http://informahealthcare.com/rst ISSN: 1079-9893 (print), 1532-4281 (electronic) J Recept Signal Transduct Res, Early Online: 1–7 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10799893.2014.922577
Association of vitamin D receptor gene polymorphism with the risk of systemic lupus erythematosus
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Tian-Biao Zhou1, Zong-Pei Jiang1, Zhi-Jun Lin2, and Ning Su1 1
Department of Nephrology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China and 2Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China Abstract
Keywords
Relationship between vitamin D receptor (VDR) gene polymorphism and the risk of systemic lupus erythematosus (SLE) from the published reports are still conflicting. This study was conducted to evaluate the relationship between VDR BsmI (rs1544410), Fok1 (rs2228570), ApaI (rs7975232) and TaqI (rs731236) gene polymorphism and the risk of SLE using meta-analysis method. The association studies were identified from PubMed and Cochrane Library on 1 March 2014, and eligible investigations were included and synthesized using meta-analysis method. Thirteen reports were recruited into this meta-analysis for the association of VDR gene polymorphism with SLE susceptibility. In this meta-analysis for overall populations, the BsmI B allele and bb genotype, Fok1 f allele and ff genotype, and ApaI aa genotype, were associated with the risk of SLE. In Asians, the BsmI B allele, BB genotype and bb genotype, Fok1 f allele and ff genotype were associated with the risk of SLE. In Africans, the BsmI B allele, BB genotype and bb genotype, Fok1 f allele and ff genotype, ApaI A allele, AA genotype and aa genotype were associated with the risk of SLE. However, VDR BsmI, Fok1, ApaI and TaqI gene polymorphism were not associated with the risk of SLE in Caucasians. In conclusion, the BsmI B allele and bb genotype, Fok1 f allele and ff genotype were associated with the risk of SLE in overall populations, and in Asians, but these associations were not found in Caucasians. However, more studies should be conducted to confirm it.
Gene polymorphism, meta-analysis, systemic lupus erythematosus, vitamin D receptor
Introduction Vitamin D has been recently associated with several renal, cardiovascular and inflammatory diseases, beyond mineral metabolism and bone health, and this is due in part to widespread expression of vitamin D receptor (VDR) on tissues and cells, such as heart, kidney, immune cells, brain and muscle (1). There have been several polymorphisms named according to the restriction sites, such as VDR BsmI (rs1544410), Fok1 (rs2228570), ApaI (rs7975232) and TaqI (rs731236), etc. VDR gene polymorphisms have been reported to influence susceptibility to some diseases, such as metabolic syndrome (2), type 1 diabetes mellitus (3), rheumatoid arthritis and rheumatoid-related osteoporosis (4). Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder, and the genetic background and environmental factors can influence the SLE onset (5,6). It is characterized clinically by heterogeneous clinical manifestations and target tissue damage, including joints, skin and kidney (7). There lacks a well-documented diagnostic
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 22 April 2014 Revised 1 May 2014 Accepted 06 May 2014 Published online 22 May 2014
approach for the SLE risk, and the etiology of SLE is not clear. Current evidence indicates that gene polymorphism of some genes are associated with the susceptibility of SLE. Gene polymorphism factor has been reported to be an important factor which increases the susceptibility of SLE. Most of the epidemiologic investigations studying the relationship between VDR gene polymorphism and the SLE 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 metaanalysis might be powerful compared with the individual investigation. We performed this meta-analysis to investigate whether the VDR gene polymorphism was associated with the risk of SLE, by widely collecting the reported studies.
Materials and methods Search strategy for the relationship between vitamin D receptor gene polymorphism and the risk of systemic lupus erythematosus The relevant studies were searched from the electronic databases of PubMed and Cochrane Library on 1 March 2014. The retrieval strategy of ‘‘(vitamin D receptor OR VDR) and (systemic lupus erythematosus OR SLE)’’ was entered into these databases. The additional reports were identified through references cited in recruited articles.
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T.-B. Zhou et al.
J Recept Signal Transduct Res, Early Online: 1–7
Inclusion and exclusion criteria
Results
Inclusion criteria: (1) The outcome had to be systemic lupus erythematosus; (2) there had to be at least two comparison groups (case group versus control group); (3) investigation should provide the data of VDR genotype distribution. Exclusion criteria: (1) Review articles and editorials; (2) case reports; (3) preliminary result not on VDR gene polymorphism or outcome; (4) investigating the role of VDR gene expression to disease; (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
Data extraction and synthesis
Association of VDR BsmI gene polymorphism with SLE susceptibility
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 (Cochrane Library, Version 5, Oxford, UK) was used to calculate the available data from each study. The pooled statistics were counted using the fixed 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.
Thirteen studies (12–24) reporting the relationship between VDR gene polymorphism and SLE susceptibility were recruited into this meta-analysis (Table 1). The data of our interest were extracted (Table 1). Nine studies (12,14,16,17,20–24) were for BsmI (rs1544410) gene polymorphism, six studies (13–15,19,21,22) were for Fok1 (rs2228570) gene polymorphism and three studies (14,18,22) were for VDR ApaI (rs7975232) gene polymorphism, and one study (22) was for TaqI (rs731236) gene polymorphism.
In this meta-analysis, we found that VDR BsmI B allele and bb genotype were associated with SLE risk, but the BB genotype was not associated with the risk of SLE in overall populations (B allele: OR ¼ 1.60, 95% CI: 1.05– 2.45, p ¼ 0.03; BB genotype: OR ¼ 1.19, 95% CI: 0.76–1.86, p ¼ 0.45; bb genotype: OR ¼ 0.51, 95% CI: 0.29–0.89, p ¼ 0.02; Figure 1 and Table 2). In Asian population and in African population, B allele, BB genotype and bb genotype were associated with the risk of SLE (Table 2). However, BsmI B allele, BB genotype and bb genotype were not associated with SLE risk in Caucasian population (Table 2). Association of VDR Fok1 gene polymorphism with SLE susceptibility In this meta-analysis, we found that VDR Fok1 f allele and ff genotype were associated with SLE risk, but the association for FF genotype was not found in overall
Table 1. Characteristics of the studies evaluating the effects of VDR gene polymorphism on SLE risk. Gene sites
Author, Year
Ethnicity
Country/ Subgroup
Source of control
Ozaki, 2000 Huang, 2002 Sakulpipatsin, 2006 Abbasi, 2010 Monticielo, 2012
Asian Asian Asian Caucasian Mix Caucasian Asian Caucasian Caucasian African
Japan China Thailand Iran Brazil Brazil China Poland Poland Egypt
Population Population Population Population Population Population Population Population Population Population
Mostowska, 2013 Bogaczewicz, 2013 Emerah, 2013
Asian Asian Mix Caucasian Caucasian Caucasian African
China China Brazil Brazil Poland Poland Egypt
Population Population Population Population Population Population Population
Luo, 2012 Mostowska, 2013 Emerah, 2013
Asian Caucasian African
China Poland Egypt
Population Population Population
Mostowska, 2013
Caucasian
Poland
Population
BB
Bb
Case bb
Total
BB
Bb
Control bb
Total
9 2 2 14 23 20 8 28 9 20 ff 7 57 16 11 40 7 35 AA 67 78 25 tt 28
25 33 22 36 82 61 47 121 20 59 Ff 34 98 74 56 113 38 50 Aa 95 118 43 Tt 122
24 12 77 10 58 40 282 109 33 28 FF 11 116 83 64 105 17 22 aa 82 62 39 TT 108
58 47 101 60 163 121 337 258 62 107 Total 52 271 173 131 258 62 107 Total 244 258 107 Total 258
5 3 2 15 31 31 3 82 17 8 ff 26 36 5 5 100 18 63 AA 57 152 15 tt 81
10 9 31 21 97 97 22 245 42 55 Ff 43 61 18 18 243 53 58 Aa 36 257 49 Tt 247
72 78 161 9 73 73 214 218 41 66 FF 21 33 19 19 202 29 8 aa 69 136 65 TT 217
87 90 194 45 201 201 239 545 100 129 Total 90 130 42 42 545 100 129 Total 162 545 129 Total 545
BsmI
Luo, 2012 Mostowska, 2013 Kaleta, 2013 Emerah, 2013 Fok1 Huang, 2002 Luo, 2011 Monticielo, 2012
ApaI
TaqI
Association of VDR with SLE
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DOI: 10.3109/10799893.2014.922577
Figure 1. Association of VDR BsmI gene polymorphism with SLE susceptibility in overall populations.
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Table 2. Meta analysis of the association of VDR gene polymorphism with SLE risk. Genetic contrasts BsmI B versus b
BB versus Bb + bb
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bb versus Bb + BB
Fok1 f versus F
ff versus Ff + FF
FF versus Ff + ff
ApaI A versus a
AA versus Aa + aa
aa versus AA + Aa
TaqI t versus T tt versus Tt + TT TT versus Tt + tt
Group and subgroups
Studies number
Q test p value
Model selected
Overall Asian Caucasian African Overall Asian Caucasian African Overall Asian Caucasian African
9 4 4 1 9 4 4 1 9 4 4 1
50.0001 0.0002 0.51 – 0.03 0.88 0.63 – 50.00001 50.00001 0.42 –
Random Random Fixed Fixed Random Fixed Fixed Fixed Random Random Fixed Fixed
1.60 2.91 0.90 2.27 1.19 2.16 0.78 3.48 0.51 0.25 1.08 0.34
(1.05, (1.42, (0.77, (1.55, (0.76, (1.05, (0.57, (1.46, (0.29, (0.08, (0.86, (0.19,
2.45) 5.99) 1.06) 3.33) 1.86) 4.47) 1.07) 8.26) 0.89) 0.72) 1.35) 0.59)
0.03 0.004 0.21 50.0001 0.45 0.04 0.12 0.005 0.02 0.01 0.54 0.0001
Overall Asian Caucasian African Overall Asian Caucasian African Overall Asian Caucasian African
6 2 3 1 6 2 3 1 6 2 3 1
0.13 0.44 0.99 – 0.62 0.26 0.79 – 0.02 0.06 0.84 –
Fixed Fixed Fixed Fixed Fixed Fixed Fixed Fixed Random Random Fixed Fixed
0.75 0.65 0.87 0.51 0.66 0.60 0.76 0.51 1.42 1.49 1.13 1.49
(0.65, (0.51, (0.73, (0.35, (0.52, (0.39, (0.54, (0.30, (0.96, (0.61, (0.87, (0.61,
0.86) 0.84) 1.05) 0.75) 0.83) 0.92) 1.08) 0.87) 2.11) 3.61) 1.46) 3.61)
50.0001 0.001 0.15 0.0006 0.0006 0.02 0.13 0.01 0.08 0.38 0.36 0.38
Overall Asian Caucasian African Overall Asian Caucasian African Overall Asian Caucasian African
3 1 1 1 3 1 1 1 3 1 1 1
0.06 – – – 0.01 – – – 0.21 – – –
Random Fixed Fixed Fixed Random Fixed Fixed Fixed Fixed Fixed Fixed Fixed
1.20 1.03 1.07 1.74 1.14 0.70 1.12 2.32 0.77 0.68 0.95 0.56
(0.91, (0.77, (0.87, (1.19, (0.66, (0.45, (0.81, (1.15, (0.61, (0.45, (0.67, (0.33,
1.58) 1.36) 1.32) 2.54) 1.99) 1.07) 1.55) 4.67) 0.97) 1.03) 1.34) 0.95)
0.20 0.86 0.54 0.004 0.63 0.10 0.49 0.02 0.03 0.07 0.78 0.03
Caucasian Caucasian Caucasian
1 1 1
– – –
populations (f allele: OR ¼ 0.75, 95% CI: 0.65–0.86, p50.0001; ff genotype: OR ¼ 0.66, 95% CI: 0.52–0.83, p ¼ 0.0006; FF genotype: OR ¼ 1.42, 95% CI: 0.96–2.11, p ¼ 0.08; Figure 2 and Table 2). In Asian population and in Africans, VDR Fok1 f allele and ff genotype were associated with SLE risk, but the association for FF genotype was not found. However, f allele, ff genotype and FF genotype were not associated with SLE risk in Caucasian population (Table 2). Association of VDR ApaI gene polymorphism with SLE susceptibility In this meta-analysis, we found that VDR ApaI aa genotype was associated with SLE risk, but the A allele and AA genotype were not associated with SLE risk in overall populations (A allele: OR ¼ 1.20, 95% CI: 0.91– 0.91, p ¼ 0.20; AA genotype: OR ¼ 1.14, 95% CI: 0.66–1.99, p ¼ 0.63; aa genotype: OR ¼ 0.77, 95% CI: 0.61–0.97, p ¼ 0.03; Figure 3 and Table 2).
Fixed Fixed Fixed
OR (95% CI)
0.88 (0.70, 1.09) 0.70 (0.44, 1.10) 1.09 (0.81, 1.47)
p
0.24 0.12 0.58
In Africans, VDR ApaI A allele, AA genotype and aa genotype were associated with SLE risk (Table 2). However, A allele, AA genotype and aa genotype were not associated with SLE risk in Asian population and in Caucasian population (Table 2). Association of VDR TaqI gene polymorphism with SLE susceptibility In this meta-analysis, we found there is only one report from Caucasian population. VDR TaqI t allele, tt genotype and TT genotype were not associated with SLE risk in Caucasian population (t allele: OR ¼ 0.88, 95% CI: 0.70–1.09, p ¼ 0.24; tt genotype: OR ¼ 0.70, 95% CI: 0.44–1.10, p ¼ 0.12; TT genotype: OR ¼ 1.09, 95% CI: 0.81–1.47, p ¼ 0.58; Table 2).
Discussion In this meta-analysis, VDR BsmI B allele and bb genotype were associated with SLE risk, but the BB genotype was not
Association of VDR with SLE
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DOI: 10.3109/10799893.2014.922577
Figure 2. Association of VDR Fok1 gene polymorphism with SLE susceptibility in overall populations.
associated with the risk of SLE in overall populations. There were nine studies included for this meta-analysis, and the results for overall populations might be robust to some extent. Furthermore, in Asian population and in African population, B allele, BB genotype and bb genotype were associated with the risk of SLE. However, BsmI B allele, BB genotype and bb genotype were not associated with SLE risk in Caucasian population. The number of studies included for Asian population, African population or Caucasian population was small, and the results might be less robust. More studies for
the association between VDR BsmI gene polymorphism and SLE risk should be performed in the future. In this meta-analysis for VDR Fok1, f allele and ff genotype were associated with SLE risk, but the association for FF genotype was not found in overall populations. There were six included studies for this meta-analysis, and the results for overall populations might be robust to some extent. In Asian population and in Africans, VDR Fok1 f allele and ff genotype were associated with SLE risk, but the association for FF genotype was not found. However, f allele, ff genotype
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Figure 3. Association of VDR ApaI gene polymorphism with SLE susceptibility in overall populations.
and FF genotype were not associated with SLE risk in Caucasian population. The number of studies included for Asian population, African population or Caucasian population was small, and the results might be less robust. More studies for the association between VDR Fok1 gene polymorphism and SLE risk should be performed in the future. In this meta-analysis, VDR ApaI aa genotype was associated with SLE risk in overall populations, and VDR ApaI A allele, AA genotype and aa genotype were associated with SLE risk in Africans. However, A allele, AA genotype and aa genotype were not associated with SLE risk in Asian population and in Caucasian population. However, there are only three studies included for this meta-analysis, and the conclusion was less robust. More studies should be conducted in the future. In this meta-analysis, we found that there is only one report from Caucasian population. VDR TaqI t allele, tt genotype and TT genotype were not associated with SLE risk in Caucasian population. More studies should be performed to improve this conclusion.
The ApaI AA genotype, BsmI BB genotype, Fok1 f allele and Fok1 FF genotype were associated with the risk of renal cell carcinoma in Asians. However, the number of studies included was small. The conclusion might be less robust. Furthermore, VDR ApaI, BsmI, TaqI and Fok1 gene polymorphism were not associated with the risk of renal cell carcinoma in overall populations and in Caucasians. More studies in Asians and in Caucasians should be performed in the future. Earlier, Lee et al. (25) performed a meta-analysis including three studies to the associations between the BsmI, TaqI, FokI and ApaI polymorphisms of VDR and SLE, and reported that the B allele and BB genotype of the BsmI polymorphism showed significant associations with SLE in Asians. Xiong et al. (26) performed a meta-analysis including 11 casecontrol studies to detect the association between the vitamin D receptor gene polymorphisms and SLE, and indicated that the BsmI and FokI polymorphisms were associated with an increased risk of SLE. In the subgroup analysis by ethnicity, the increased risk of SLE remained in the Asian subgroup for
Association of VDR with SLE
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DOI: 10.3109/10799893.2014.922577
the BsmI and FokI polymorphism, whereas no significant association was found in other populations for other polymorphisms. Our meta-analysis included 13 studies and reported that the VDR BsmI B allele and bb genotype, Fok1 f allele and ff genotype might become a valuable indicator to predict the risk of SLE in overall populations, and in Asians. Once it is confirmed, the early prevention would be conducted and the mortality of SLE would be improved, especially in Asians. However, those findings should be regarded cautiously because many other ingredients, such as small sample size of the included report, limited statistical power, heterogeneity of enrolled cases, variable study designs and different interventions, were closely related to affect the results. In conclusion, the BsmI B allele and bb genotype, Fok1 f allele and ff genotype were associated with the risk of SLE in overall populations, and in Asians, but these associations were not found in Caucasians. However, more studies should be conducted to confirm it.
10.
11.
12.
13.
14.
15.
16.
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. 880003311300).
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18.
References 1. Gonzalez-Parra E, Rojas-Rivera J, Tunon J, et al. Vitamin D receptor activation and cardiovascular disease. Nephrol Dial Transplant 2012;27:17–21. 2. Al-Daghri NM, Al-Attas OS, Alkharfy KM, et al. Association of VDR-gene variants with factors related to the metabolic syndrome, type 2 diabetes and vitamin D deficiency. Gene 2014;542:129–33. 3. 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). 4. Mosaad YM, Hammad EM, Fawzy Z, et al. Vitamin D receptor gene polymorphism as possible risk factor in rheumatoid arthritis and rheumatoid related osteoporosis. Hum Immunol 2014;75: 452–61. 5. Salloum R, Niewold TB. Interferon regulatory factors in human lupus pathogenesis. Transl Res 2011;157:326–31. 6. Zhou TB, Jiang ZP, Qin YH, et al. Association of STAT4 gene polymorphism with systemic lupus erythematosus/lupus nephritis risk. Nephrology (Carlton) 2014 (epub ahead of print). 7. Zhou TB, Liu YG, Lin N, et al. Relationship between angiotensinconverting enzyme insertion/deletion gene polymorphism and systemic lupus erythematosus/lupus nephritis: a systematic review and metaanalysis. J Rheumatol 2012;39:686–93. 8. Zhou TB, Drummen GP, Jiang ZP, et al. Association of peroxisome proliferator-activated receptors/retinoic acid receptors with renal diseases. J Recept Signal Transduct Res 2013;33:349–52. 9. Zhou TB, Qin YH, Su LN, et al. The association between angiotensin-converting enzyme insertion/deletion gene variant and
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risk of focal segmental glomerulosclerosis: a systematic review and meta-analysis. J Renin Angiotensin Aldosterone Syst 2011;12: 624–33. Zhou TB, Qin YH, Su LN, et al. ACE I/D gene polymorphism can’t predict the steroid responsiveness in Asian children with idiopathic nephrotic syndrome: a meta-analysis. PLoS One 2011;6:e19599. 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. Abbasi M, Rezaieyazdi Z, Afshari JT, et al. Lack of association of vitamin D receptor gene BsmI polymorphisms in patients with systemic lupus erythematosus. Rheumatol Int 2010;30:1537–9. Bogaczewicz J, Kaleta B, Sysa-Jedrzejowska A, et al. Vitamin D receptor gene polymorphism Fok I in the Polish population does not contribute to the risk of systemic lupus erythematosus. Lupus 2013; 22:750–1. Emerah AA, El-Shal AS. Role of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D level in Egyptian female patients with systemic lupus erythematosus. Mol Biol Rep 2013;40:6151–62. Huang CM, Wu MC, Wu JY, et al. No association of vitamin D receptor gene start codon fok 1 polymorphisms in Chinese patients with systemic lupus erythematosus. J Rheumatol 2002;29:1211–13. Huang CM, Wu MC, Wu JY, et al. Association of vitamin D receptor gene BsmI polymorphisms in Chinese patients with systemic lupus erythematosus. Lupus 2002;11:31–4. Kaleta B, Bogaczewicz J, Robak E, et al. Vitamin D receptor gene BsmI polymorphism in polish patients with systemic lupus erythematosus. ISRN Endocrinol 2013;2013:427818. Luo XY, Wu LJ, Chen L, et al. The association of vitamin D receptor gene ApaI and BsmI polymorphism with systemic lupus erythematosus. Zhonghua Nei Ke Za Zhi 2012;51:131–5. Luo XY, Wu LJ, Yang MH, et al. Relationship of vitamin D receptor gene Fok I polymorphism with systemic lupus erythematosus. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2011;27: 901–5. Luo XY, Yang MH, Wu FX, et al. Vitamin D receptor gene BsmI polymorphism B allele, but not BB genotype, is associated with systemic lupus erythematosus in a Han Chinese population. Lupus 2012;21:53–9. Monticielo OA, Brenol JC, Chies JA, et al. The role of BsmI and FokI vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D in Brazilian patients with systemic lupus erythematosus. Lupus 2012;21:43–52. Mostowska A, Lianeri M, Wudarski M, et al. Vitamin D receptor gene BsmI, FokI, ApaI and TaqI polymorphisms and the risk of systemic lupus erythematosus. Mol Biol Rep 2013;40:803–10. Ozaki Y, Nomura S, Nagahama M, et al. Vitamin-D receptor genotype and renal disorder in Japanese patients with systemic lupus erythematosus. Nephron 2000;85:86–91. Sakulpipatsin W, Verasertniyom O, Nantiruj K, et al. Vitamin D receptor gene BsmI polymorphisms in Thai patients with systemic lupus erythematosus. Arthritis Res Ther 2006;8:R48. Lee YH, Bae SC, Choi SJ, et al. Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Mol Biol Rep 2011;38:3643–51. Xiong J, He Z, Zeng X, et al. Association of vitamin D receptor gene polymorphisms with systemic lupus erythematosus: a metaanalysis. Clin Exp Rheumatol 2014;32:174–81.
Association of vitamin D receptor gene polymorphism with the risk of systemic lupus erythematosus
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Tian-Biao Zhou1, Zong-Pei Jiang1, Zhi-Jun Lin2, and Ning Su1 1
Department of Nephrology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China and 2Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China Abstract
Keywords
Relationship between vitamin D receptor (VDR) gene polymorphism and the risk of systemic lupus erythematosus (SLE) from the published reports are still conflicting. This study was conducted to evaluate the relationship between VDR BsmI (rs1544410), Fok1 (rs2228570), ApaI (rs7975232) and TaqI (rs731236) gene polymorphism and the risk of SLE using meta-analysis method. The association studies were identified from PubMed and Cochrane Library on 1 March 2014, and eligible investigations were included and synthesized using meta-analysis method. Thirteen reports were recruited into this meta-analysis for the association of VDR gene polymorphism with SLE susceptibility. In this meta-analysis for overall populations, the BsmI B allele and bb genotype, Fok1 f allele and ff genotype, and ApaI aa genotype, were associated with the risk of SLE. In Asians, the BsmI B allele, BB genotype and bb genotype, Fok1 f allele and ff genotype were associated with the risk of SLE. In Africans, the BsmI B allele, BB genotype and bb genotype, Fok1 f allele and ff genotype, ApaI A allele, AA genotype and aa genotype were associated with the risk of SLE. However, VDR BsmI, Fok1, ApaI and TaqI gene polymorphism were not associated with the risk of SLE in Caucasians. In conclusion, the BsmI B allele and bb genotype, Fok1 f allele and ff genotype were associated with the risk of SLE in overall populations, and in Asians, but these associations were not found in Caucasians. However, more studies should be conducted to confirm it.
Gene polymorphism, meta-analysis, systemic lupus erythematosus, vitamin D receptor
Introduction Vitamin D has been recently associated with several renal, cardiovascular and inflammatory diseases, beyond mineral metabolism and bone health, and this is due in part to widespread expression of vitamin D receptor (VDR) on tissues and cells, such as heart, kidney, immune cells, brain and muscle (1). There have been several polymorphisms named according to the restriction sites, such as VDR BsmI (rs1544410), Fok1 (rs2228570), ApaI (rs7975232) and TaqI (rs731236), etc. VDR gene polymorphisms have been reported to influence susceptibility to some diseases, such as metabolic syndrome (2), type 1 diabetes mellitus (3), rheumatoid arthritis and rheumatoid-related osteoporosis (4). Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder, and the genetic background and environmental factors can influence the SLE onset (5,6). It is characterized clinically by heterogeneous clinical manifestations and target tissue damage, including joints, skin and kidney (7). There lacks a well-documented diagnostic
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 22 April 2014 Revised 1 May 2014 Accepted 06 May 2014 Published online 22 May 2014
approach for the SLE risk, and the etiology of SLE is not clear. Current evidence indicates that gene polymorphism of some genes are associated with the susceptibility of SLE. Gene polymorphism factor has been reported to be an important factor which increases the susceptibility of SLE. Most of the epidemiologic investigations studying the relationship between VDR gene polymorphism and the SLE 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 metaanalysis might be powerful compared with the individual investigation. We performed this meta-analysis to investigate whether the VDR gene polymorphism was associated with the risk of SLE, by widely collecting the reported studies.
Materials and methods Search strategy for the relationship between vitamin D receptor gene polymorphism and the risk of systemic lupus erythematosus The relevant studies were searched from the electronic databases of PubMed and Cochrane Library on 1 March 2014. The retrieval strategy of ‘‘(vitamin D receptor OR VDR) and (systemic lupus erythematosus OR SLE)’’ was entered into these databases. The additional reports were identified through references cited in recruited articles.
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by Gazi Univ. on 08/18/14 For personal use only.
2
T.-B. Zhou et al.
J Recept Signal Transduct Res, Early Online: 1–7
Inclusion and exclusion criteria
Results
Inclusion criteria: (1) The outcome had to be systemic lupus erythematosus; (2) there had to be at least two comparison groups (case group versus control group); (3) investigation should provide the data of VDR genotype distribution. Exclusion criteria: (1) Review articles and editorials; (2) case reports; (3) preliminary result not on VDR gene polymorphism or outcome; (4) investigating the role of VDR gene expression to disease; (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
Data extraction and synthesis
Association of VDR BsmI gene polymorphism with SLE susceptibility
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 (Cochrane Library, Version 5, Oxford, UK) was used to calculate the available data from each study. The pooled statistics were counted using the fixed 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.
Thirteen studies (12–24) reporting the relationship between VDR gene polymorphism and SLE susceptibility were recruited into this meta-analysis (Table 1). The data of our interest were extracted (Table 1). Nine studies (12,14,16,17,20–24) were for BsmI (rs1544410) gene polymorphism, six studies (13–15,19,21,22) were for Fok1 (rs2228570) gene polymorphism and three studies (14,18,22) were for VDR ApaI (rs7975232) gene polymorphism, and one study (22) was for TaqI (rs731236) gene polymorphism.
In this meta-analysis, we found that VDR BsmI B allele and bb genotype were associated with SLE risk, but the BB genotype was not associated with the risk of SLE in overall populations (B allele: OR ¼ 1.60, 95% CI: 1.05– 2.45, p ¼ 0.03; BB genotype: OR ¼ 1.19, 95% CI: 0.76–1.86, p ¼ 0.45; bb genotype: OR ¼ 0.51, 95% CI: 0.29–0.89, p ¼ 0.02; Figure 1 and Table 2). In Asian population and in African population, B allele, BB genotype and bb genotype were associated with the risk of SLE (Table 2). However, BsmI B allele, BB genotype and bb genotype were not associated with SLE risk in Caucasian population (Table 2). Association of VDR Fok1 gene polymorphism with SLE susceptibility In this meta-analysis, we found that VDR Fok1 f allele and ff genotype were associated with SLE risk, but the association for FF genotype was not found in overall
Table 1. Characteristics of the studies evaluating the effects of VDR gene polymorphism on SLE risk. Gene sites
Author, Year
Ethnicity
Country/ Subgroup
Source of control
Ozaki, 2000 Huang, 2002 Sakulpipatsin, 2006 Abbasi, 2010 Monticielo, 2012
Asian Asian Asian Caucasian Mix Caucasian Asian Caucasian Caucasian African
Japan China Thailand Iran Brazil Brazil China Poland Poland Egypt
Population Population Population Population Population Population Population Population Population Population
Mostowska, 2013 Bogaczewicz, 2013 Emerah, 2013
Asian Asian Mix Caucasian Caucasian Caucasian African
China China Brazil Brazil Poland Poland Egypt
Population Population Population Population Population Population Population
Luo, 2012 Mostowska, 2013 Emerah, 2013
Asian Caucasian African
China Poland Egypt
Population Population Population
Mostowska, 2013
Caucasian
Poland
Population
BB
Bb
Case bb
Total
BB
Bb
Control bb
Total
9 2 2 14 23 20 8 28 9 20 ff 7 57 16 11 40 7 35 AA 67 78 25 tt 28
25 33 22 36 82 61 47 121 20 59 Ff 34 98 74 56 113 38 50 Aa 95 118 43 Tt 122
24 12 77 10 58 40 282 109 33 28 FF 11 116 83 64 105 17 22 aa 82 62 39 TT 108
58 47 101 60 163 121 337 258 62 107 Total 52 271 173 131 258 62 107 Total 244 258 107 Total 258
5 3 2 15 31 31 3 82 17 8 ff 26 36 5 5 100 18 63 AA 57 152 15 tt 81
10 9 31 21 97 97 22 245 42 55 Ff 43 61 18 18 243 53 58 Aa 36 257 49 Tt 247
72 78 161 9 73 73 214 218 41 66 FF 21 33 19 19 202 29 8 aa 69 136 65 TT 217
87 90 194 45 201 201 239 545 100 129 Total 90 130 42 42 545 100 129 Total 162 545 129 Total 545
BsmI
Luo, 2012 Mostowska, 2013 Kaleta, 2013 Emerah, 2013 Fok1 Huang, 2002 Luo, 2011 Monticielo, 2012
ApaI
TaqI
Association of VDR with SLE
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DOI: 10.3109/10799893.2014.922577
Figure 1. Association of VDR BsmI gene polymorphism with SLE susceptibility in overall populations.
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Table 2. Meta analysis of the association of VDR gene polymorphism with SLE risk. Genetic contrasts BsmI B versus b
BB versus Bb + bb
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bb versus Bb + BB
Fok1 f versus F
ff versus Ff + FF
FF versus Ff + ff
ApaI A versus a
AA versus Aa + aa
aa versus AA + Aa
TaqI t versus T tt versus Tt + TT TT versus Tt + tt
Group and subgroups
Studies number
Q test p value
Model selected
Overall Asian Caucasian African Overall Asian Caucasian African Overall Asian Caucasian African
9 4 4 1 9 4 4 1 9 4 4 1
50.0001 0.0002 0.51 – 0.03 0.88 0.63 – 50.00001 50.00001 0.42 –
Random Random Fixed Fixed Random Fixed Fixed Fixed Random Random Fixed Fixed
1.60 2.91 0.90 2.27 1.19 2.16 0.78 3.48 0.51 0.25 1.08 0.34
(1.05, (1.42, (0.77, (1.55, (0.76, (1.05, (0.57, (1.46, (0.29, (0.08, (0.86, (0.19,
2.45) 5.99) 1.06) 3.33) 1.86) 4.47) 1.07) 8.26) 0.89) 0.72) 1.35) 0.59)
0.03 0.004 0.21 50.0001 0.45 0.04 0.12 0.005 0.02 0.01 0.54 0.0001
Overall Asian Caucasian African Overall Asian Caucasian African Overall Asian Caucasian African
6 2 3 1 6 2 3 1 6 2 3 1
0.13 0.44 0.99 – 0.62 0.26 0.79 – 0.02 0.06 0.84 –
Fixed Fixed Fixed Fixed Fixed Fixed Fixed Fixed Random Random Fixed Fixed
0.75 0.65 0.87 0.51 0.66 0.60 0.76 0.51 1.42 1.49 1.13 1.49
(0.65, (0.51, (0.73, (0.35, (0.52, (0.39, (0.54, (0.30, (0.96, (0.61, (0.87, (0.61,
0.86) 0.84) 1.05) 0.75) 0.83) 0.92) 1.08) 0.87) 2.11) 3.61) 1.46) 3.61)
50.0001 0.001 0.15 0.0006 0.0006 0.02 0.13 0.01 0.08 0.38 0.36 0.38
Overall Asian Caucasian African Overall Asian Caucasian African Overall Asian Caucasian African
3 1 1 1 3 1 1 1 3 1 1 1
0.06 – – – 0.01 – – – 0.21 – – –
Random Fixed Fixed Fixed Random Fixed Fixed Fixed Fixed Fixed Fixed Fixed
1.20 1.03 1.07 1.74 1.14 0.70 1.12 2.32 0.77 0.68 0.95 0.56
(0.91, (0.77, (0.87, (1.19, (0.66, (0.45, (0.81, (1.15, (0.61, (0.45, (0.67, (0.33,
1.58) 1.36) 1.32) 2.54) 1.99) 1.07) 1.55) 4.67) 0.97) 1.03) 1.34) 0.95)
0.20 0.86 0.54 0.004 0.63 0.10 0.49 0.02 0.03 0.07 0.78 0.03
Caucasian Caucasian Caucasian
1 1 1
– – –
populations (f allele: OR ¼ 0.75, 95% CI: 0.65–0.86, p50.0001; ff genotype: OR ¼ 0.66, 95% CI: 0.52–0.83, p ¼ 0.0006; FF genotype: OR ¼ 1.42, 95% CI: 0.96–2.11, p ¼ 0.08; Figure 2 and Table 2). In Asian population and in Africans, VDR Fok1 f allele and ff genotype were associated with SLE risk, but the association for FF genotype was not found. However, f allele, ff genotype and FF genotype were not associated with SLE risk in Caucasian population (Table 2). Association of VDR ApaI gene polymorphism with SLE susceptibility In this meta-analysis, we found that VDR ApaI aa genotype was associated with SLE risk, but the A allele and AA genotype were not associated with SLE risk in overall populations (A allele: OR ¼ 1.20, 95% CI: 0.91– 0.91, p ¼ 0.20; AA genotype: OR ¼ 1.14, 95% CI: 0.66–1.99, p ¼ 0.63; aa genotype: OR ¼ 0.77, 95% CI: 0.61–0.97, p ¼ 0.03; Figure 3 and Table 2).
Fixed Fixed Fixed
OR (95% CI)
0.88 (0.70, 1.09) 0.70 (0.44, 1.10) 1.09 (0.81, 1.47)
p
0.24 0.12 0.58
In Africans, VDR ApaI A allele, AA genotype and aa genotype were associated with SLE risk (Table 2). However, A allele, AA genotype and aa genotype were not associated with SLE risk in Asian population and in Caucasian population (Table 2). Association of VDR TaqI gene polymorphism with SLE susceptibility In this meta-analysis, we found there is only one report from Caucasian population. VDR TaqI t allele, tt genotype and TT genotype were not associated with SLE risk in Caucasian population (t allele: OR ¼ 0.88, 95% CI: 0.70–1.09, p ¼ 0.24; tt genotype: OR ¼ 0.70, 95% CI: 0.44–1.10, p ¼ 0.12; TT genotype: OR ¼ 1.09, 95% CI: 0.81–1.47, p ¼ 0.58; Table 2).
Discussion In this meta-analysis, VDR BsmI B allele and bb genotype were associated with SLE risk, but the BB genotype was not
Association of VDR with SLE
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DOI: 10.3109/10799893.2014.922577
Figure 2. Association of VDR Fok1 gene polymorphism with SLE susceptibility in overall populations.
associated with the risk of SLE in overall populations. There were nine studies included for this meta-analysis, and the results for overall populations might be robust to some extent. Furthermore, in Asian population and in African population, B allele, BB genotype and bb genotype were associated with the risk of SLE. However, BsmI B allele, BB genotype and bb genotype were not associated with SLE risk in Caucasian population. The number of studies included for Asian population, African population or Caucasian population was small, and the results might be less robust. More studies for
the association between VDR BsmI gene polymorphism and SLE risk should be performed in the future. In this meta-analysis for VDR Fok1, f allele and ff genotype were associated with SLE risk, but the association for FF genotype was not found in overall populations. There were six included studies for this meta-analysis, and the results for overall populations might be robust to some extent. In Asian population and in Africans, VDR Fok1 f allele and ff genotype were associated with SLE risk, but the association for FF genotype was not found. However, f allele, ff genotype
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Figure 3. Association of VDR ApaI gene polymorphism with SLE susceptibility in overall populations.
and FF genotype were not associated with SLE risk in Caucasian population. The number of studies included for Asian population, African population or Caucasian population was small, and the results might be less robust. More studies for the association between VDR Fok1 gene polymorphism and SLE risk should be performed in the future. In this meta-analysis, VDR ApaI aa genotype was associated with SLE risk in overall populations, and VDR ApaI A allele, AA genotype and aa genotype were associated with SLE risk in Africans. However, A allele, AA genotype and aa genotype were not associated with SLE risk in Asian population and in Caucasian population. However, there are only three studies included for this meta-analysis, and the conclusion was less robust. More studies should be conducted in the future. In this meta-analysis, we found that there is only one report from Caucasian population. VDR TaqI t allele, tt genotype and TT genotype were not associated with SLE risk in Caucasian population. More studies should be performed to improve this conclusion.
The ApaI AA genotype, BsmI BB genotype, Fok1 f allele and Fok1 FF genotype were associated with the risk of renal cell carcinoma in Asians. However, the number of studies included was small. The conclusion might be less robust. Furthermore, VDR ApaI, BsmI, TaqI and Fok1 gene polymorphism were not associated with the risk of renal cell carcinoma in overall populations and in Caucasians. More studies in Asians and in Caucasians should be performed in the future. Earlier, Lee et al. (25) performed a meta-analysis including three studies to the associations between the BsmI, TaqI, FokI and ApaI polymorphisms of VDR and SLE, and reported that the B allele and BB genotype of the BsmI polymorphism showed significant associations with SLE in Asians. Xiong et al. (26) performed a meta-analysis including 11 casecontrol studies to detect the association between the vitamin D receptor gene polymorphisms and SLE, and indicated that the BsmI and FokI polymorphisms were associated with an increased risk of SLE. In the subgroup analysis by ethnicity, the increased risk of SLE remained in the Asian subgroup for
Association of VDR with SLE
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DOI: 10.3109/10799893.2014.922577
the BsmI and FokI polymorphism, whereas no significant association was found in other populations for other polymorphisms. Our meta-analysis included 13 studies and reported that the VDR BsmI B allele and bb genotype, Fok1 f allele and ff genotype might become a valuable indicator to predict the risk of SLE in overall populations, and in Asians. Once it is confirmed, the early prevention would be conducted and the mortality of SLE would be improved, especially in Asians. However, those findings should be regarded cautiously because many other ingredients, such as small sample size of the included report, limited statistical power, heterogeneity of enrolled cases, variable study designs and different interventions, were closely related to affect the results. In conclusion, the BsmI B allele and bb genotype, Fok1 f allele and ff genotype were associated with the risk of SLE in overall populations, and in Asians, but these associations were not found in Caucasians. However, more studies should be conducted to confirm it.
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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. 880003311300).
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