http://informahealthcare.com/rst ISSN: 1079-9893 (print), 1532-4281 (electronic) J Recept Signal Transduct Res, Early Online: 1–5 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10799893.2014.919592
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by National University of Singapore on 06/07/14 For personal use only.
RESEARCH ARTICLE
Association of vitamin D receptor BsmI gene polymorphism with the risk of type 2 diabetes mellitus Bo Zhu, Hui-Liu Zhao, Chao Ou, Ling-Sha Huang, Pei-Zhang Li, and Ming Lao Department of Clinical laboratory, The Affiliated Tumor Hospital of Guangxi Medical University, NanNing, Guangxi Province, China
Abstract
Keywords
Relationship between vitamin D receptor (VDR) BsmI (rs1544410) gene polymorphism and the type 2 diabetes mellitus (T2DM) susceptibility is still conflicting at present. This meta-analysis was conducted to assess the association between VDR BsmI gene polymorphism and the risk of T2DM. The association studies were identified from PubMed, and Cochrane Library on 1 January 2014, and eligible investigations were included and synthesized using meta-analysis method. Eleven reports were recruited into this meta-analysis for the association of VDR BsmI gene polymorphism with T2DM susceptibility. In overall populations, B allele, BB genotype and bb genotype were not associated with T2DM risk. VDR BsmI gene polymorphism was also not associated with the T2DM risk in Asians and Caucasians. In conclusion, VDR BsmI gene polymorphism was also not associated with T2DM risk in overall populations, Asians and Caucasians. However, more studies should be conducted to confirm it.
Gene polymorphism, meta-analysis, type 2 diabetes mellitus, vitamin D receptor
Introduction Low vitamin D status has been shown to be a risk factor for several metabolic traits such as obesity, diabetes and cardiovascular disease, and the biological actions of 1, 25dihydroxyvitamin D, are mediated through the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor, gamma (1). VDR, a member of the nuclear receptor superfamily, mediates vitamin D signaling involved in cellular growth and differentiation (2,3). Vitamin D status is reported to correlate negatively with insulin production and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM) (4). The present data indicated that VDR gene polymorphism was associated with the risk of T2DM. BsmI (rs1544410) gene polymorphism is one of the most important gene mutation types of VDR. T2DM exerts a substantial economic burden on patients, health care systems, and society (5).T2DM is one of the most common chronic diseases, and it is a complex disorder influenced by both genetic and environmental factors. However, the etiology of T1DM is not clear. Current evidence indicates that gene polymorphism of some genes are associated with the susceptibility of T2DM. Gene polymorphism factor has been reported to be an important factor which was associated with the susceptibility
Address for correspondence: Chao Ou, Department of Clinical laboratory, The Affiliated Tumor Hospital of Guangxi Medical University, NanNing, Guangxi Province 530021, China. E-mail: [email protected]
History Received 26 March 2014 Accepted 27 April 2014 Published online 19 May 2014
of T2DM. Most of the epidemiologic investigations studying the relationship between VDR BsmI gene polymorphism and the T2DM 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. We performed this meta-analysis to investigate whether the VDR BsmI gene polymorphism was associated with the risk of T2DM.
Materials and methods Search strategy for the relationship between vitamin D receptor BsmI gene polymorphism and the risk of diabetes mellitus The relevant studies were searched from the electronic databases of PubMed, and Cochrane Library on 1 January 2014. The retrieval strategy of ‘‘(vitamin D receptor OR VDR) and (diabetes mellitus)’’ was entered into these databases. The additional reports were identified through references cited in recruited articles. Inclusion and exclusion criteria Inclusion criteria (1) The outcome had to be diabetes mellitus; (2) There had to be at least two comparison groups (case group versus control group); (3) Investigation should provide the data of VDR BsmI genotype distribution.
2
B. Zhu et al.
J Recept Signal Transduct Res, Early Online: 1–5
Exclusion criteria (1) Review articles and editorials; (2) Case reports; (3) Preliminary result not on VDR gene polymorphism or outcome; (4) Investigating the role VDR BsmI 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.
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by National University of Singapore on 06/07/14 For personal use only.
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 BsmI genotypes. The results were compared and disagreement was resolved by discussion. Statistical analysis Cochrane Review Manager Version 5 (Cochrane Library, RevMan, Version 5, Oxford, UK) was used to calculate the available data from each study. The pooled statistic was 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 (6,7). 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 (8,9). I2 was used to test the heterogeneity among the included studies. A chi-square test using a web-based program was applied to determine if genotype distribution of the control population reported conformed to Hardy–Weinberg equilibrium (HWE) (HWE; p50.05 was considered significant), and sensitivity analysis according to HWE was tested. Sensitivity assessment based on the source of the controls (healthy versus hospital) was also conducted.
Results Study characteristics Eleven studies (10–20) reporting the relationship between VDR BsmI gene polymorphism and T2DM susceptibility were recruited into this meta-analysis (Table 1). The data of our interest were extracted (Table 1). Six studies (14,16–20) were from Asian populations and five studies (10–13,15) were
from Caucasians. Those 11 investigations contained 1650 patients with lung cancer and 2608 controls. Association of VDR BsmI gene polymorphism with T2DM susceptibility In this meta-analysis, in overall populations, we found that VDR BsmI B allele was not associated with T2DM risk, and BB genotype and bb genotype were also not associated with T2DM risk (B allele: OR ¼ 1.21, 95% CI: 0.89–1.64, p ¼ 0.23; BB genotype: OR ¼ 0.87, 95% CI: 0.62– 1.21, p ¼ 0.40; bb genotype: OR ¼ 0.75, 95% CI: 0.51–1.09, p ¼ 0.14; Figures 1–3 and Table 2). In Asian population, B allele and BB genotype were not associated with the risk of T2DM, and the BB genotype was also not associated with the risk of T2DM (B allele: OR ¼ 1.68, 95% CI: 0.73–3.85, p ¼ 0.22; BB genotype: OR ¼ 1.07, 95% CI: 0.40–2.83, p ¼ 0.90; bb genotype: OR ¼ 0.59, 95% CI: 0.25–1.39, p ¼ 0.23; Table 2). In Caucasians, no association was found between VDR BsmI gene polymorphism and T2DM risk (B allele: OR ¼ 1.00, 95% CI: 0.88–1.13, p ¼ 0.96; BB genotype: OR ¼ 0.96, 95% CI: 0.78–1.18, p ¼ 0.71; bb genotype: OR ¼ 0.98, 95% CI: 0.81–1.18, p ¼ 0.80; Table 2). Sensitivity analysis Sensitivity analysis according to genotype distribution of the control population for VDR BsmI gene polymorphism conformed to HWE for the relationship between VDR BsmI gene polymorphism and T2DM risk. One study (12) in Caucasians was not in HWE. The results from sensitivity analysis for Asians according to HWE were the same as those from non-sensitivity analysis (Table 2). The sensitivity analysis results for overall populations and in Caucasians were similar to results from non-sensitivity analysis (Table 2). Sensitivity assessment based on the source of the controls (healthy versus hospital) was also conducted, and all the source of the controls was from healthy. So, the results from the sensitivity analysis were the same to those from nonsensitivity analysis.
Discussion The genetic factor for T2DM risk is a focus of research at present, and the etiology of T2DM is not elucidated now.
Table 1. Characteristics of the studies evaluating the effects of VDR gene polymorphism on T2DM risk. Case
Control
Author, Year
Ethnicity
Country/Subgroup
Source of control
BB
Bb
bb
Total
BB
Bb
bb
Total
HWE
Speer 2001 Ye 2001 Oh 2002 Malecki 2003 Shen 2004 Shi 2007 Xu 2007 Zhang 2008 Bid 2009 Lan 2009 Vedralova´ 2012
Caucasian Caucasian Caucasian Caucasian Asian Asian Asian Asian Asian Asian Caucasian
Hungary France USA Poland China China China China India China Czech Republic
Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy
7 52 49 85 3 1 41 4 30 5 43
23 135 107 159 34 17 46 41 52 13 47
19 119 86 64 59 139 19 71 18 48 14
49 306 242 308 96 157 106 116 100 66 104
26 24 253 77 0 1 68 0 60 0 30
66 65 590 110 7 18 28 15 77 5 33
46 54 460 52 45 177 6 97 23 75 20
138 143 1303 239 52 196 102 112 160 80 83
0.787 0.557 0.01 0.284 0.603 0.47 0.192 0.448 0.831 0.773 0.079
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by National University of Singapore on 06/07/14 For personal use only.
DOI: 10.3109/10799893.2014.919592
Association of VDR BsmI with T2DM
Figure 1. Association of VDR BsmI B allele with T2DM susceptibility in overall populations.
Figure 2. Association of VDR BsmI BB genotype with T2DM susceptibility in overall populations.
Figure 3. Association of VDR BsmI bb genotype with T2DM susceptibility in overall populations.
3
4
B. Zhu et al.
J Recept Signal Transduct Res, Early Online: 1–5
Table 2. Meta-analysis of the association of VDR gene polymorphism with T2DM risk. Group and subgroups
Studies number
Q test p value
Model selected
Overall Asian Caucasian Overall Asian Caucasian Overall Asian Caucasian
11 6 5 11 6 5 11 6 5
50.00001 50.00001 0.47 0.01 0.009 0.67 50.00001 50.00001 0.41
Random Random Fixed Random Random Fixed Random Random Fixed
1.21 1.68 1.00 0.87 1.07 0.96 0.75 0.59 0.98
(0.89–1.64) (0.73–3.85) (0.88–1.13) (0.62–1.21) (0.40–2.83) (0.78–1.18) (0.51–1.09) (0.25–1.39) (0.81–1.18)
0.23 0.22 0.96 0.40 0.90 0.71 0.14 0.23 0.80
Sensitivity analysis according to HWE B versus b Overall Asian Caucasian BB versus Bb+bb Overall Asian Caucasian bb versus Bb+BB Overall Asian Caucasian
10 6 4 10 6 4 10 6 4
50.00001 50.00001 0.32 0.01 0.009 0.58 50.00001 50.00001 0.27
Random Random Fixed Random Random Fixed Random Random Fixed
1.27 1.68 0.99 0.85 1.07 0.91 0.71 0.59 0.95
(0.87–1.85) (0.73–3.85) (0.84–1.16) (0.57–1.26) (0.40–2.83) (0.71–1.18) (0.45–1.13) (0.25–1.39) (0.74–1.22)
0.22 0.22 0.87 0.41 0.90 0.49 0.15 0.23 0.69
Genetic contrasts B versus b BB versus Bb+bb
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by National University of Singapore on 06/07/14 For personal use only.
bb versus Bb+BB
There were a lot of significant evidences indicating that the VDR had participated in the etiology of T2DM, and some studies found that the VDR BsmI gene mutation might affect the VDR activation to play the multifunctional physiological processes. However, findings on the association of VDR BsmI gene polymorphism with the susceptibility of T2DM have been controversial since the first investigation was reported. In this meta-analysis, we investigated whether the VDR BsmI gene polymorphism could become a valuable indicator to predict the risk of T2DM, and tried to draw a more robust conclusion. In this meta-analysis, in overall populations, B allele, BB genotype and bb genotype were not associated with T2DM. This no association was also found in Asians and Caucasians. However, more studies with larger sample size should be performed in the future. Li et al. (21) performed a meta-analysis to explore the relationship between VDR BsmI gene polymorphism and T2DM risk including eight studies, and reported that there was no statistical evidence of an association between the BsmI polymorphism and overall T2DM risks. Our results were similar to Li et al. (21). However, the sample size in our study was larger, and the results in our meta-analysis might be more robust. This meta-analysis indicated that there was no an association between VDR BsmI B allele, bb genotype and T1DM risk in Asians, in Caucasians and in overall populations. 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, VDR BsmI B allele, BB genotype and bb genotype were not associated with T2DM risk in Asians, in Caucasians and in overall populations. However, more studies with larger sample size should be conducted to confirm it.
OR (95% CI)
p
Declaration of interest The authors declare no competing interests.
References 1. Vimaleswaran KS, Cavadino A, Berry DJ, et al. Interaction between allelic variations in vitamin D receptor and retinoid X receptor genes on metabolic traits. BMC Genet 2014;15:37. 2. Zerr P, Vollath S, Palumbo-Zerr K, et al. Vitamin D receptor regulates TGF-beta signalling in systemic sclerosis. Ann Rheum Dis 2014 (epub ahead of print). 3. Cheng J, Fang ZZ, Kim JH, et al. Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in vitamin D receptor intestine-deficient mice. J Lipid Res 2014;55:455–65. 4. Jehle S, Lardi A, Felix B, et al. Effect of large doses of parenteral vitamin D on glycaemic control and calcium/phosphate metabolism in patients with stable type 2 diabetes mellitus: a randomised, placebo-controlled, prospective pilot study. Swiss Med Wkly 2014; 144:w13942. 5. Meyers JL, Parasuraman S, Bell KF, et al. The high-cost, type 2 diabetes mellitus patient: an analysis of managed care administrative data. Arch Public Health 2014;72:6. 6. 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. 7. Zhou TB, Qin YH, Su LN, et al. The association between angiotensin-converting enzyme insertion/deletion gene variant and risk of focal segmental glomerulosclerosis: a systematic review and meta-analysis. J Renin Angiotensin Aldosterone Syst 2011;12: 624–33. 8. 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. 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. 10. Speer G, Cseh K, Winkler G, et al. Vitamin D and estrogen receptor gene polymorphisms in type 2 diabetes mellitus and in android type obesity. Eur J Endocrinol 2001;144:385–9. 11. Ye WZ, Reis AF, Dubois-Laforgue D, et al. Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset. Eur J Endocrinol 2001;145:181–6. 12. Oh JY, Barrett-Connor E. Association between vitamin D receptor polymorphism and type 2 diabetes or metabolic syndrome in community-dwelling older adults: the Rancho Bernardo Study. Metabolism 2002;51:356–9.
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by National University of Singapore on 06/07/14 For personal use only.
DOI: 10.3109/10799893.2014.919592
13. Malecki MT, Frey J, Moczulski D, et al. Vitamin D receptor gene polymorphisms and association with type 2 diabetes mellitus in a Polish population. Exp Clin Endocrinol Diabetes 2003;111:505–9. 14. Bid HK, Konwar R, Aggarwal CG, et al. Vitamin D receptor (FokI, BsmI and TaqI) gene polymorphisms and type 2 diabetes mellitus: a North Indian study. Indian J Med Sci 2009;63:187–94. 15. Vedralova M, Kotrbova-Kozak A, Zeleznikova V, et al. Polymorphisms in the vitamin D receptor gene and parathyroid hormone gene in the development and progression of diabetes mellitus and its chronic complications, diabetic nephropathy and non-diabetic renal disease. Kidney Blood Press Res 2012;36:1–9. 16. Shen B. The association of vitamin D receptor gene Polymorphism with diabetes mellitus in the Han nationality of Tianjin area (Chinese) [thesis]. Tianjin: Tianjin Medical University; 2004. Available from: http://d.wanfangdata.com.cn/Thesis_Y627633.aspx
Association of VDR BsmI with T2DM
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17. Shi Y, Shen Y, Cai L, et al. Relationship between angiotensin converting enzyme gene polymorphism and diabetes mellitus. Chin J Diabetes 2007;15:219–21. 18. Xu J, Lu Y, Geng H, et al. Association between the polymorphism of human vitamin D receptor gene and type 2 diabetes. J Clin Rehab Tissue Eng Res 2007;11:5881–3. 19. Zhang P, Su W, Shen B, et al. Association between vitamin D receptor gene polymorphism and type 2 diabetes mellitus of Han nationality in Tianjin. Tianjin Med J 2008;36:255–7. 20. Lan X, Huo X. Association of vitamin D receptor gene FokI polymorphism and type 2 diabetes. Strait Pharmaceutical J 2009; 21:141–2. 21. Li L, Wu B, Liu JY, Yang LB. Vitamin D receptor gene polymorphisms and type 2 diabetes: a meta-analysis. Arch Med Res 2013;44:235–41.
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by National University of Singapore on 06/07/14 For personal use only.
RESEARCH ARTICLE
Association of vitamin D receptor BsmI gene polymorphism with the risk of type 2 diabetes mellitus Bo Zhu, Hui-Liu Zhao, Chao Ou, Ling-Sha Huang, Pei-Zhang Li, and Ming Lao Department of Clinical laboratory, The Affiliated Tumor Hospital of Guangxi Medical University, NanNing, Guangxi Province, China
Abstract
Keywords
Relationship between vitamin D receptor (VDR) BsmI (rs1544410) gene polymorphism and the type 2 diabetes mellitus (T2DM) susceptibility is still conflicting at present. This meta-analysis was conducted to assess the association between VDR BsmI gene polymorphism and the risk of T2DM. The association studies were identified from PubMed, and Cochrane Library on 1 January 2014, and eligible investigations were included and synthesized using meta-analysis method. Eleven reports were recruited into this meta-analysis for the association of VDR BsmI gene polymorphism with T2DM susceptibility. In overall populations, B allele, BB genotype and bb genotype were not associated with T2DM risk. VDR BsmI gene polymorphism was also not associated with the T2DM risk in Asians and Caucasians. In conclusion, VDR BsmI gene polymorphism was also not associated with T2DM risk in overall populations, Asians and Caucasians. However, more studies should be conducted to confirm it.
Gene polymorphism, meta-analysis, type 2 diabetes mellitus, vitamin D receptor
Introduction Low vitamin D status has been shown to be a risk factor for several metabolic traits such as obesity, diabetes and cardiovascular disease, and the biological actions of 1, 25dihydroxyvitamin D, are mediated through the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor, gamma (1). VDR, a member of the nuclear receptor superfamily, mediates vitamin D signaling involved in cellular growth and differentiation (2,3). Vitamin D status is reported to correlate negatively with insulin production and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM) (4). The present data indicated that VDR gene polymorphism was associated with the risk of T2DM. BsmI (rs1544410) gene polymorphism is one of the most important gene mutation types of VDR. T2DM exerts a substantial economic burden on patients, health care systems, and society (5).T2DM is one of the most common chronic diseases, and it is a complex disorder influenced by both genetic and environmental factors. However, the etiology of T1DM is not clear. Current evidence indicates that gene polymorphism of some genes are associated with the susceptibility of T2DM. Gene polymorphism factor has been reported to be an important factor which was associated with the susceptibility
Address for correspondence: Chao Ou, Department of Clinical laboratory, The Affiliated Tumor Hospital of Guangxi Medical University, NanNing, Guangxi Province 530021, China. E-mail: [email protected]
History Received 26 March 2014 Accepted 27 April 2014 Published online 19 May 2014
of T2DM. Most of the epidemiologic investigations studying the relationship between VDR BsmI gene polymorphism and the T2DM 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. We performed this meta-analysis to investigate whether the VDR BsmI gene polymorphism was associated with the risk of T2DM.
Materials and methods Search strategy for the relationship between vitamin D receptor BsmI gene polymorphism and the risk of diabetes mellitus The relevant studies were searched from the electronic databases of PubMed, and Cochrane Library on 1 January 2014. The retrieval strategy of ‘‘(vitamin D receptor OR VDR) and (diabetes mellitus)’’ was entered into these databases. The additional reports were identified through references cited in recruited articles. Inclusion and exclusion criteria Inclusion criteria (1) The outcome had to be diabetes mellitus; (2) There had to be at least two comparison groups (case group versus control group); (3) Investigation should provide the data of VDR BsmI genotype distribution.
2
B. Zhu et al.
J Recept Signal Transduct Res, Early Online: 1–5
Exclusion criteria (1) Review articles and editorials; (2) Case reports; (3) Preliminary result not on VDR gene polymorphism or outcome; (4) Investigating the role VDR BsmI 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.
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by National University of Singapore on 06/07/14 For personal use only.
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 BsmI genotypes. The results were compared and disagreement was resolved by discussion. Statistical analysis Cochrane Review Manager Version 5 (Cochrane Library, RevMan, Version 5, Oxford, UK) was used to calculate the available data from each study. The pooled statistic was 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 (6,7). 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 (8,9). I2 was used to test the heterogeneity among the included studies. A chi-square test using a web-based program was applied to determine if genotype distribution of the control population reported conformed to Hardy–Weinberg equilibrium (HWE) (HWE; p50.05 was considered significant), and sensitivity analysis according to HWE was tested. Sensitivity assessment based on the source of the controls (healthy versus hospital) was also conducted.
Results Study characteristics Eleven studies (10–20) reporting the relationship between VDR BsmI gene polymorphism and T2DM susceptibility were recruited into this meta-analysis (Table 1). The data of our interest were extracted (Table 1). Six studies (14,16–20) were from Asian populations and five studies (10–13,15) were
from Caucasians. Those 11 investigations contained 1650 patients with lung cancer and 2608 controls. Association of VDR BsmI gene polymorphism with T2DM susceptibility In this meta-analysis, in overall populations, we found that VDR BsmI B allele was not associated with T2DM risk, and BB genotype and bb genotype were also not associated with T2DM risk (B allele: OR ¼ 1.21, 95% CI: 0.89–1.64, p ¼ 0.23; BB genotype: OR ¼ 0.87, 95% CI: 0.62– 1.21, p ¼ 0.40; bb genotype: OR ¼ 0.75, 95% CI: 0.51–1.09, p ¼ 0.14; Figures 1–3 and Table 2). In Asian population, B allele and BB genotype were not associated with the risk of T2DM, and the BB genotype was also not associated with the risk of T2DM (B allele: OR ¼ 1.68, 95% CI: 0.73–3.85, p ¼ 0.22; BB genotype: OR ¼ 1.07, 95% CI: 0.40–2.83, p ¼ 0.90; bb genotype: OR ¼ 0.59, 95% CI: 0.25–1.39, p ¼ 0.23; Table 2). In Caucasians, no association was found between VDR BsmI gene polymorphism and T2DM risk (B allele: OR ¼ 1.00, 95% CI: 0.88–1.13, p ¼ 0.96; BB genotype: OR ¼ 0.96, 95% CI: 0.78–1.18, p ¼ 0.71; bb genotype: OR ¼ 0.98, 95% CI: 0.81–1.18, p ¼ 0.80; Table 2). Sensitivity analysis Sensitivity analysis according to genotype distribution of the control population for VDR BsmI gene polymorphism conformed to HWE for the relationship between VDR BsmI gene polymorphism and T2DM risk. One study (12) in Caucasians was not in HWE. The results from sensitivity analysis for Asians according to HWE were the same as those from non-sensitivity analysis (Table 2). The sensitivity analysis results for overall populations and in Caucasians were similar to results from non-sensitivity analysis (Table 2). Sensitivity assessment based on the source of the controls (healthy versus hospital) was also conducted, and all the source of the controls was from healthy. So, the results from the sensitivity analysis were the same to those from nonsensitivity analysis.
Discussion The genetic factor for T2DM risk is a focus of research at present, and the etiology of T2DM is not elucidated now.
Table 1. Characteristics of the studies evaluating the effects of VDR gene polymorphism on T2DM risk. Case
Control
Author, Year
Ethnicity
Country/Subgroup
Source of control
BB
Bb
bb
Total
BB
Bb
bb
Total
HWE
Speer 2001 Ye 2001 Oh 2002 Malecki 2003 Shen 2004 Shi 2007 Xu 2007 Zhang 2008 Bid 2009 Lan 2009 Vedralova´ 2012
Caucasian Caucasian Caucasian Caucasian Asian Asian Asian Asian Asian Asian Caucasian
Hungary France USA Poland China China China China India China Czech Republic
Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy
7 52 49 85 3 1 41 4 30 5 43
23 135 107 159 34 17 46 41 52 13 47
19 119 86 64 59 139 19 71 18 48 14
49 306 242 308 96 157 106 116 100 66 104
26 24 253 77 0 1 68 0 60 0 30
66 65 590 110 7 18 28 15 77 5 33
46 54 460 52 45 177 6 97 23 75 20
138 143 1303 239 52 196 102 112 160 80 83
0.787 0.557 0.01 0.284 0.603 0.47 0.192 0.448 0.831 0.773 0.079
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by National University of Singapore on 06/07/14 For personal use only.
DOI: 10.3109/10799893.2014.919592
Association of VDR BsmI with T2DM
Figure 1. Association of VDR BsmI B allele with T2DM susceptibility in overall populations.
Figure 2. Association of VDR BsmI BB genotype with T2DM susceptibility in overall populations.
Figure 3. Association of VDR BsmI bb genotype with T2DM susceptibility in overall populations.
3
4
B. Zhu et al.
J Recept Signal Transduct Res, Early Online: 1–5
Table 2. Meta-analysis of the association of VDR gene polymorphism with T2DM risk. Group and subgroups
Studies number
Q test p value
Model selected
Overall Asian Caucasian Overall Asian Caucasian Overall Asian Caucasian
11 6 5 11 6 5 11 6 5
50.00001 50.00001 0.47 0.01 0.009 0.67 50.00001 50.00001 0.41
Random Random Fixed Random Random Fixed Random Random Fixed
1.21 1.68 1.00 0.87 1.07 0.96 0.75 0.59 0.98
(0.89–1.64) (0.73–3.85) (0.88–1.13) (0.62–1.21) (0.40–2.83) (0.78–1.18) (0.51–1.09) (0.25–1.39) (0.81–1.18)
0.23 0.22 0.96 0.40 0.90 0.71 0.14 0.23 0.80
Sensitivity analysis according to HWE B versus b Overall Asian Caucasian BB versus Bb+bb Overall Asian Caucasian bb versus Bb+BB Overall Asian Caucasian
10 6 4 10 6 4 10 6 4
50.00001 50.00001 0.32 0.01 0.009 0.58 50.00001 50.00001 0.27
Random Random Fixed Random Random Fixed Random Random Fixed
1.27 1.68 0.99 0.85 1.07 0.91 0.71 0.59 0.95
(0.87–1.85) (0.73–3.85) (0.84–1.16) (0.57–1.26) (0.40–2.83) (0.71–1.18) (0.45–1.13) (0.25–1.39) (0.74–1.22)
0.22 0.22 0.87 0.41 0.90 0.49 0.15 0.23 0.69
Genetic contrasts B versus b BB versus Bb+bb
Journal of Receptors and Signal Transduction Downloaded from informahealthcare.com by National University of Singapore on 06/07/14 For personal use only.
bb versus Bb+BB
There were a lot of significant evidences indicating that the VDR had participated in the etiology of T2DM, and some studies found that the VDR BsmI gene mutation might affect the VDR activation to play the multifunctional physiological processes. However, findings on the association of VDR BsmI gene polymorphism with the susceptibility of T2DM have been controversial since the first investigation was reported. In this meta-analysis, we investigated whether the VDR BsmI gene polymorphism could become a valuable indicator to predict the risk of T2DM, and tried to draw a more robust conclusion. In this meta-analysis, in overall populations, B allele, BB genotype and bb genotype were not associated with T2DM. This no association was also found in Asians and Caucasians. However, more studies with larger sample size should be performed in the future. Li et al. (21) performed a meta-analysis to explore the relationship between VDR BsmI gene polymorphism and T2DM risk including eight studies, and reported that there was no statistical evidence of an association between the BsmI polymorphism and overall T2DM risks. Our results were similar to Li et al. (21). However, the sample size in our study was larger, and the results in our meta-analysis might be more robust. This meta-analysis indicated that there was no an association between VDR BsmI B allele, bb genotype and T1DM risk in Asians, in Caucasians and in overall populations. 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, VDR BsmI B allele, BB genotype and bb genotype were not associated with T2DM risk in Asians, in Caucasians and in overall populations. However, more studies with larger sample size should be conducted to confirm it.
OR (95% CI)
p
Declaration of interest The authors declare no competing interests.
References 1. Vimaleswaran KS, Cavadino A, Berry DJ, et al. Interaction between allelic variations in vitamin D receptor and retinoid X receptor genes on metabolic traits. BMC Genet 2014;15:37. 2. Zerr P, Vollath S, Palumbo-Zerr K, et al. Vitamin D receptor regulates TGF-beta signalling in systemic sclerosis. Ann Rheum Dis 2014 (epub ahead of print). 3. Cheng J, Fang ZZ, Kim JH, et al. Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in vitamin D receptor intestine-deficient mice. J Lipid Res 2014;55:455–65. 4. Jehle S, Lardi A, Felix B, et al. Effect of large doses of parenteral vitamin D on glycaemic control and calcium/phosphate metabolism in patients with stable type 2 diabetes mellitus: a randomised, placebo-controlled, prospective pilot study. Swiss Med Wkly 2014; 144:w13942. 5. Meyers JL, Parasuraman S, Bell KF, et al. The high-cost, type 2 diabetes mellitus patient: an analysis of managed care administrative data. Arch Public Health 2014;72:6. 6. 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. 7. Zhou TB, Qin YH, Su LN, et al. The association between angiotensin-converting enzyme insertion/deletion gene variant and risk of focal segmental glomerulosclerosis: a systematic review and meta-analysis. J Renin Angiotensin Aldosterone Syst 2011;12: 624–33. 8. 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. 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. 10. Speer G, Cseh K, Winkler G, et al. Vitamin D and estrogen receptor gene polymorphisms in type 2 diabetes mellitus and in android type obesity. Eur J Endocrinol 2001;144:385–9. 11. Ye WZ, Reis AF, Dubois-Laforgue D, et al. Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset. Eur J Endocrinol 2001;145:181–6. 12. Oh JY, Barrett-Connor E. Association between vitamin D receptor polymorphism and type 2 diabetes or metabolic syndrome in community-dwelling older adults: the Rancho Bernardo Study. Metabolism 2002;51:356–9.
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DOI: 10.3109/10799893.2014.919592
13. Malecki MT, Frey J, Moczulski D, et al. Vitamin D receptor gene polymorphisms and association with type 2 diabetes mellitus in a Polish population. Exp Clin Endocrinol Diabetes 2003;111:505–9. 14. Bid HK, Konwar R, Aggarwal CG, et al. Vitamin D receptor (FokI, BsmI and TaqI) gene polymorphisms and type 2 diabetes mellitus: a North Indian study. Indian J Med Sci 2009;63:187–94. 15. Vedralova M, Kotrbova-Kozak A, Zeleznikova V, et al. Polymorphisms in the vitamin D receptor gene and parathyroid hormone gene in the development and progression of diabetes mellitus and its chronic complications, diabetic nephropathy and non-diabetic renal disease. Kidney Blood Press Res 2012;36:1–9. 16. Shen B. The association of vitamin D receptor gene Polymorphism with diabetes mellitus in the Han nationality of Tianjin area (Chinese) [thesis]. Tianjin: Tianjin Medical University; 2004. Available from: http://d.wanfangdata.com.cn/Thesis_Y627633.aspx
Association of VDR BsmI with T2DM
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17. Shi Y, Shen Y, Cai L, et al. Relationship between angiotensin converting enzyme gene polymorphism and diabetes mellitus. Chin J Diabetes 2007;15:219–21. 18. Xu J, Lu Y, Geng H, et al. Association between the polymorphism of human vitamin D receptor gene and type 2 diabetes. J Clin Rehab Tissue Eng Res 2007;11:5881–3. 19. Zhang P, Su W, Shen B, et al. Association between vitamin D receptor gene polymorphism and type 2 diabetes mellitus of Han nationality in Tianjin. Tianjin Med J 2008;36:255–7. 20. Lan X, Huo X. Association of vitamin D receptor gene FokI polymorphism and type 2 diabetes. Strait Pharmaceutical J 2009; 21:141–2. 21. Li L, Wu B, Liu JY, Yang LB. Vitamin D receptor gene polymorphisms and type 2 diabetes: a meta-analysis. Arch Med Res 2013;44:235–41.
