|Year : 2022 | Volume
| Issue : 7 | Page : 1163-1172
The relationship between vitamin D receptor gene polymorphisms and periodontitis in turkish individuals with type 2 diabetes mellitus
A Saatman Yildiz1, FD Ustundag2, P Mega Tiber3, B Dogan4
1 Department of Periodontology, Institute of Health Sciences, Marmara University, Istanbul, Turkey
2 Department of Biophysics, Institute of Health Sciences, Istanbul, Turkey
3 Department of Biophysics, Faculty of Medicine, Marmara University, Istanbul, Turkey
4 Department of Periodontology, Faculty of Dentistry, Marmara University, Istanbul, Turkey
|Date of Submission||18-Oct-2021|
|Date of Acceptance||25-May-2022|
|Date of Web Publication||20-Jul-2022|
Prof. B Dogan
Recep Tayyip Erdogan Külliyesi Saglik Yerleskesi, Basibüyük Yolu 9/3 34854 Basibüyük, Maltepe, Istanbul
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background and Aim: Vitamin D receptor (VDR) gene polymorphisms have been implicated in the pathogenesis of many diseases, such as periodontitis and diabetes mellitus (DM). The present study aimed to evaluate the distributions of VDR polymorphisms in diabetic individuals with healthy periodontium (DMH), diabetic individuals with periodontitis (DMP), nondiabetic individuals with healthy periodontium (H), and nondiabetic individuals with periodontitis (P). Material and Methods: A total of 200 individuals (DMH = 40, DMP = 60, H = 40, and P = 60) were recruited. All clinical periodontal parameters, demographical, and biochemical variables were recorded. Blood samples were collected, and genomic DNA was isolated by Purelink® Genomic DNA Mini Kit. Genotyping of VDR polymorphisms ApaI, BsmI, FokI, and TaqI were determined by real-time polymerase chain reaction (PCR) using allele-specific probes. Results: The distribution of the BsmI variant showed differences between DMH and H groups (P = 0.034). In addition, carrying the GG genotype (OR = 0.317; 95% CI = 0.126–0.797; P = 0.013) and the G allele (OR = 2.373; 95% CI = 1.203–4.681; P = 0.012) increased the risk of type 2 DM. Moreover, it was determined that the frequency of CC genotype of FokI variant was higher in DMP compared to DMH (P = 0.046). It was determined that having the CC genotype (OR = 2.706; 95% CI = 1.185–6.176; P = 0.017) and the C allele (OR = 1.917; 95% CI = 0.995–3.694; P = 0.049) increased the risk of periodontitis among diabetic individuals. No differences were detected among groups in the genotype and allele distributions of ApaI and TaqI variants (P > 0.05). Conclusions: The present study showed that the BsmI variant was a risk factor for DM among periodontally healthy individuals and the FokI variant for periodontitis among diabetic individuals.
Keywords: Periodontitis, polymorphism, type 2 diabetes mellitus, vitamin D
|How to cite this article:|
Yildiz A S, Ustundag F D, Tiber P M, Dogan B. The relationship between vitamin D receptor gene polymorphisms and periodontitis in turkish individuals with type 2 diabetes mellitus. Niger J Clin Pract 2022;25:1163-72
|How to cite this URL:|
Yildiz A S, Ustundag F D, Tiber P M, Dogan B. The relationship between vitamin D receptor gene polymorphisms and periodontitis in turkish individuals with type 2 diabetes mellitus. Niger J Clin Pract [serial online] 2022 [cited 2022 Aug 15];25:1163-72. Available from: https://www.njcponline.com/text.asp?2022/25/7/1163/351463
| Introduction|| |
Periodontitis, a chronic inflammatory disease, is caused by the host's response to the pathogenic microflora in dental plaque, resulting in the destruction of the gingiva, supportive connective tissue, and alveolar bone, which are the structural components of the periodontium., According to the extensive and epidemiologic pieces of evidence, several risk factors play roles in the initiation, progression, and severity of periodontitis. Having multiple of these significantly increases the risk of periodontitis. These factors can be modifiable or nonmodifiable. The modifiable risk factors such as diabetes mellitus, use of tobacco, and obesity are generally environmental and behavioral. Eliminating or modifying these risk factors as part of the management of periodontal disease may provide positive results on the prognosis. However, the nonmodifiable risk factors such as genetic factors, pregnancy, and age are usually individual-specific and cannot be changed. Therefore, identifying people at risk for adverse outcomes helps in deciding interventions for the management of periodontitis.,
Diabetes mellitus (DM) as a metabolic disease is characterized by hyperglycemia caused by a deficiency in insulin action, insulin secretion, or both. A bilateral relationship has been described between DM and periodontitis. Periodontitis is associated with an enhanced risk for diabetic complications, and periodontal treatment improves glycemic control.,,,,, The meta-analysis by Engebretson et al. demonstrated that the HbA1c level decreased by 0.4% 3 months after periodontal treatment, and this result has a clinical effect equivalent to that of a second drug added to the treatment of DM patients. Furthermore, the importance of glycemic control was demonstrated in several studies in which the prevalence and severity of periodontal destruction were higher in poorly controlled DM patients.,, DM causes deterioration in neutrophil adhesion, chemotaxis, and phagocytosis, resulting in the impaired host response against the bacterial accumulation in the periodontal pocket and increased periodontal destruction., Thus, periodontitis is considered the sixth complication of DM.
Genetic polymorphisms are nonmodifiable risk factors for periodontitis. The role of genetics in periodontal diseases was introduced in the 1990s, then the concepts such as susceptibility and predisposition to periodontal disease emerged. Vitamin D receptor (VDR) gene polymorphism is one of the genetic polymorphisms thought to be associated with periodontal disease that affects both immunomodulation and bone mineral density., VDR polymorphisms are also associated with DM. The mechanism behind this association probably is that the biological form of vitamin D, [1,25(OH) 2D3], by binding to VDR, improves pancreatic ß cell function, insulin receptor sensitivity, and decreases systemic inflammation.,
VDR is an intracellular receptor that is a member of the core receptor gene family and is located on chromosome 12 (12q13.11). It consists of nine exons and eight introns, which contain four polymorphic areas. Three of them are the polymorphic areas in which the restriction enzymes ApaI, BsmI, and TaqI are located at the 3′ end, and the fourth is the restriction of the FokI enzyme in the starting codon. The ApaI variant is characterized by G>T changes in the 8th intron, the BsmI variant by A>G changes between the 8th intron and the 9th exon, and the TaqI variant by T>C changes in the 9th exon. These three are known as silent single nucleotide polymorphism (SNP) as they do not cause any changes in amino acid sequence, protein amount, or function but can affect gene expression by regulating mRNA stability. Different from these three, the FokI variant is characterized by T>C changes in an initial codon located at 5′ end in the 2nd exon and is the only VDR polymorphism known to result in two different protein products., These polymorphisms usually destroy or create new cut sites for a particular restriction enzyme on the gene. As a result of that, nucleotide sequences of different lengths are formed depending on the presence of polymorphism.
The VDR gene includes several SNPs, but the most common variants studied in periodontitis or DM the ApaI, BsmI, FokI, and TaqI variants are subject of several studies with conflicting reports., Due to the different ethnicities, sample sizes, study designs, or population heterogeneities of the studies, it is difficult to establish a global view of VDR polymorphisms' clear effect on periodontitis or DM. A meta-analysis that investigated the relationship between VDR polymorphisms and DM showed that only the BsmI variant might be a risk factor for DM. Furthermore, Wan et al. revealed that there was a link between the FokI and the BsmI variants and periodontitis in overall populations, but the TaqI variant in only Caucasian populations in their meta-analysis. However, no association was found between the ApaI variant and periodontitis. Although the relationship between DM and periodontitis is well documented,, it is known that genetic factors also affect the severity of the periodontal disease. Based on the literature review, there are limited VDR polymorphism studies evaluating individuals diagnosed with both DM and periodontitis. Therefore, the purpose of the present study was to investigate VDR polymorphisms as a possible risk factor in periodontally healthy and periodontitis patients with or without DM in Turkish subjects.
| Material and Methods|| |
In this present case-control study, a total of 200 individuals consisting of 40 nondiabetic individuals with healthy periodontium (H), 40 diabetic individuals with healthy periodontium (DMH), 60 non-diabetic individuals with periodontitis (P), and 60 diabetic individuals with periodontitis (DMP) were recruited from the Department of Periodontology and Oral Diagnostics, Faculty of Dentistry, Marmara University, Istanbul, Turkey between January 2018 and January 2020.
This study was reviewed and approved by Marmara University, Faculty of Medicine, Clinical Research Ethics Committee (06.10.2017-09.2917.608). Each participant signed an informed consent before the study. This study was conducted according to the Helsinki Declaration of 2008 as revised in 2013.
The inclusion criteria for all individuals were being a nonsmoker, having more than 15 teeth (except third molars), no pregnancy or lactation, no usage of systemic antibiotics in the past 3 months, and no periodontal treatment in the past 6 months. For periodontally healthy individuals, the criteria were having no history of periodontal disease, probing pocket depth ≤3 mm, with no evidence of radiological bone loss, without clinical signs of gingival inflammation. For individuals with DM, the criteria were having been diagnosed with type 2 DM for at least 1 year according to the American Diabetes Association criteria, using oral antidiabetics and/or insulin, and having no major complications such as retinopathy, nephropathy, and neuropathy. Periodontitis patients were selected as severe periodontitis according to the case definition model of the Centers for Disease Control and Prevention in partnership with the American Academy of Periodontology. Inclusion criteria for periodontitis patients were the presence of ≥1 interproximal site with probing pocket depth ≥5 mm and ≥2 interproximal sites with clinical attachment loss ≥6 mm (not on the same tooth).
Demographic and general health-related parameters
A medical and dental history, age, gender, weight, and height were recorded, and body mass index (BMI) was calculated for all individuals during their first visit. In addition, individuals with DM were consulted with a physician to register their recent (<48 h) biochemical test results including fasting plasma glucose (FPG) and HbA1c level. The systemically healthy individuals also underwent these biochemical tests, in order to confirm their nondiabetic condition.
Full mouth clinical and radiological examinations for all individuals were performed by a single calibrated examiner (ASY). Intraexaminer calibration was carried out in five periodontitis patients who were not included in the study. Probing pocket depth (PPD) and clinical attachment loss (CAL) were measured twice at a 1-day interval. Intraexaminer reliability was 0.91 for PPD and 0.90 for CAL. Periodontal measurements including plaque index (PI), gingival index (GI), PPD, bleeding on probing (BOP%), and CAL were recorded at six sites (mesiobuccal, midbuccal, distobuccal, mesiolingual, midlingual, distolingual) of each tooth as previously described by Doğan et al. All periodontal parameters were measured using a University of North Carolina-15 (UNC-15) periodontal probe (Hu-Friedy, Chicago, IL).
Sample collection, DNA isolation, and genotyping
Blood samples were collected from the right or left antecubital areas of all individuals into sterile ethylene diamine tetra-acetic acid (EDTA) tubes and were stored at -80°C until the analysis day. Genomic DNA was isolated from 2.5 mL blood samples with PurelinkTM Genomic DNA Mini Kit (Invitrogen by life Technologies, CA, USA). Genotyping of VDR polymorphisms ApaI, BsmI, FokI, and TaqI were determined by real-time polymerase chain reaction (PCR) using allele-specific probes, TaqmanTM (Thermo Fisher, Foster City, USA) [Table 1], and Applied BiosystemsTM, 7500 Real-Time PCR instrument. PCR reactions consisted of 2.25 μL of genomic DNA, 2.5 μl TaqPathTM ProAmpTM Master Mix, 0.25 μL TaqManTM SNP Genotyping Assay, and 5 μL nuclease-free water. Cycling parameters comprised initial denaturation at 95°C for 10 min and 40 cycles of denaturation at 95°C for 15 sand annealing with extension at 60°C for 60 s.
Statistical Package for Social Sciences 24 package program was used for statistical analysis. Descriptive data such as mean and standard deviation were used to present demographic, clinical, and biochemical data. The normality of distributions was determined by Kolmogorov–Smirnov test. An independent t-test was used to compare quantitative data with normal distribution. Mann–Whitney U test was used to compare quantitative data that did not show normal distribution. Genotype distributions, allele frequencies and Hardy-Weinberg equilibrium were analyzed with the Chi square test. Chi-square test was also used to calculate odds ratio in intergroup risk analysis. Statistical significance was accepted as P < 0.05. Sample size calculation was done based on the study by Malik et al., and the power analysis was calculated with 5% alpha error and 90% power to ascertain the associations between VDR polymorphisms and periodontitis or DM. Accordingly, it was determined that at least 37 individuals should be included in each group.
| Results|| |
Study population, biochemical and clinical measurements
Demographic, biochemical, and periodontal parameters among groups are presented in [Table 2]. The mean age was significantly higher in the DMH group compared to the H group and in the DMP group compared to the P group (P < 0.001 and P = 0.006, respectively). The gender distributions were similar between the periodontally healthy groups (H and DMH) and between the periodontitis groups (P and DMP) (P > 0.05).
|Table 2: Demographic, biochemical, and clinical characteristics of the subjects included in this study|
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Among 100 DM patients, 69 of them had been using oral antidiabetic drugs, 22 insulin, and 9 both. The frequency of the patients using insulin or both was higher in the DMP group compared to the DMH group (P = 0.007). Similarly, the frequency of poorly controlled DM patients was significantly higher in the DMP group compared to the DMH group (P = 0.009).
BMI, FPG, and HbA1c levels were significantly lower in the P and H groups compared to the DM groups (P < 0.001). However, there was no difference in both DM groups in terms of BMI (P = 0.635). Biochemical variables including FPG and HbA1c levels were found higher in the DMP group compared to the DMH group (P = 0.001 and P = 0.001, respectively) [Table 2].
The values of the mean PI and the percentage of sites with PPD = 4–6 mm were significantly higher in the DMP group compared to the P group (P = 0.003 and P = 0.018, respectively).
Genotype and allele frequencies
The genotype and allele frequencies and the HWE of each VDR polymorphism are shown in [Table 3]. All genotype distributions were in HWE as the observed and expected genotype frequencies were similar (P > 0.05). There was no difference neither between the different genotypes nor allele frequencies among groups for any analyzed polymorphism (P > 0.05).
|Table 3: Genotypic and allelic distributions of VDR polymorphisms in all study groups|
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The distributions of genotypes and alleles of VDR polymorphisms in relation to periodontal status are shown in [Table 4], and diabetes mellitus status are shown in [Table 5], respectively. Both genotype and allele frequencies among the groups were similar (P > 0.05).
|Table 4: Genotypic and allelic distributions of VDR polymorphisms in relation to periodontal status|
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|Table 5: Genotypic and allelic distributions of VDR polymorphisms in relation to diabetes mellitus status|
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All intergroup analyses of genotypic and allelic distributions of each polymorphism are presented in [Table 6]. The frequency of the GG genotype and G allele of BsmI variant was significantly higher in the DMH group compared to the H group (P = 0.034 and P = 0.012, respectively). Moreover, the frequency of the CC genotype or C allele of the FokI variant was significantly higher in the DMP group compared to the DMH group (P = 0.046 and P = 0.049, respectively).
|Table 6: Intergroup analysis of genotypic and allelic distributions of VDR polymorphisms|
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The VDR polymorphisms and the susceptibility to diabetes mellitus or periodontitis are shown in [Table 7]. No associations were found between any group comparisons for the ApaI and the TaqI variants of VDR polymorphisms. However, for the BsmI variant, having the GG genotype was 0.3 times, and carrying the G allele was 2.3 times more susceptible to diabetes mellitus in periodontally healthy individuals (P = 0.013 and P = 0.012, respectively). Furthermore, for the FokI variant, having the CC genotype was 2.7 times and carrying the C allele was 1.9 times more susceptible to periodontitis in the presence of DM (P = 0.017 and P = 0.049, respectively).
|Table 7: Associations between VDR polymorphisms and the risk of periodontitis or diabetes mellitus|
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| Discussion|| |
To the best of our knowledge, the present study is the first study that investigated the genotypic and allelic distributions of VDR polymorphism in both periodontally healthy and periodontitis patients with DM in order to demonstrate the susceptibility to periodontitis and DM or both in Turkish subjects.
The results of this study showed that the genotypic and allelic distributions of ApaI, BsmI, FokI, and TaqI variants of VDR were similar between the H and P groups (P > 0.05) in agreement with previous studies in Turkey,, Brazil,, England, and Columbia. However, studies from Korea, Italia, Japan, Romania, Thailand, and China reported that at least one of these genotypes or alleles were seen predominantly in periodontitis patients rather than the periodontally healthy controls. Moreover, two meta-analyses, investigated these variants according to the ethnicities such as Caucasians and Asians and revealed that the ApaI, BsmI, and FokI variants were not associated with periodontitis in Caucasian populations, which is in accordance with this present findings. The results of TaqI variant in Caucasians were conflicting in these two meta-analyses. Similar to our findings, Deng et al. showed no association between this variant and periodontitis, but Wan et al. reported an association. Although the Turkish population consists of Caucasians, it is notable that Turkey is the meeting point of East and West due to being geographically and epidemiologically in the middle. The differences between results may derive from population heterogeneities.
In the present study, it is worthy to note that an association was found between the BsmI variant and DM in periodontally healthy individuals. In addition, the frequency of the G allele was significantly higher in the DMH group compared to the H group, and the individuals with the G allele were 2.3 times more susceptible to the development of DM (P = 0.012). However, no significant difference was found between the DMP and P groups (P > 0.05). Several studies evaluated the association between the BsmI variant and DM. Some of these studies, in line with our findings, revealed that this variant was a risk factor for DM,, but others did not.,, However, there was no information about the periodontal status of individuals included in these studies. Moreover, we also analyzed individuals according to only the presence or absence of DM regardless of periodontal status and failed to demonstrate a link between the BsmI variant and DM. This result may be due to the number of periodontally healthy individuals being relatively lower than periodontitis patients. It was quite difficult to find higher numbers of diabetic individuals with healthy periodontium as the possibility of periodontitis comes up with age. Moreover, it should be kept in mind that the periodontal status of individuals may affect the risk of developing DM.
Another important result of the present study was observed in the comparison of the DMH and DMP groups. Significantly higher frequencies of the CC genotype (P = 0.046) and C allele (P = 0.049) of the FokI variant were detected in the DMP group compared to the DMH group. Contradictory to our findings, Pinho et al. showed no association between periodontitis and this variant in DM patients. However, other studies reported that the FokI variant was a risk for the development of periodontitis but in non-DM patients.,,,, It is well known that poorly-controlled DM increases the likelihood and severity of periodontitis., So, for the risk assessment of periodontitis in DM patients, in addition to glycemic control level, the analysis of the FokI variant can be useful. Furthermore, the detection of this variant in individuals with DM may be important for the awareness of the periodontal disease and its management.
| Conclusion|| |
Within the limits of the study, our findings suggested that the BsmI variant, especially the G allele, was associated with DM in periodontally healthy individuals. Moreover, in the presence of DM, carrying the CC genotype and C allele of the FokI variant was associated with an increased risk of periodontitis. These associations should be confirmed in future studies with different populations and larger sample sizes.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This study was supported by Marmara University, Scientific Research Projects Unit (#SAG-C-DRP-081117-0619).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]