). Results were expressed with odds ratios (OR) for dichotomous data, and 95% confidence intervals (CI) were also calculated. p50.05 was required for the pooled OR to be statistically significant (10,11). I2 was used to test the heterogeneity among the included studies.
Exclusion criteria (1) Review articles and editorials, (2) case reports, (3) preliminary result not on VDR BsmI, Fok1, TaqI and ApaI gene polymorphism or outcome, (4) investigating the role VDR gene expression to disease and (5) if multiple publications for the same data from the same study group occurred, we only recruited the later paper into our final analysis.
Study characteristics Six studies (12–17) reporting the relationship between VDR BsmI, Fok1, TaqI or ApaI gene polymorphism and nephrolithiasis susceptibility were recruited into this meta-analysis (Table 1). The data of our interest were extracted (Table 1). Four studies (12–15) were for BsmI (rs1544410) gene polymorphism, three studies (14,15,17) were for Fok1 (rs2228570) gene polymorphism, four studies (13,15–17) were for VDR TaqI (rs731236) gene polymorphism, and four study (13,14,16,17) were for ApaI (rs7975232) gene polymorphism. Association of VDR BsmI gene polymorphism with nephrolithiasis susceptibility
Data extraction and synthesis The following information from each eligible study was extracted independently by two investigators: first author’s surname, year of publication, location of the study performed, control source of the control group and the number of cases and controls for VDR genotypes. The results were compared and disagreement was resolved by discussion. Statistical analysis Cochrane Review Manager Version 5 (RevMan, Version 5, Oxford, UK) was used to calculate the available data from each study. The pooled statistic was counted using the fixed
In this meta-analysis, we found that VDR BsmI B allele, BB genotype and bb genotype were not associated with nephrolithiasis risk in overall populations (B allele: OR ¼ 0.91, 95% CI: 0.74–1.12, p ¼ 0.36; BB genotype: OR ¼ 0.99, 95% CI: 0.71–1.39, p ¼ 0.96; bb genotype: OR ¼ 1.37, 95% CI: 0.83– 2.27, p ¼ 0.22; Figure 1 and Table 2). Interestingly, all the included studies for the meta-analysis of were conducted in Caucasian population, and the results for association of VDR BsmI gene polymorphism with nephrolithiasis susceptibility were the same as those in overall populations (Table 2).
Table 1. Characteristics of the studies evaluating the effects of VDR BsmI, Fok1, TaqI and ApaI gene polymorphism on nephrolithiasis risk. Case Gene sites BsmI
Fok1
TaqI
ApaI
Control
Author, Year
Ethnicity
Country/subgroup
Source of control
BB
Bb
bb
Total
BB
Bb
bb
Total
Ruggiero, 1999 Ozkaya, 2003 Rendina, 2004 Mossetti, 2004
Caucasian Caucasian Caucasian Caucasian
Italy Turkey Turkey Italy
Population Population Population Population
4 5 47 40
12 36 69 46
11 23 43 24
27 64 159 110
18 13 39 40
108 49 56 56
24 28 29 31
150 90 124 127
ff
Ff
FF
Total
ff
Ff
FF
Total
22 20 2
68 47 98
69 43 25
159 110 125
16 19 5
55 55 76
53 53 69
124 127 150
tt
Tt
TT
Total
tt
Tt
TT
Total
4 4 36 8
27 30 53 61
33 49 21 56
64 83 110 125
10 1 38 16
30 22 68 50
50 60 21 84
90 83 127 150
AA
Aa
aa
Total
AA
Aa
aa
Total
13 14 43 43
30 34 87 70
21 35 29 12
64 83 159 125
4 9 37 57
50 37 68 71
36 37 19 22
90 83 124 150
Rendina, 2004 Mossetti, 2004 Mittal, 2010
Ozkaya, 2003 Nishijima, 2002 Mossetti, 2004 Mittal, 2010
Ozkaya, 2003 Nishijima, 2002 Rendina, 2004 Mittal, 2010
Caucasian Caucasian Asian
Caucasian Asian Caucasian Asian
Caucasian Asian Caucasian Asian
Turkey Italy India
Turkey Japan Italy India
Turkey Japan Turkey India
Population Population Population
Population Population Population Population
Population Population Population Population
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DOI: 10.3109/10799893.2014.936459
Association of VDR with nephrolithiasis
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Figure 1. Association of VDR BsmI gene polymorphism with nephrolithiasis susceptibility in overall populations.
Association of VDR Fok1 gene polymorphism with nephrolithiasis susceptibility
Association of VDR TaqI gene polymorphism with nephrolithiasis susceptibility
In this meta-analysis, we found that VDR Fok1 f allele, ff genotype and FF genotype were not associated with nephrolithiasis risk in overall populations (f allele: OR ¼ 1.09, 95% CI: 0.90–1.32, p ¼ 0.37; ff genotype: OR ¼ 1.36, 95% CI: 0.72–2.56, p ¼ 0.35; FF genotype: OR ¼ 0.87, 95% CI: 0.63–1.20, p ¼ 0.39; Figure 2 and Table 2). In Caucasian population, VDR Fok1 f allele, ff genotype and FF genotype were also not associated with nephrolithiasis risk (Table 2). However, f allele and FF genotype were associated with nephrolithiasis risk in Asian population, but the ff genotype not (Table 2).
In this meta-analysis, VDR TaqI t allele, tt genotype and TT genotype were not associated with nephrolithiasis risk in overall populations (t allele: OR ¼ 1.15, 95% CI: 0.93–1.42, p ¼ 0.21; tt genotype: OR ¼ 0.93, 95% CI: 0.61–1.41, p ¼ 0.74; TT genotype: OR ¼ 0.74, 95% CI: 0.55–1.00, p ¼ 0.05; Figure 3 and Table 2). In Caucasian population, the association of VDR TaqI gene polymorphism with nephrolithiasis susceptibility was also not found (Table 2). However, VDR TaqI TT genotype was associated with nephrolithiasis risk in Asians, but the t allele and tt genotype were not (Table 2).
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T.-B. Zhou et al.
J Recept Signal Transduct Res, Early Online: 1–8
Table 2. Meta analysis of the association of VDR BsmI, Fok1, TaqI and ApaI gene polymorphism with nephrolithiasis risk. Genetic contrasts BsmI B vs b BB vs Bb + bb bb vs BB + Bb Fok1 f vs F
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ff vs Ff + FF FF vs Ff + ff TaqI t vs T tt vs Tt + TT TT vs Tt + tt ApaI A vs a AA vs Aa + aa aa vs AA + Aa
Group and subgroups
Studies number
Q test p value
Model selected
Overall Caucasian Overall Caucasian Overall Caucasian
4 4 4 4 4 4
0.32 0.32 0.48 0.48 0.07 0.07
Fixed Fixed Fixed Fixed Random Random
0.91 0.91 0.99 0.99 1.37 1.37
(0.74,1.12) (0.74,1.12) (0.71,1.39) (0.71,1.39) (0.83,2.27) (0.83,2.27)
Overall Asian Caucasian Overall Asian Caucasian Overall Asian Caucasian
3 1 2 3 1 2 3 1 2
0.21 – 0.65 0.02 – 0.76 0.52 – 0.84
Fixed Fixed Fixed Random Fixed Fixed Fixed Fixed Fixed
1.09 1.71 1.06 1.36 0.47 1.17 0.87 0.29 0.97
(0.90,1.32) (1.20,2.45) (0.82,1.37) (0.72,2.56) (0.09,2.47) (0.72,1.91) (0.63,1.20) (0.17,0.51) (0.68,1.37)
Overall Asian Caucasian Overall Asian Caucasian Overall Asian Caucasian
4 2 2 4 2 2 4 2 2
0.38 0.25 0.93 0.24 0.10 0.26 0.35 0.73 0.48
Fixed Fixed Fixed Fixed Fixed Fixed Fixed Fixed Fixed
1.15 1.33 1.00 0.93 0.81 0.99 0.74 0.61 1.00
(0.93,1.42) (0.98,1.82) (0.74,1.34) (0.61,1.41) (0.37,1.74) (0.60,1.62) (0.55,1.00) (0.41,0.89) (0.63,1.59)
0.21 0.07 0.98 0.74 0.58 0.97 0.05 0.01 1.00
Overall Asian Caucasian Overall Asian Caucasian Overall Asian Caucasian
4 2 2 4 2 2 4 2 2
0.09 0.60 0.04 0.56 0.20 0.005 0.001 0.44 0.27
Random Fixed Random Fixed Fixed Random Random Fixed Fixed
1.25 1.09 1.18 1.08 1.00 2.02 0.65 0.77 0.97
(0.91,1.72) (0.83,1.44) (0.65,2.14) (0.68,1.72) (0.65,1.54) (0.33,12.24) (0.30,1.39) (0.48,1.24) (0.61,1.52)
0.17 0.53 0.59 0.75 0.99 0.44 0.27 0.29 0.88
Association of VDR ApaI gene polymorphism with nephrolithiasis susceptibility In this meta-analysis, the association of VDR ApaI gene polymorphism with nephrolithiasis susceptibility was not found in overall populations (A allele: OR ¼ 1.25, 95% CI: 0.91–1.72, p ¼ 0.17; AA genotype: OR ¼ 1.08, 95% CI: 0.68–1.72, p ¼ 0.75; aa genotype: OR ¼ 0.65, 95% CI: 0.30–1.39, p ¼ 0.27; Figure 4 and Table 2). In Caucasian population and Asian population, we found that VDR ApaI A allele, AA genotype and aa genotype were not associated with nephrolithiasis risk (Table 2).
Discussion In this meta-analysis for VDR BsmI B allele, BB genotype and bb genotype were not associated with nephrolithiasis risk in overall populations and in Caucasian population. Only four studies were included for this meta-analysis, and the results for overall populations might be less robust to some extent. More studies for the association between VDR BsmI gene polymorphism and nephrolithiasis risk should be performed in the future. In this meta-analysis, there were three included studies for this meta-analysis and the results for overall populations
OR (95% CI)
p Value 0.36 0.36 0.96 0.96 0.22 0.22 0.37 0.003 0.64 0.35 0.37 0.53 0.39 50.00001 0.84
might be slightly robust to some extent. VDR Fok1 f allele, ff genotype and FF genotype were not associated with nephrolithiasis risk in overall populations, and VDR Fok1 f allele, ff genotype and FF genotype were also not associated with nephrolithiasis risk in Caucasian population. However, f allele and FF genotype were associated with nephrolithiasis risk in Asian population, but the ff genotype not. However, there was only one report from Asian population, and the results for Asian population were less robust. More studies for the association between VDR Fok1 gene polymorphism and nephrolithiasis risk should be performed in the future. In this meta-analysis, VDR TaqI t allele, tt genotype and TT genotype were not associated with nephrolithiasis risk in overall populations, and the association of VDR TaqI gene polymorphism with nephrolithiasis susceptibility was also not found in Caucasian population. However, VDR TaqI TT genotype was associated with nephrolithiasis risk in Asians, but the t allele and tt genotype were not. There were two studies for Caucasian population and two studies for Asian population. The results from this meta-analysis should be confirmed in the future. In this meta-analysis, VDR ApaI A allele, AA genotype and aa genotype were not associated with nephrolithiasis risk in Caucasian population, Asians and overall populations.
Association of VDR with nephrolithiasis
Figure 2. Association of VDR Fok1 gene polymorphism with nephrolithiasis susceptibility in overall populations.
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DOI: 10.3109/10799893.2014.936459
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T.-B. Zhou et al.
Figure 3. Association of VDR TaqI gene polymorphism with nephrolithiasis susceptibility in overall populations.
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Association of VDR with nephrolithiasis
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DOI: 10.3109/10799893.2014.936459
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Figure 4. Association of VDR ApaI gene polymorphism with nephrolithiasis susceptibility in overall populations.
There were two recruited studies for Caucasian population, and two recruited studies for Asians in this meta-analysis. More studies should be conducted in the future. There was no any meta-analysis to study the association of VDR BsmI (rs1544410), Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism with the risk of nephrolithiasis using meta-analysis method. In our metaanalysis, VDR BsmI, Fok1, TaqI and ApaI gene polymorphism were not associated with nephrolithiasis susceptibility for overall populations and in Caucasians. However, the Fok1 f allele and ff genotype, TaqI TT genotype, ApaI gene polymorphism were associated with the risk of nephrolithiasis in Asians. However, the number of included studies was small. The conclusion might be less robust, and more studies should be performed in the future.
In conclusion, VDR BsmI, Fok1, TaqI and ApaI gene polymorphism were not associated with nephrolithiasis risk in overall populations and in Caucasians. But, the Fok1 f allele and ff genotype, TaqI TT genotype, ApaI gene polymorphism were associated with the risk of nephrolithiasis in Asians. However, more studies should be conducted to confirm it.
Declaration of interest The authors declare no competing interests. This study was supported by the sub-item of 985 Project Foundation of Sun Yat-Sen (The Hundred Talents Program Foundation; No. 88000-3311300).
References 1. Belorusova AY, Eberhardt J, Potier N, et al. Structural insights into the molecular mechanism of Vitamin D Receptor activation by
8
2. 3.
4.
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by Dokuz Eylul Univ. on 11/07/14 For personal use only.
5.
6. 7. 8. 9.
T.-B. Zhou et al. lithocholic acid involving a new mode of ligand recognition. J Med Chem 2014;57:4710–9. Santoro D, Gagliostro G, Alibrandi A, et al. Vitamin D receptor gene polymorphism and left ventricular hypertrophy in chronic kidney disease. Nutrients 2014;6:1029–37. Qin WH, Wang HX, Qiu JL, et al. A meta-analysis of association of vitamin D receptor BsmI gene polymorphism with the risk of type 1 diabetes mellitus. J Recept Signal Transduct Res 2014. (Epub ahead of print). Ou C, Zhao HL, Zhu B, et al. Association of vitamin D receptor gene polymorphism with the risk of renal cell carcinoma: a metaanalysis. J Recept Signal Transduct Res 2014. (Epub ahead of print). Colombini A, Brayda-Bruno M, Lombardi G, et al. FokI polymorphism in the vitamin D receptor gene (VDR) and its association with lumbar spine pathologies in the Italian population: a casecontrol study. PLoS One 2014;9:e97027. Kan WC, Chou YH, Chiu SJ, et al. Study of the Association between ITPKC Genetic Polymorphisms and Calcium Nephrolithiasis. Biomed Res Int 2014;2014:397826. Aggarwal KP, Narula S, Kakkar M, Tandon C. Nephrolithiasis: molecular mechanism of renal stone formation and the critical role played by modulators. Biomed Res Int 2013;2013:292953. Zhou TB, Yin SS. Association of matrix metalloproteinase-9 level with the risk of renal involvement for Henoch–Schonlein purpura in children. Ren Fail 2013;35:425–9. Zhou TB, Yin SS, Jiang ZP. Association of angiotensin II type-1 receptor A1166C gene polymorphism with the susceptibility of end-stage renal disease. J Recept Signal Transduct Res 2013;33: 325–31.
J Recept Signal Transduct Res, Early Online: 1–8
10. Liu G, Zhou TB, Jiang Z, et al. Relationship between PPARgamma Pro12Ala gene polymorphism and type 2 diabetic nephropathy risk in Asian population: results from a meta-analysis. J Recept Signal Transduct Res 2014;34:131–6. 11. Zhou TB, Guo XF, Yin SS. Association of peroxisome proliferatoractivated receptor gamma Pro12Ala gene polymorphism with type 2 diabetic nephropathy risk in Caucasian population. J Recept Signal Transduct Res 2014;34:180–4. 12. Ruggiero M, Pacini S, Amato M, et al. Association between vitamin D receptor gene polymorphism and nephrolithiasis. Miner Electrolyte Metab 1999;25:185–90. 13. Ozkaya O, Soylemezoglu O, Misirlioglu M, et al. Polymorphisms in the vitamin D receptor gene and the risk of calcium nephrolithiasis in children. Eur Urol 2003;44:150–4. 14. Rendina D, Mossetti G, Viceconti R, et al. Association between vitamin D receptor gene polymorphisms and fasting idiopathic hypercalciuria in recurrent stone-forming patients. Urology 2004; 64:833–8. 15. Mossetti G, Rendina D, Viceconti R, et al. The relationship of 30 vitamin D receptor haplotypes to urinary supersaturation of calcium oxalate salts and to age at onset and familial prevalence of nephrolithiasis. Nephrol Dial Transplant 2004;19:2259–65. 16. Nishijima S, Sugaya K, Naito A, et al. Association of vitamin D receptor gene polymorphism with urolithiasis. J Urol 2002;167: 2188–91. 17. Mittal RD, Mishra DK, Srivastava P, et al. Polymorphisms in the vitamin D receptor and the androgen receptor gene associated with the risk of urolithiasis. Indian J Clin Biochem 2010;25: 119–26.
