Abstract
Objective of the study was to find the association of vitamin D receptor (VDR) polymorphisms (Fokl, Taql and Apal) with vitamin D levels in diabetic foot ulcer (DFU) patients in South India. In this case–control study, plasma vitamin D levels and VDR genotype frequencies of 70 cases (DFU patients) were compared with 70 diabetic (diabetes mellitus [DM] [non‐DFU]) patients and 70 apparently healthy controls (HC) from South India. Plasma vitamin D levels were measured using the ELISA technique, and genotyping of VDR polymorphisms was carried out using real‐time polymerase chain reaction. Logistic regression was used to find the association between DFU versus HC and DFU versus DM traits. Association analysis was performed based on additive, dominant and recessive models with age and gender as covariates. A 45.7% of DFU patients have sufficient vitamin D levels than 48.6% and 40% of DM patients and HC, respectively. Linkage disequilibrium analysis for DFU versus HC and DFU versus DM traits shows that single nucleotide polymorphisms (SNPs) Taq1 (rs731236) and Apal (rs7975232) are in strong linkage disequilibrium in DFU patients. The alleles and genotype frequencies were similar in all three groups. Although the additive model does not show statistical significance, age and sex correlate with the three SNPs (Fokl, Taql and Apal). No association was found between VDR gene polymorphisms and vitamin D levels in DFU patients in Southern India. On the other hand, age and sex correlate with the three SNPs.
Keywords: diabetic foot ulcer, VDR, vitamin D
1. INTRODUCTION
Diabetic foot ulcers (DFUs) are a severe and potentially debilitating complication of diabetes mellitus (DM). In DM patients, these ulcers can be slow to heal and are prone to infection, subsequently a major concern for healthcare professionals. DFU often develops due to a combination of factors, including poor blood circulation (peripheral arterial disease), nerve damage (neuropathy) and trauma or pressure on the feet. Uncontrolled blood sugar in DM patients can impair the body's innate healing processes. 1
Vitamin D, a fat‐soluble nutrient, is vital for multiple facets of health, including bone health, immune function and wound healing. In recent years, the potential link between vitamin D deficiency (VDD) and DFU and its adverse impact on preventing and treating these ulcers has been the focus. Diabetic feet are highly prone to infection. Vitamin D is involved in producing antimicrobial peptides and immune regulation, essential for the body's defence against infections. Moreover, vitamin D plays a role in collagen synthesis and the formation of connective tissues, which are critical for wound healing. 2
Preventing DFU is crucial due to its detrimental effect on patients' quality of life and the economic strain they place on the healthcare system. 3 The active form of vitamin D, calcitriol, exerts its effect by binding to the vitamin D receptor (VDR), expressed in several cells, including macrophages and pancreatic beta cells. This suggests its anti‐inflammatory, anti‐proliferative, immunosuppressive, antioxidative and pro‐differentiating properties. VDRs are nuclear receptors of transcription factors that regulate several gene expressions. VDR is also involved in the microRNA‐dependent post‐transcriptional processes. This indicates that it plays significant roles in transcriptional and posttranscriptional cellular events. 4
The commonly studied single nucleotide polymorphisms (SNPs) of VDR are Fokl (rs2228570), Taql (rs731236) and Apal (rs7975232). Moreover, these are amongst the known SNPs correlated with immune dysregulation. Therefore, we aimed to study the association between VDR gene polymorphisms (Fokl, Taql and Apal) and vitamin D levels in DFU patients.
2. METHODS
2.1. Study Participants and data collection
This case–control study was conducted in Kasturba Hospital (KH), Manipal, a tertiary care hospital in Coastal Karnataka, India, from 2019 to 2022, which followed a non‐random sampling. The Institutional Ethics Committee of KH approved the study (reference no. 516/2019).
In the study, 210 participants of both genders, more than 18 years old and willing to consent, were enrolled. Amongst them, 70 patients with DFU (based on International Working Group on the Diabetic Foot [IWGDF] criteria) were considered as the cases, with infections classified as mild or moderate according to the Infectious Diseases Society of America and were enrolled from the Department of Surgery. Meanwhile, control group 1, comprising 70 patients with type 2 DM (without DFU), as per the American Diabetes Association, was included by the Department of Endocrinology. In control group 2, 70 staff members of KH who are not diabetic and considered apparently healthy volunteers were included. The exclusion criteria of all the above three groups were (i) individuals with hepatic disease, renal disease or other comorbidities that can alter vitamin D levels, (ii) patients with arterial or venous causes (lower limb critical ischemia or clinical evidence of vascular insufficiency), (iii) patients on medications that can alter vitamin D status, (iv) patients on vitamin D supplements or any specific diet (fortified with vitamin D) prior to the enrolment and (v) pregnant and breastfeeding women. All necessary participant data were collected from direct participant interaction.
2.2. Vitamin D estimation, DNA extraction and VDR genotyping
A 3 mL blood sample was collected into tubes with ethylenediaminetetraacetic acid anticoagulant to estimate plasma vitamin D levels and perform VDR genotyping analysis. We used a commercial ELISA Kit for estimating 25‐hydroxyvitamin D (Catalogue no: VD220B, Calbiotech) according to the manufacturer's instructions. VDD was defined as 25‐hydroxyvitamin D ≤20 ng/mL, whereas insufficiency ranging 21–29 ng/mL, and sufficiency ≥30 ng/mL.
Genomic DNA extraction from whole blood was performed using the QIAamp DNA Blood Mini Kit (Catalogue no: 51106). The DNA purity (260/280 ratio) and concentration were measured using a Biotek spectrophotometer. The analysis of three VDR SNPs, Fokl (Catalogue no: C__12060045_20), Taql (Catalogue no: C___2404008_10) and Apal (Catalogue no: C__28977635_10), were evaluated by allelic discrimination real‐time polymerase chain reaction (RT‐PCR) using predesigned TaqMan genotyping assays (Applied Biosystems, Foster City, CA). The PCR steps comprised a hot start at 95°C for 10 min followed by 40 cycles of 94°C for 15 s and 60°C for 1 min. All the genotyping was performed using TaqMan genotyping master mix in Quantstudio 5 Realtime PCR (Applied Biosystems). Samples were randomly re‐tested to confirm the observed results.
2.3. Statistical analysis
All statistical analyses were conducted using SPSS statistics version 22.0. Where applicable, values were expressed as mean ± standard deviation and median (interquartile range; IQR). One‐way ANOVA, Kruskal–Wallis, Pearson's Chi‐squared test and Mann–Whitney U‐test were used to compare variables. Data quality check parameters Hardy–Weinberg equilibrium, heterozygosity and minor allele frequency were assessed. The Chi‐squared test was used to determine allelic and genotypic frequencies. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to evaluate the correlation between the polymorphisms and DFU quantitatively. Linkage disequilibrium (LD) was calculated using Haploview. Logistic regression was used to perform association analysis for DFU versus healthy controls (HC) and DFU versus DM traits. Association analysis was performed based on additive, dominant and recessive models with age and gender as covariates.
3. RESULTS
3.1. Baseline characteristics of the study population
Seventy participants, each of DFU, DM and HC, were included. The mean age of the DFU, DM and HC groups were 56.06 ± 10.02, 50.44 ± 10.91 and 41.10 ± 8.96 years, respectively. Out of 210 participants, 145 were male. The median (IQR) for the duration of type 2 DM in DFU and DM groups were 10.0 (9.5) and 4.0 (8.25) years, respectively. The mean HbA1c of DFU and DM groups were 10.09 ± 2.04% and 8.76 ± 2.22%, respectively. The median (IQR) plasma vitamin D levels in DFU, DM and HC were 27.47 (9.76) ng/mL, 28.66 (11.12) ng/mL and 27.17 (9.76) ng/mL, respectively. Table 1 shows the baseline details of all participants.
TABLE 1.
Baseline characteristics of the study population.
| DFU | DM | HC | p‐Value | |
|---|---|---|---|---|
| Age | 56.06 ± 10.02 | 50.44 ± 10.91 | 41.10 ± 8.96 | 0.001 a |
| Gender | ||||
| Female | 7 | 25 | 33 | 0.001 b |
| Male | 63 | 45 | 37 | |
| Duration of diabetes mellitus (years) | 10.0 (9.5) | 4.0 (8.25) | — | 0.001 c |
| HbA1c (%) | 10.09 ± 2.04 | 8.76 ± 2.22 | — | 0.001 d |
| Plasma vitamin D levels (ng/mL) | 27.47 (9.76) | 28.66 (11.12) | 27.17 (9.76) |
χ 2 = 0.797 p = 0.671 e |
| Vitamin D | ||||
| Deficient | 10 | 12 | 11 | 0.796 b |
| Insufficient | 28 | 24 | 31 | |
| Sufficient | 32 | 34 | 28 | |
Abbreviations: DFU, diabetic foot ulcer; DM, diabetes mellitus; HC, healthy controls.
One‐way ANOVA.
Pearson's Chi‐square test.
MANN–Whitney U‐test.
Independent sample T‐test.
Kruskal–Wallis test.
3.2. Linkage disequilibrium
LD analysis for DFU versus HC shows that SNPs Taql (rs731236) and Apal (rs7975232) are in strong linkage (D′ = 0.864, r 2 = 0.256). Similarly, for DFU versus DM, SNP pair Taql (rs731236) and Apal (rs7975232) are in close linkage (D′ = 0.904, r 2 = 0.293). However, LD analysis in DFU versus HC and DFU versus DM shows that SNP pairs Taql (rs731236) and Fokl (rs2228570), as well as Apal (rs7975232) and Fokl (rs2228570), respectively, are not in LD (see Figure 1).
FIGURE 1.
Linkage disequilibrium. DFU, diabetic foot ulcer; DM, diabetes mellitus; HC, healthy controls.
3.3. Genotype frequencies of VDR SNPs
All three genotyped SNPs passed quality control checks and were included in further analysis. The allelic and genotype distribution was in Hardy–Weinberg equilibrium. Most of the participants in the DFU group had the GG genotype, AA genotype and AA genotype for Fokl (rs2228570), Taql (rs731236) and Apal (rs7975232), respectively. The allele and genotype frequencies of the VDR polymorphisms are shown in Table 2. We observed a similar distribution across the three groups. No significant association was observed when comparing plasma vitamin D levels with genotypes of DFU patients (see Table 3).
TABLE 2.
Distribution of allele and genotype frequencies of vitamin D receptor polymorphisms (Fokl, Taql and Apal) in diabetic foot ulcer (DFU) versus diabetes mellitus (DM) and DFU versus healthy controls (HC).
| SNP allele/genotype | DFU | DM | Odds ratio (95% CI) | p‐Value a | DFU | HC | Odds ratio (95% CI) | p‐Value a |
|---|---|---|---|---|---|---|---|---|
| rs2228570 (Fokl) | ||||||||
| AA | 5 | 3 | 2.14 (0.48–9.58) | 0.46 | 5 | 4 | 1.35 (0.34–5.46) | 0.67 |
| AG | 30 | 22 | 1.75 (0.86–3.55) | 0.11 | 30 | 28 | 1.16 (0.58–2.32) | 0.67 |
| GG | 35 | 45 | REF | 35 | 38 | REF | ||
| Alleles | ||||||||
| A | 40 | 28 | 1.60 (0.92–2.78) | 0.09 | 40 | 36 | 1.16 (0.68–1.96) | 0.59 |
| G | 100 | 112 | REF | 100 | 104 | REF | ||
| rs731236 (Taql) | ||||||||
| AA | 33 | 31 | REF | 33 | 29 | REF | ||
| AG | 24 | 30 | 0.75 (0.36–1.56) | 0.44 | 24 | 36 | 0.59 (0.29–1.20) | 0.14 |
| GG | 13 | 9 | 1.36 (0.51–3.62) | 0.54 | 13 | 5 | 2.29 (0.73–7.19) | 0.15 |
| Alleles | ||||||||
| A | 90 | 92 | REF | 90 | 94 | REF | ||
| G | 50 | 48 | 1.07 (0.65–1.74) | 0.80 | 50 | 46 | 1.14 (0.69–1.86) | 0.62 |
| rs7975232 (Apal) | ||||||||
| AA | 30 | 23 | REF | 30 | 28 | REF | ||
| AC | 29 | 33 | 0.67 (0.32–1.41) | 0.29 | 29 | 24 | 1.13 (0.53–2.38) | 0.75 |
| CC | 11 | 14 | 0.60 (0.23–1.57) | 0.29 | 11 | 18 | 0.57 (0.23–1.42) | 0.22 |
| Alleles | ||||||||
| A | 89 | 79 | REF | 89 | 80 | REF | ||
| C | 51 | 61 | 0.742 (0.46–1.20) | 0.22 | 51 | 60 | 0.76 (0.47–1.24) | 0.27 |
Abbreviations: CI, confidence intervals; SNP, single nucleotide polymorphism.
Pearson's Chi‐square test.
TABLE 3.
Association of plasma vitamin D with various genotypes in diabetic foot ulcer.
| SNP allele/genotype | Vitamin D median (IQR) | p‐Value |
|---|---|---|
| rs2228570 (Fokl) | ||
| AA | 23.05 (5.48) |
χ 2 = 5.192, p = 0.075 a |
| AG | 28.31 (8.74) | |
| GG | 29.03 (12.06) | |
| rs731236 (Taql) | ||
| AA | 30.75 (21.13) |
χ 2 = 4.26, p = 0.119 a |
| AG | 25.89 (7.56) | |
| GG | 26.74 (14.30) | |
| rs7975232 (Apal) | ||
| AA | 26.76 (9.94) |
χ 2 = 0.296, p = 0.863 a |
| AC | 28.17 (7.99) | |
| CC | 29.57 (12.16) | |
Abbreviations: IQR, interquartile range; SNP, single nucleotide polymorphism.
Kruskal Wallis test.
Although the additive model does not show statistical significance, age and sex appear to be associated with the three SNPs (see Table 4). After adjustment for covariates, ORs for Fokl (rs2228570) are higher than Taql (rs731236) and Apa1 (rs7975232) in DFU versus HC and DFU versus DM in association analysis, although p‐values are not significant. This indicates that the frequency of Fokl (rs2228570) allele ‘A’ is higher in the DFU group than in the HC and DM groups.
TABLE 4.
Association analysis (covariates—age, gender)—additive model—diabetic foot ulcer (DFU) versus healthy controls (HC) and diabetes mellitus (DM).
| ID | REF | A1 | TEST | OR | 95% CI | p‐Value a |
|---|---|---|---|---|---|---|
| DFU versus HC | ||||||
| rs2228570 | G | A | ADD | 1.58 | 0.76, 3.34 | 0.22 |
| rs2228570 | G | A | Age | 1.19 | 1.12, 1.27 | 0.001 |
| rs2228570 | G | A | Sex | 0.14 | 0.05, 0.43 | 0.001 |
| rs731236 | A | G | ADD | 0.69 | 0.33, 1.43 | 0.32 |
| rs731236 | A | G | Age | 1.19 | 1.12, 1.27 | 0.001 |
| rs731236 | A | G | Sex | 0.12 | 0.04, 0.38 | 0.001 |
| rs7975232 | A | C | ADD | 0.88 | 0.47, 1.67 | 0.71 |
| rs7975232 | A | C | Age | 1.18 | 1.11, 1.25 | 0.001 |
| rs7975232 | A | C | Sex | 0.12 | 0.04, 0.38 | 0.001 |
| DFU versus DM | ||||||
| rs2228570 | G | A | ADD | 1.74 | 0.95, 3.19 | 0.07 |
| rs2228570 | G | A | Age | 1.04 | 1.01, 1.08 | 0.001 |
| rs2228570 | G | A | Sex | 0.22 | 0.08, 0.57 | 0.001 |
| rs731236 | A | G | ADD | 1.17 | 0.70, 1.94 | 0.52 |
| rs731236 | A | G | Age | 1.04 | 1.00, 1.08 | 0.01 |
| rs731236 | A | G | Sex | 0.21 | 0.08, 0.55 | 0.001 |
| rs7975232 | A | C | ADD | 0.75 | 0.45, 1.24 | 0.26 |
| rs7975232 | A | C | Age | 1.04 | 1.00, 1.08 | 0.01 |
| rs7975232 | A | C | Sex | 0.22 | 0.08, 0.56 | 0.001 |
Abbreviation: ADD, additive model; CI, confidence interval; OR, odds ratio.
Logistic regression.
4. DISCUSSION
The VDR gene encodes a nuclear hormone receptor that mediates the biological effects of vitamin D. The Fokl (rs2228570) polymorphism is located in exon 2 near the 5′‐coding regions in the VDR gene. 5 This polymorphism results in a variation in the length of the translated VDR protein, with the longer protein being associated with increased transcriptional activity than the shorter protein. It has been reported that individuals with longer protein are regarded as ‘low responders’ to vitamin D supplementation in patients with DM. 5 , 6 Taql (rs731236) and Apal (rs7975232) are present near the 3′ untranslated region. This region regulates gene expression by regulating mRNA stability and protein translation efficiency. Taql (rs731236) and Apal (rs7975232) are closely located and genetically linked. On the other hand, Fokl (rs2228570) is the only VDR polymorphism not linked to the others and, hence, can be considered an independent marker in the VDR gene. 7
Only three studies have explored VDR SNPs in DFU patients. 8 , 9 , 10 Soroush et al. 8 explored the role of Fokl (rs2228570) polymorphism in the 105 DFU (cases) and 107 DM (control) in the Iranian population. TT and TC genotypes were more frequent in cases, correlating with T allele dominance. However, logistic regression showed no significant association with DFU after adjusting for confounders. Notably, grade 3 ulcers exhibited higher TT genotype and T allele frequencies. Whilst Fokl (rs2228570) polymorphism correlated with DFU severity and oxidative stress, its direct association with DFU risk remains inconclusive. Raflis et al. 9 explored the role of Fokl (rs2228570) and vitamin D levels in 36 Indonesian DFU patients. Vitamin D status varied, with 47.2% sufficient, 33.3% insufficient and 19.4% deficient. Fokl (rs2228570) VDR gene polymorphisms were prevalent, with 44.4% (Ff) heterozygous and 41.7% (FF) homozygous mutants. There were no significant differences in BMI, Ankle Brachial Index, fasting blood glucose, HbA1c or vitamin D levels across VDR Fokl (rs2228570) genotypes. However, VDD was more frequent in F allele mutants. Overall, genotype did not significantly influence DFU subject characteristics, but VDD showed trends amongst genotypic subgroups. Klashami et al., 10 explored VDR gene polymorphism among 262 diabetic patients (127 DFU subjects). Genotype frequencies of Taql and Bsml showed no significant differences between control and case groups. However, GC genotype frequency in Apal (rs7975232) polymorphism was higher in some cases. Vitamin D levels did not significantly correlate with VDR gene polymorphisms.
We have tried to evaluate the associations between Vitamin D levels and polymorphisms of genes involved in vitamin D actions Fokl (rs2228570), Taql (rs731236) and Apal (rs7975232) on DFU patients compared to DM (without ulcers) and HCs in South Indian patients. Our results indicate that genotype and allele frequencies in the three SNPs studied were not significantly different amongst DFU patients and both controls. No study has evaluated the VDR polymorphism in Indian DFU patients.
Although previous evidence indicates that low vitamin D levels are associated with DFU, 11 , 12 our investigation revealed no difference in vitamin D levels between DFU patients and both controls. The occurrence rates of vitamin D insufficiency and deficiency were comparable between the groups. In addition, the plasma vitamin D levels across the various genotypes of Fokl (rs2228570), Taql (rs731236) and Apal (rs7975232) were not significant. Selvarajan et al. 13 studied the VDR polymorphism amongst T2DM patients in South India; they reported that AA and AG genotypes of Fokl (rs2228570) were associated with lower vitamin D levels, whereas Taql (rs731236) and Apal (rs7975232) were not associated with vitamin D levels.
The study's limitations include a lack of dietary information, its association with vitamin D levels and a small sample size. Also, the control group participants were not matched by age and gender. Another limitation is that our study did not assess the daily dietary intake of vitamin D‐containing food using any specific food frequency questionnaire amongst the groups. Nevertheless, this is the only study that has explored the VDR polymorphism status in DFU from the Indian population, providing evidence from the South Indian population.
5. CONCLUSION
Our study concludes that vitamin D levels were similar amongst the groups. Also, the VDR gene polymorphism (Fokl, Taql and Apal) alleles and genotype frequencies were similar amongst diabetic patients with and without foot ulcers and apparently healthy individuals. It is important to note that DFUs are multifactorial in nature, influenced by various factors, including micronutrient status, glycemic control, vascular health, neuropathy and immune function, amongst others. Nutrient and genetic factors, including variations in the vitamin D levels and VDR gene, may contribute to individual susceptibility or risk, but they are unlikely to be the sole determinant of DFU development or progression. We suggest that the present results require confirmation in further and larger studies in the Indian population.
FUNDING INFORMATION
All authors thank the Manipal Centre for Infectious Diseases, Prasanna School of Public Health, Manipal, for the seed grant and Manipal Academy of Higher Education, Manipal, for the contingency grant.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
ACKNOWLEDGEMENTS
SJK is thankful to the Indian Council of Medical Research (ICMR), New Delhi, for granting Senior Research Fellowship [No. 3/1/3(16)/Endo‐fellowship/21‐NCD‐III]. All the authors are thankful to the Department of Science & Technology‐ Fund for Improvement of S&T Infrastructure in Universities and Higher Educational Institutions (DST‐FIST) (TPN: 32196) for providing Quant 5 Studio real‐time PCR (Applied Biosystems, USA). Additionally, SSM is thankful to the Department of Health Research, Ministry of Health & Family Welfare, New Delhi, for providing grant‐in‐aid (GIA) grant [No. R.11014/01/2023‐GIA/HR] for conducting VDR gene expression studies in DFUs.
Kurian SJ, Baral T, Benson R, et al. Association of vitamin D status and vitamin D receptor polymorphism in diabetic foot ulcer patients: A prospective observational study in a South‐Indian tertiary healthcare facility. Int Wound J. 2024;21(8):e70027. doi: 10.1111/iwj.70027
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author.
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Associated Data
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Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author.