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Association of vitamin D receptor gene rs739837 polymorphism with type 2 diabetes and gestational diabetes mellitus susceptibility: a systematic review and meta-analysis
European Journal of Medical Research volume 27, Article number: 65 (2022)
Increasing evidence shows that genetic variants of genes in the diabetes mellitus (DM) metabolic pathway, such as the vitamin D receptor (VDR) gene rs739837 polymorphism, increase the risk of DM susceptibility. However, the findings have been inconsistent. The present study was performed to evaluate the association of VDR gene rs739837 and type 2 diabetes (T2DM) or gestational diabetes mellitus (GDM) risk.
A comprehensive meta-analysis and a subgroup analysis were conducted to assess the association between VDR rs739837 and T2DM or GDM among five genetic models (dominant, recessive, homozygote heterozygote, and allele models) using a fixed or random model.
The meta-analysis included 9 studies. In the overall analysis, the results showed that VDR rs739837 was associated with an increased risk of T2DM or GDM in the allele model (T vs. G: OR = 1.088; 95% CI: 1.018–1.163; P = 0.012) and dominant model (TT + GT vs. GG: OR = 1.095; 95% CI: 1.001–1.197; P = 0.047). In the subgroup analysis, VDR rs739837 was also associated with an increased risk of T2DM in the allele model (T vs. G: OR = 1.159; 95% CI: 1.055–1.273; P = 0.002) and dominant model (TT + GT vs. GG: OR = 1.198; 95% CI: 1.048–1.370; P = 0.008). However, VDR rs739837 was not associated with GDM.
Significant associations were found between the VDR rs739837 polymorphism and T2DM susceptibility, but not with GDM.
Diabetes mellitus (DM) is a common chronic disorder that includes type 1 DM (T1DM), type 2 DM (T2DM), gestational DM (GDM) and other types of DM with T2DM accounting for the majority of the DM cases . T2DM is a disease of multifactorial etiologies caused by insulin resistance and impaired insulin secretion . Increasing evidence indicates that genetic factors contribute to T2DM susceptibility . Moreover, genetic variations associated with insulin resistance and β-cell dysfunction have been suggested to play key roles in the development of GDM [4, 5]. Studies have shown that women with a history of GDM are at an increased risk of developing T2DM [6,7,8], and women with a family history of diabetes may have an increased risk of GDM . Thus, GDM may share similar genetic susceptibilities and risk factors with T2DM [10,11,12].
Vitamin D (Vit D) has important immunoregulatory immune characteristics. Supplementation with vitamin D has been shown to prevent the development of T2DM . Conversely, the depletion of vitamin D may be involved in the etiology of T2DM by influencing insulin secretion [14, 15]. Increasing evidence shows that genetic variants of genes in the DM metabolic pathway may increase the risk of DM susceptibility, such as the vitamin D receptor (VDR) gene, which is located on human chromosome 12q13.11 and is primarily expressed in the pancreas . Alterations in VDR activation and expression may increase fatty acid synthase expression and lipogenesis [17, 18], resulting in a reduction in lipolysis and lipid deposition . In addition, abnormal VDR expression contributes to calcium signal-mediated lipid accumulation through the p38 MAPK pathway , which results in high lipid deposition in the liver, disturbs insulin signaling and causes β-cell dysfunction . Abnormal VDR expression may play an important role in the development of T2DM.
The rs739837 polymorphism is located in the 3′-untranslated region (UTR) of the VDR gene, and the rs739837 variation may affect VDR posttranscriptional regulation by binding with microRNA . MiRNAs play an important role in the regulation of gene expression; thus, SNPs in the seed sites of miRNA targets may create or destroy miRNA-binding sites and further affect phenotypes and disease susceptibility . We queried rs739837 polymorphism located in predicted miRNA target sites through the "MirSNP" database (http://bioinfo.bjmu.edu.cn/mirsnp/search/), which showed that rs739837 destroyed, created or disrupted putative miRNA target sites (Fig. 1). This polymorphism may affect the normal expression of VDR and further increase the risk of DM . In recent years, several studies have shown associations of VDR rs739837 with T2DM [25,26,27,28,29] or GDM [30,31,32], but the results are controversial. Therefore, we conducted a meta-analysis to evaluate the association of VDR rs739837 with the risk of T2DM and GDM.
Materials and methods
The present meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.
The Google Scholar, PubMed and Chinese National Knowledge Infrastructure databases were systematically searched for relevant studies using the following terms:
(1) “VDR” or “vitamin D receptor” or “rs739837” or “polymorphism” or “type 2 diabetes mellitus” and “T2DM”; and (2) “VDR” or “vitamin D receptor” or “rs739837” or “polymorphism” and “gestational diabetes mellitus” and “GDM”.
The search was performed with no date or language restrictions. All the studies were evaluated by reading the title and abstract to exclude irrelevant studies. The full texts of eligible studies were then assessed by reading the full text to confirm inclusion in the study.
Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) case–control/cohort studies; (2) studies that evaluated the association between VDR SNP rs739837 and T2DM/GDM; (3) adequate raw data or sufficient data to calculate odds ratios (ORs) with corresponding 95% confidence intervals (CIs); (4) a T2DM diagnosis based on the clinical criteria of the World Health Organization; and (5) a GDM diagnosis based on the clinical criteria of the World Health Organization.
The exclusion criteria were as follows: (1) not a case–control/cohort study; (2) not related to VDR SNP rs739837 and T2DM/GDM; (3) insufficient data; and (4) non-diabetic mellitus (NDM) subject data not in Hardy—Weinberg equilibrium (HWE).
Two authors independently extracted the following data from the included studies:
first author; origin; year of publication; type of DM; numbers of T2DM/GDM patients and NDM controls; distribution of alleles and genotypes; and ORs with 95% CIs of the allele distribution.
The following five genetic models were evaluated for rs739837: dominant model (TT + GT vs. GG), recessive model (TT vs. GG + GT), homozygote model (TT vs. GG), heterozygote model (GT vs. GG) and allele model (T vs. G). Genetic heterogeneity was estimated using the Q-test and I2 test. Lower heterogeneity was defined as I2 < 50% and P > 0.01 when using the fixed effects model (Mantel–Haenszel) to calculate ORs with corresponding 95% CIs. Otherwise, the random effects model (Mantel–Haenszel) was used [33, 34]. The significance of the ORs was evaluated using the Z test. Begg’s and Egger’s tests were used to determine publication bias. STATA v.14.0 software (Stata Corporation, TX, USA) was used to perform all statistical analyses.
Study inclusion and characteristics
A total of 89 studies were searched using the inclusion and exclusion criteria. Figure 2 shows a flowchart of the study selection process. The following 9 eligible studies were included in the final analysis: 5 arteticles, which included 6 studies related to VDR SNP rs739837 and T2DM (one study only had allele mode data); and 3 articles, which included 3 studies related to VDR SNP rs739837 and GDM. The characteristics of each included study are shown in Table 1.
Overall heterogeneity analysis
Low heterogeneity among studies was detected in the allele model (T vs. G: I2 = 0.0%; P = 0.472) [25,26,27,28,29,30,31,32], homozygote model (TT vs. GG: I2 = 0.0%; P = 0.787), heterozygote model (GT vs. GG: I2 = 0.0%; P = 0.996) and dominant model (TT + GT vs. GG: I2 = 1.5%; P = 0.418). High heterogeneity was detected in the recessive model (TT vs. GG + GT: I2 = 82.9%; P < 0.001) [25, 26, 28,29,30,31,32] (Fig. 3).
Subgroup heterogeneity analysis
In the T2DM subgroup, low heterogeneity among studies was detected in the allele model (T vs. G: I2 = 0.0%; P = 0.652) [25,26,27,28,29], homozygote model (TT vs. GG: I2 = 0.0%; P = 0.675), heterozygote model (GT vs. GG: I2 = 0.0%; P = 0.936) and dominant model (TT + GT vs. GG: I2 = 0.0%; P = 0.595). High heterogeneity was detected in the recessive model (TT vs. GG + GT: I2 = 86.6%; P < 0.001) [25, 26, 28, 29] (Fig. 4).
In the GDM subgroup, low heterogeneity among studies was detected in the allele model (T vs. G: I2 = 0.0%; P = 0.635), homozygote model (TT vs. GG: I2 = 0.0%; P = 0.850), heterozygote model (GT vs. GG: I2 = 0.0%; P = 0.971), recessive model (TT vs. GG + GT: I2 = 0.0%; P = 0.829) and dominant model (TT + GT vs. GG: I2 = 0.0%; P = 0.553) [30,31,32] (Fig. 4).
Overall meta-analysis results
In the overall analysis, a fixed effects model was used to analyze the allele, homozygote, heterozygote and dominant models. VDR rs739837 was shown to be significantly associated with increased DM (T2DM and GDM) risk in the allele model (T vs. G: OR = 1.088; 95% CI: 1.018–1.163; P = 0.012) and dominant model (TT + GT vs. GG: OR = 1.095; 95% CI: 1.001–1.197; P = 0.047). No significant associations were found under the homozygote model (TT vs. GG: OR = 1.144; 95% CI: 0.973–1.346; P = 0.103) and heterozygote model (GT vs. GG: OR = 1.073; 95% CI: 0.909–1.266; P = 0.406). A random effects model indicated no significant difference for the recessive model (TT vs. GG + GT: OR = 0.764; 95% CI: 0.517–1.129; P = 0.177) (Fig. 3).
Subgroup meta-analysis results
We performed subgroup analysis according to the type of DM to evaluate the association between VDR rs739837 and T2DM or GDM susceptibility.
In the T2DM subgroup, the results showed that rs739837 was significantly related to an increased risk of T2DM in the allele model (T vs. G: OR = 1.159; 95% CI: 1.055–1.273; P = 0.002) and dominant model (TT + GT vs. GG: OR = 1.198; 95% CI: 1.048–1.370; P = 0.008) using a fixed effects model. No significant associations were found under the homozygote model (TT vs. GG: OR = 1.273; 95% CI: 0.992–1.633; P = 0.058) or heterozygote model (GT vs. GG: OR = 1.094; 95% CI: 0.849–1.410; P = 0.486) using a fixed effects model. A random effects model also showed that no significant difference was found for the recessive model (TT vs. GG + GT: OR = 0.269; 95% CI: 0.684–0.349; P = 0.269) (Fig. 4).
In the GDM subgroup, no significant associations were found under the allele model (T vs. G: OR = 1.023; 95% CI: 0.932–1.123; P = 0.631), homozygote model (TT vs. GG: OR = 1.060; 95% CI: 0.857–1.313; P = 0.590), heterozygote model (GT vs. GG: OR = 1.057; 95% CI: 0.850–1.315; P = 0.618), recessive model (TT vs. GG + GT: OR = 0.931; 95% CI: 0.758–1.143; P = 0.493) or dominant model (TT + GT vs. GG: OR = 1.018; 95% CI: 0.903–1.148; P = 0.765) using a fixed effects model (Fig. 4).
According to Begg’s and Egger’s tests, no significant publication bias was found in any of the genetic models (all P > 0.05, Additional file 1: Tables S1–S3), and the funnel plots are shown in Figs. 5, 6.
In this systematic review and meta-analysis study, we performed a systematic and objective assessment of the associations between the VDR rs739837 polymorphism and DM. The findings of the meta-analysis of 9 case–control studies in the overall type of DM determined a significant association of the T allele and TT + GT genotype with DM risk. Moreover, the subgroup analysis also revealed that rs739837 was significantly related to an increased risk of T2DM in the T allele and TT + GT genotype, but no significant associations were found under any models in the GDM subgroup.
The VDR gene has been confirmed to be significantly involved in the regulation of the endocrine system, suggesting that it is a potential candidate gene for metabolic disorders. Rs739837 is located in the 3′-untranslated region (UTR) of the VDR gene, which regulates gene expression. A series of investigations have reported that the rs739837 SNP is associated with diabetes risk. Zhang et al. demonstrated a significant association between the T allele and TT + GT genotype of rs739837 and T2DM risk . Yu et al. found a significant relationship between the rs739837 polymorphism and T2DM in the T allele, recessive model (GG/GT + TT) and additive model (GG/TT) . A previous study has identified that the rs739837 genotype distributions show significant differences across T2DM cases and controls . Interestingly, Jia et al. found that the T and C allele frequencies of rs739837 are 70.2% and 29.8% in cases, respectively, and 73 and 27%, in controls, respectively. The control group results reported by Jia et al. were inconsistent with other reports; they reported that rs739837 is significantly associated with an increased risk of T2DM in the additive model (TT vs. TC vs. CC) and dominant (TT vs. TC/CC) model . Due to the differences in allele frequencies from other reports, the study by Jia et al. was not included in the meta-analysis. Vimaleswaran and Lin showed that rs739837 is not associated with T2DM risk [27, 29]. Moreover, four studies demonstrated no relationship between the genotypic model of rs739837 and GD [30,31,32, 36]. A previous meta-analysis has suggested that women with a history of GDM are almost 10 times more likely to develop T2DM than those with a normoglycemic pregnancy . The magnitude of this risk is consistent with evidence that T2DM and GDM share common pathogenic mechanisms and risk factors.
Interestingly, in the overall analysis, low heterogeneity among studies was detected in the allele, dominant, homozygote and heterozygote genetic models, and high heterogeneity among studies was detected under the recessive model as well as in the subgroup analysis. Although the GDM studies only contained women, there was no significant heterogeneity in the meta-analysis with T2DM research involving men and women, except for the recessive model. The subtype analysis revealed that the T2DM group had higher heterogeneity, while the GDM group had lower heterogeneity. Therefore, it was possible to combine T2DM and GDM for meta-analysis to explore potential common susceptibility factors. However, due to the small GDM sample size, there was no powerful conclusion of the results.
There were several limitations in the present meta-analysis. First, there were limited studies that estimated VDR rs739837 and T2DM or GDM risk. In particular, few articles have researched the association between VDR rs739837 and GDM. Only three articles contained data from five genetic models, and one article did not have available data for meta-analysis, which may affect the overall estimation. Moreover, the present study included only Chinese studies. Thus, studies using larger sample sizes of other ethnic groups worldwide need to be performed. Finally, the present study only evaluated the association between rs739837 genotypes and T2DM or GDM risk without adjusting the effects of other risk factors, such as interacting gene–gene and gene–environment factors . Therefore, further study is required to evaluate the susceptibility factors of T2DM or GDM.
To our knowledge, this study is the first to assess the role of VDR rs739837 and T2DM or GDM risk. Significant associations were found between the VDR rs739837 polymorphism and T2DM susceptibility but not association with GDM.
Availability of data and materials
All data used or generated during the study are available from the corresponding author on reasonable request: Runmin Guo, E-mail: firstname.lastname@example.org.
A Kautzky Willer J Harreiter G Pacini 2016 Sex and gender differences in risk pathophysiology and complications of type diabetes mellitus Endocr Rev 37 3 278 316
M Banerjee P Vats 2014 Reactive metabolites and antioxidant gene polymorphisms in type 2 diabetes mellitus Indian J Hum Genet 20 1 10 19
Y Tian J Xu T Huang 2019 A novel polymorphism (rs35612982) in CDKAL1 is a risk factor of type 2 diabetes: a case-control study Kidney Blood Press Res 44 6 1313 1326
SH Kwak SH Kim YM Cho 2012 A genome-wide association study of gestational diabetes mellitus in Korean women Diabetes 61 2 531 541
L Wu WH Cui Tam, 2016 Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis Sci Rep 6 30539
L Bellamy JP Casas AD Hingorani 2009 Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis Lancet 373 9677 1773 1779
E Vounzoulaki K Khunti SC Abner 2020 Progression to type 2 diabetes in women with a known history of gestational diabetes systematic review and meta-analysis BMJ (Clin Res Ed) 369 m1361
H You J Hu Y Liu 2021 Risk of type 2 diabetes mellitus after gestational diabetes mellitus: a systematic review & meta-analysis Indian J Med Res 154 1 62 77
MA Williams C Qiu JC Dempsey 2003 Familial aggregation of type 2 diabetes and chronic hypertension in women with gestational diabetes mellitus J Reprod Med 48 12 955 962
H Mao Q Li S Gao 2012 Meta-analysis of the relationship between common type 2 diabetes risk gene variants with gestational diabetes mellitus PLoS ONE 7 9 e45882
SY Rhee JY Kim JT Woo 2010 Familial clustering of type 2 diabetes in Korean women with gestational diabetes mellitus Korean J Intern Med 25 3 269 272
J Pu B Zhao EJ Wang 2015 Racial/Ethnic differences in gestational diabetes prevalence and contribution of common risk factors Paediatr Perinat Epidemiol 29 5 436 443
IH Boer de LF Tinker S Connelly 2008 Calcium plus vitamin D supplementation and the risk of incident diabetes in the women's health initiative Diabetes Care 31 4 701 707
K Müller K Bendtzen 1992 Inhibition of human T lymphocyte proliferation and cytokine production by 1,25-dihydroxyvitamin D3. differential effects on CD45RA+ and CD45R0+ cells Autoimmunity 14 1 37 43
X Palomer JM González-Clemente F Blanco-Vaca 2008 Role of vitamin D in the pathogenesis of type 2 diabetes mellitus obesity metabolism Diabetes Obes Metab 10 3 185 197
JA Johnson JP Grande PC Roche 1994 Immunohistochemical localization of the 1,25(OH)2D3 receptor and calbindin D28k in human and rat pancreas Am J Physiol 267 3 Pt 1 E356 E360
LM McCann J Beto 2010 Roles of calcium-sensing receptor and vitamin d receptor in the pathophysiology of secondary hyperparathyroidism J Ren Nutr 20 3 141 150
MB Zemel 2002 Regulation of adiposity and obesity risk by dietary calcium: mechanisms and implications J Am Coll Nutr 21 2 146S 151S
RE Duncan M Ahmadian K Jaworski 2007 Regulation of lipolysis in adipocytes Annu Rev Nutr 27 79 101
C Sun R Qi L Wang 2012 p38 MAPK regulates calcium signal-mediated lipid accumulation through changing VDR expression in primary preadipocytes of mice Mol Biol Rep 39 3 3179 3184
J Sonnenberg VN Luine LC Krey 1986 1,25-Dihydroxyvitamin D3 treatment results in increased choline acetyltransferase activity in specific brain nuclei Endocrinology 118 4 1433 1439
DP Bartel 2004 MicroRNAs: genomics, biogenesis, mechanism, and function Cell 116 2 281 297
BM Ryan AI Robles CC Harris 2010 Genetic variation in microRNA networks: the implications for cancer research Nat Rev Cancer 10 6 389 402
D Saccone F Asani L Bornman 2015 Regulation of the vitamin D receptor gene by environment, genetics and epigenetics Gene 561 2 171 180
D Zhang C Cheng Y Wang 2021 The influence of VDR polymorphisms on the type 2 diabetes susceptibility in Chinese: an interaction with hypertriglyceridemia Mol Genet Genomics 296 4 837 844
C Yu LWang Wang 2017 Study and evaluation the impact of vitamin D receptor variants on the risk of type 2 diabetes mellitus in Han Chinese J Diabetes 9 3 275 284
KS Vimaleswaran C Power E Hyppönen 2014 Interaction between vitamin D receptor gene polymorphisms and 25-hydroxyvitamin D concentrations on metabolic and cardiovascular disease outcomes Diabetes Metab 40 5 386 389
JR Xu Y Yang XM Liu 2014 Association of VDR polymorphisms with type 2 diabetes mellitus in Chinese Han and Hui populations Genet Mol Res 13 4 9588 9598
XH Lin Study the relationship of clinical index and gene polymorphisms with the diabetic retinopathy Doctoral Dissertation of Chongqing Medical University (in Chinese)
J Liu Q Dai W Li 2021 Association of vitamin D receptor gene polymorphisms with gestational diabetes mellitus-a case control study in Wuhan China BMC Pregnancy Childbirth 21 1 142
Y Wang O Wang W Li 2015 Variants in vitamin D binding protein gene are associated with gestational diabetes mellitus Medicine 94 40 e1693
H Chen M XIAO J SUN 2021 Association of polymorphisms in vitamin D receptor gene with gestational diabetes mellitus J Practical Med 37 22 2866 2870 in Chinese
Q Zeng D Zou Q Zeng 2021 Association between insulin-like growth factor-1 rs35767 polymorphism and type 2 diabetes mellitus susceptibility: a meta-analysis Front Genet 12 774489
Q Han W Geng D Zhang 2020 ADIPOQ rs2241766 gene polymorphism and predisposition to diabetic kidney disease J Diabetes Res 2020 5158497
J Jia H Ding K Yang 2015 Vitamin D receptor genetic polymorphism is significantly associated with risk of type 2 diabetes mellitus in Chinese Han population Arch Med Res 46 7 572 579
A Shi J Wen G Liu 2016 Genetic variants in vitamin D signaling pathways and risk of gestational diabetes mellitus Oncotarget 7 42 67788 67795
Y Wu Y Ding Y Tanaka 2014 Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention Int J Med Sci 11 11 1185 1200
Support for this work includes funding from the National Natural Science Foundation of China (81873649); Doctoral scientific research Initiate funding project of Shunde Women and Children’s Hospital of Guangdong Medical University (Maternity & Child Healthcare Hospital of Shunde Foshan) (2020BSQD007); Guangdong Medical University Research Foundation (GDMUM2020008 and GDMUM2020012); Medical Research Project of Foshan Health Bureau (20210188 and 20210289).
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Additional file 1:
Table S1 Begg’s and Egger’s tests in overall analysis. Table S2 Begg’s and Egger’s tests in T2DM subgroup analysis. Table S3 Begg’s and Egger’s tests in GDM subgroup analysis.
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Zeng, Q., Zou, D., Wei, Y. et al. Association of vitamin D receptor gene rs739837 polymorphism with type 2 diabetes and gestational diabetes mellitus susceptibility: a systematic review and meta-analysis. Eur J Med Res 27, 65 (2022). https://doi.org/10.1186/s40001-022-00688-x
- Type 2 diabetes mellitus
- Gestational diabetes mellitus
- Vitamin D receptor