|Year : 2019 | Volume
| Issue : 6 | Page : 483-491
Effects of genetic polymorphisms in Vitamin D metabolic pathway on Vitamin D level and asthma control in South Indian patients with bronchial asthma
Manju Rajaram1, Sandhiya Selvarajan2, Revathy Neelamegan3, Sadishkumar Kamalanathan4, Vikneswaran Gunaseelan5, Alphienes Stanley Xavier2, Saibal Das2, Vignesh Karthikeyan6, Vinodkumar Saka1, Adithan Chandrasekaran2
1 Department of Pulmonary Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3 Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
4 Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
5 Department of Clinical Research, Narayana Hrudalya, Bengaluru, Karnataka, India
6 Centre for Biotechnology, Cell Signaling Laboratory, Anna University, Chennai, Tamil Nadu, India
|Date of Web Publication||31-Oct-2019|
Dr. Sandhiya Selvarajan
Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry - 605 006
Source of Support: None, Conflict of Interest: None
Clinical trial registration CTRI/2013/05/003674
| Abstract|| |
Objectives: The study was designed to evaluate the single-nucleotide polymorphisms (SNPs) of genes involved in Vitamin D actions (rs2228570) and metabolic pathways (rs2248137 and rs10766197) and their associations with serum 25-hydroxy Vitamin D (25(OH)D) level and asthma control in South Indian patients with bronchial asthma. Materials and Methods: One hundred and two patients of South Indian origin with bronchial asthma either naive to inhaled corticosteroids (ICSs) or not receiving ICS for ≥1 month were included and were treated with ICS (beclomethasone 200 μg twice daily) for 8 weeks. One hundred and one unrelated healthy South Indians were used as controls. Pulmonary function test and fractional exhaled nitric oxide were used to assess asthma control. Serum 25(OH)D levels (chemiluminescence immunoassay) and SNPs in Vitamin D pathway (real-time polymerase chain reaction) were assessed. The associations of SNPs and serum 25(OH)D with asthma control was determined using linear regression. All analyses were performed using SPSS (version 19) and “SNPStats.” P < 0.05 was considered as statistically significant. Results: Vitamin D receptor (VDR) polymorphism (rs2228570) was found to be protective against asthma (P = 0.022), while there were no significant associations between the other two SNPs and asthma. Similarly, poor correlation and insignificant associations between the SNPs and serum 25(OH)D levels were observed in both cases and controls. There were also insignificant associations between the SNPs and asthma control. Conclusion: VDR polymorphism (rs2228570) was found to be protective against asthma in South Indians, while other genes involved in the metabolic pathway of Vitamin D did not show associations with asthma.
Keywords: Associations, bronchial asthma, inhaled corticosteroids, single-nucleotide polymorphisms, Vitamin D
|How to cite this article:|
Rajaram M, Selvarajan S, Neelamegan R, Kamalanathan S, Gunaseelan V, Xavier AS, Das S, Karthikeyan V, Saka V, Chandrasekaran A. Effects of genetic polymorphisms in Vitamin D metabolic pathway on Vitamin D level and asthma control in South Indian patients with bronchial asthma. Lung India 2019;36:483-91
|How to cite this URL:|
Rajaram M, Selvarajan S, Neelamegan R, Kamalanathan S, Gunaseelan V, Xavier AS, Das S, Karthikeyan V, Saka V, Chandrasekaran A. Effects of genetic polymorphisms in Vitamin D metabolic pathway on Vitamin D level and asthma control in South Indian patients with bronchial asthma. Lung India [serial online] 2019 [cited 2019 Nov 14];36:483-91. Available from: http://www.lungindia.com/text.asp?2019/36/6/483/270078
| Introduction|| |
Bronchial asthma, a chronic inflammatory disease characterized by hyperresponsiveness of bronchial tree and reversible airway narrowing, manifests in the form of breathlessness, wheezing, cough, and chest tightness. This disease affects nearly 300 million people worldwide, with an estimated prevalence of 3%–38% and 2%–12% among the children and adults, respectively. In India, the prevalence of asthma is about 18 million, affecting >2% of the population above 15 years of age. Vitamin D, the sunshine hormone, is known for its vital role in the maintenance of bone health and calcium-phosphorus balance. In recent times, the beneficial effect of Vitamin D has been being explored in various health conditions including inflammatory diseases, cancer, autoimmune diseases, and cardiovascular and respiratory diseases., Vitamin D has been found to offer defense against respiratory infections, improve lung function, and inhibit airway smooth muscle proliferation.,,, Further, Vitamin D has been shown to improve steroid responsiveness by enhancing their anti-inflammatory actions with resultant reduction in asthma exacerbations.,,,,
Corticosteroids, both inhalational and systemic, play a major role in the management of asthma. Among them, inhaled corticosteroids (ICSs) are widely used in the control of persistent asthma. Although the majority of the patients with asthma respond to corticosteroids, nearly 5%–10% depict resistance to therapy. Steroid resistance is shown to have poor prognosis owing to reduced asthma control and accelerated deterioration of lung function. One of the explanations given for the varied clinical response to ICS is diminished sensitivity to anti-inflammatory effect of glucocorticoids. In an experimental model of corticosteroid resistance, Vitamin D has been found to restore the immunosuppressive functions and anti-inflammatory effects of dexamethasone, which was further confirmed in a clinical study showing anti-inflammatory and corticosteroid enhancing actions of Vitamin D in the monocytes of patients with steroid resistance asthma. Likewise, an Indian study done in asthmatic children aged 1–15 years has shown between serum 25-hydroxy Vitamin D (25(OH)D) insufficiency and level of asthma control.
Vitamin D (cholecalciferol) synthesized primarily in the skin following sunlight exposure undergoes hydroxylation at positions 25 and 1 in the liver as well as kidney, respectively, to become 1,25-dihydroxycholecalciferol, an active metabolite. The metabolism of Vitamin D depends on the gene CYP2R1 encoding 25-hydroxylase enzyme and CYP27B1 coding 1-α-hydroxylase enzyme. The active Vitamin D enters the cells and exerts its actions by binding to Vitamin D receptor (VDR) encoded by VDR gene. CYP24A1 gene codes 24-hydroxylase enzyme responsible for deactivating the active form of Vitamin D.
Cumulative observations have implicated the role of Vitamin D pathway in immune responses and asthma., VDR, which has been shown to be expressed in respiratory epithelium, is the primary binding receptor for 1,25-dihydroxy Vitamin D3 (1,25(OH)2D3). It has also been mapped to chromosome 12q, an area of the genome with multiple loci previously associated with asthma. CYP24A1 encodes mitochondrial 1,25(OH)2D3 24-hydroxylase. Expressed in many tissues, including bronchial smooth muscle, it initiates the degradation of 1,25(OH)2D3 by hydroxylation. CYP2R1 encodes Vitamin D 25-hydroxylase, a microsomal hydroxylase enzyme that converts Vitamin D into the active ligand for the VDR. The localization and function of these genes suggest an active role in airway function and respiratory diseases, including asthma.
The polymorphisms in the genes encoding various enzymes involved in Vitamin D actions and metabolic pathways [Figure 1] have been studied for their associations with asthma., The associations of these genetic polymorphisms with asthma control have not been established among the Indian patients. Hence, this study aimed to evaluate the single-nucleotide polymorphisms (SNPs) of genes involved in Vitamin D actions (FokI) (VDR [rs2228570, C > T]) and metabolic pathways (CYP24A1 [rs2248137, C > G] and CYP2R1 [rs10766197, G > A]) and their associations with serum 25(OH)D level and asthma control in South Indian patients with bronchial asthma.
|Figure 1: Genes encoding the enzymes involved in Vitamin D action and metabolic pathway|
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| Materials and Methods|| |
This study protocol was approved by Institutional Ethics Committee (Human Studies), Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry.
Patients attending the Outpatient Department of Pulmonary Medicine, JIPMER, Puducherry, were screened for eligibility, and written informed consent was obtained from all the study participants. Patients of South Indian origin (residing in South India for the past three generations and speaking any South Indian language as mother tongue), aged between 18 and 50 years, belonging to either gender, diagnosed with mild-to-moderate persistent asthma and either naive to ICS therapy or without ICS treatment at least for the past 1 month were included in the study. Pregnant women, lactating mothers, and patients on leukotriene antagonists, anti-immunoglobulin E (IgE) therapy, or steroid-based medications for other indications were excluded. Patients nor conforming to previously described spirometric criteria defining asthma  were excluded. Unrelated healthy South Indians were used as controls.
The eligible patients were treated with ICS (beclomethasone 200 μg twice daily) for 8 weeks.
Assessment of parameters
For the eligible patients, pulmonary function test was done using spirometer (Medikro ® SpiroStar USB) at the baseline and after 8 weeks of starting ICS (follow-up visit) to assess FEV1. Similarly, fractional exhaled nitric oxide (FeNO) was measured in the exhaled breath, both at the baseline and during follow-up visit, using Nitric Oxide Breath Monitor (Bedfont ®) to evaluate airway inflammation. Blood sample was collected from both responders and nonresponders for estimation of serum 25(OH)D levels and three SNPs (VDR [rs2228570, C > T], CYP24A1 [rs2248137, C > G], and CYP2R1 [rs10766197, G > A]). The same parameters were assessed in healthy controls.
Serum 25-hydroxy Vitamin D estimation
Estimation of serum 25(OH)D was done using standardized chemiluminescence immunoassay.
DNA was extracted from whole blood by conventional phenol–chloroform method, and genotyping (VDR [rs2228570, C > T], CYP24A1 [rs2248137, C > G], and CYP2R1 [rs10766197, G > A]) was carried out with real-time polymerase chain reaction using SNP Genotyping Assay kits (TaqMan ®), as per manufacturer's instructions.
Continuous data were expressed as mean ± standard deviation. Categorical data including frequency of genotypes and alleles were expressed as numbers and percentages. Comparison of continuous variables was carried out using independent Student's t-test or one-way analysis of variance. Bonferroni correction was done for multiple comparisons. Genotype frequencies of SNPs were assessed for Hardy–Weinberg equilibrium using Chi-square test. The distribution of genotypes between the two groups was also compared using Chi-square test. The association of the different SNPs and haplotypes with asthma was evaluated using unconditional logistic regression model. The associations of the different SNPs with serum 25(OH)D level in asthma patients and healthy controls were calculated using linear regression, and Pearson's correlation was also calculated. The associations of the different SNPs and serum 25(OH)D with asthma control was determined using linear regression with sex, body mass index, duration of asthma, severity of asthma, history of allergic rhinitis and allergic dermatitis, smoking and alcohol status, and usage of ICS (naïve or not) as covariates. Pearson's correlations between serum 25(OH)D level and posttreatment changes in FEV1 and FeNO were calculated. Pearson's correlation was also estimated between the posttreatment deterministic parameters of asthma control (percentage change in FEV1) and FeNO score from baseline till the end of 8 weeks' treatment). The asthma patients were divided as responders and nonresponders to treatment by the change in FeV1 from baseline. The serum 25(OH)D levels across the genotype distribution between the responders and nonresponders as well as the healthy controls were compared. All analyses were performed using SPSS (version 19) (IBM, New York, USA) and “SNPStats.” P < 0.05 was considered as statistically significant.
| Results|| |
The baseline demographic characteristics of asthma patients and healthy volunteers have been enumerated in [Table 1]. The frequencies of the genotypes were in Hardy–Weinberg equilibrium in both the cases and controls. The distribution of genotypic and allelic frequencies among asthma patients and healthy controls is shown in [Table 2]. The associations of the three SNPs with asthma have been depicted in [Figure 2]. VDR polymorphism (rs2228570, C > T) was found to be protective against asthma (P = 0.022). However, there were no significant associations with the other two SNPs (CYP24A1 [rs2248137, C > G] and CYP2R1 [rs10766197, G > A]) and asthma. There were no significant associations between any of the haplotypes and asthma [Figure 3].
|Table 1: Baseline demographic characteristics of asthma patients and healthy controls|
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|Table 2: Distribution of genotypic and allelic frequencies among asthma patients and healthy controls|
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There were poor correlations and insignificant associations between the SNPs and serum 25(OH)D levels in both the groups taken together [Table 3]. [Table 4] shows the associations of the three SNPs with asthma control, as diagnosed by posttreatment changes in FEV1 and FeNO score, which were all statistically insignificant. Pearson's correlation between serum 25(OH)D level and posttreatment changes in FEV1 was –0.19 and between serum 25(OH)D level and changes in FeNO score was −0.18. Posttreatment, Pearson's correlation between the percentage change in FEV1 and FeNO score was −0.026. Serum 25(OH)D level in the responders (61/102) was significantly lower as compared to that of the nonresponders (41/102) (20.57 ± 11.57 vs. 25.53 ± 9.51, P < 0.05). Although the distribution of CYP24A1 (rs2248137, C > G) and CYP2R1 (rs10766197, G > A) SNPs did not vary between the responders and nonresponders, the distribution of VDR (rs2228570, A > G) was significantly different (P < 0.05) between these two groups. The serum 25(OH)D levels in the responders and nonresponders were significantly different from that in the healthy controls across different genotypes [Table 5].
|Table 3: Association of the single-nucleotide polymorphisms with serum 25-hydroxy Vitamin D level in asthma patients and healthy controls|
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|Table 4: Associations of the single-nucleotide polymorphisms with asthma control (n=102)|
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| Discussion|| |
In this study, we have tried to evaluate the associations between Vitamin D levels and polymorphisms of genes involved in Vitamin D actions (rs2228570) and metabolic pathways (rs2248137 and rs10766197) on asthma control as well as response to ICS in South Indian patients. The genotype and allele frequencies in the three SNPs studied were not significantly different among asthma patients and healthy controls. However, the frequency was different from Indians of other states and global populations, as shown in [Table 6] and [Table 7].,,,,,,,
|Table 6: Comparison of allele and genotype frequencies in other populations (values are expressed as number [percentage])|
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|Table 7: Comparison of allele and genotype frequencies of Vitamin D receptor polymorphism (rs2228570, A>G) with other Indian studies (values are expressed as number [percentage])|
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Vitamin D has been shown to be associated with respiratory viral infections and asthma. Recent studies have shown that low Vitamin D levels are linked to increased asthma severity in older children  and increased prenatal Vitamin D intake may reduce childhood asthma incidence. In our study, among the three SNPs studied, VDR polymorphism (rs2228570) was found to be protective against asthma. Variants within VDR, CYP2R1, and CYP24A1 genes have been shown to be associated with asthma in the Caucasians , and Egyptians. Some previous studies have raised the susceptibility of VDR gene to be a candidate gene for childhood asthma,, and it has been shown that VDR influences asthma and allergy susceptibility in a complex manner. A recent study of the VDR gene in Caucasian French Canadian families demonstrated associations between six alleles (rs3782905C, rs1540339A, rs2239185C, rs2239185G, BsmIG, and TaqIT) and asthma and four alleles (rs2239185C, BsmIG, ApaIC, and TaqIT) and atopy (P < 0.05), respectively., In the same population, three alleles (rs2239185C, ApaIC, and TaqIT) were significantly associated with higher IgE levels. In the Childhood Asthma Management Program cohort, the ApaI SNP was significantly associated with asthma in the overall population. In another study, VDR gene polymorphisms (rs7975232, rs2239185, rs2107301, rs1540339, rs3782905, and rs2228570) were significantly associated with increased asthma severity. A recent meta-analysis has demonstrated that rs2228570, rs7975232, rs731236, and rs3782905 gene polymorphisms in VDR are associated with increased susceptibility to asthma, indicating that VDR polymorphisms could be developed as biomarkers for asthma susceptibility. Another recent meta-analysis concluded that VDR gene polymorphism (rs2228570, C > T) may be connected with pediatric asthma in the Caucasian population.
However, there are few studies showing no associations between VDR gene polymorphisms and asthma., In a study conducted in Han Chinese population, of the five studied SNPs in VDR gene (rs2228570, rs3782905, rs1544410, rs7975232, and rs731236), only rs7975232 was significantly associated with asthma. In another study in Han Chinese population, polymorphisms in VDR and CYP2R1 genes were not associated with asthma. A study conducted in the German population has demonstrated that VDR gene is not associated with asthma or the expression of related allergic phenotypes such as eosinophilia and changes in IgE level. In a recent systematic review and meta-analysis including 483 unique studies, it was demonstrated that Vitamin D supplementation, as compared to placebo, reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids in people with a baseline serum 25(OH)D of <10 ng/ml, but Vitamin D supplementation did not result in a statistically significant reduction in exacerbation rate in participants with a baseline serum 25(OH)D of ≥10 ng/ml. The authors could not find definitive evidence that the effects of this intervention differed across subgroups of patients. Some previous authors have also suggested that FF genotype of FokI (rs2228570) in VDR gene is protective for asthma., Interestingly, a recent study in Serbian patients has demonstrated that FF genotype and F allele of FokI (rs2228570) in VDR gene have a protective effect on asthma. Likewise, our study has demonstrated that (rs2228570, C > T) is protective for asthma.
SNPs in CYP24A1 has been shown to be associated with asthma and atopy. In our study, although CYP24A1 polymorphism (rs2248137, C > G) showed associations with asthma, it was not of statistical significance. In a German adult cohort, a 5-point frequent CYP24A1 haplotype (rs2296241, rs17219315, rs276942, rs2248137, and rs2248359) was significantly associated with asthma and IgE level. In another study, CYP24A1 polymorphisms were significantly associated with decreased asthma control (rs2296241), higher baseline lung function (rs2248137), decreased response to bronchodilators (rs17219315, rs2248137, and rs2248359), and decrease in 25(OH)D level (rs2248137).
SNPs in CYP2R1 genes are also found to be associated with asthma and atopy. However, in our study, CYP2R1 (rs10766197, G > A) showed no associations with asthma. A German study reported a significant association between CYP2R1 SNP rs10766197 and IgE level. In another study, CYP2R1 polymorphism (rs10766197) homozygous genotype was associated with asthma. Significant associations were also found between rs10766197 of CYP2R1, rs7041 and rs4588 of CG, rs4646536 of CYP27B1, rs2228570, rs7975232, and rs1544410 of VDR, and susceptibility to and prognosis of childhood asthma. In a genome-wide association study on the role of Vitamin D in asthmatic individuals, four SNPs (rs11002969, rs163221, rs1678849, and rs4864976) were found to have consistent genetic associations with asthma in selected populations.
In our study, nonsignificant associations were observed between all the haplotypes and asthma. There were poor and nonsignificant correlations between the three SNPs and serum 25(OH)D levels in both asthma patients and healthy controls. Interestingly, there were nonsignificant associations between all the three SNPs and serum 25(OH)D levels with asthma control, as determined by the posttreatment changes in FEV1 and FeNO.
It is pertinent here to mention that the endogenous serum metabolite of Vitamin D (calcitriol, 1,25(OH)2D3) is considered a true steroid hormone (D hormone). Regarding a possible synergism between Vitamin D and glucocorticoids, several studies have shown that 1,25(OH)2D3 has significant additive effects on dexamethasone-mediated inhibition of human lymphocyte and monocyte proliferation. Steroid hormones derived from Vitamin D act through classical nuclear receptors, as well as specific binding sites on the plasma membrane of target cells that are coupled to signal transduction systems. One study has suggested that Vitamin D interacts with clinically relevant glucocorticoid signaling pathways. Likewise, another study found an association between lower Vitamin D levels and increased ICS requirements in children, with a reduced need for anti-inflammatory controller therapy, as serum 25(OH)D levels increased. An experimental model of corticosteroid resistance suggested that Vitamin D may restore the immunosuppressive function of dexamethasone. Thus, Vitamin D supplementation may accentuate the anti-inflammatory function of corticosteroids in asthma. It has been demonstrated clinically that Vitamin D sufficiency in patients treated with ICS is associated with improved lung function in patients with asthma., The correlation between higher serum 25(OH)D levels and improved lung function was stronger in ICS-naïve patients than who were previously treated with ICS. Likewise, in our study, there were good correlations between serum 25(OH)D level and response to ICS, as determined by posttreatment changes in FEV1 and FeNO score [Table 4].
Our study has few limitations. First of all, the selected SNPs of genes involved in Vitamin D actions and metabolic pathways might be having a relatively minor role in the complex disease process. The cumulative effects of other genetic polymorphisms in the same pathway (CYP27A1, CYP27B1, GC, etc.) or genes known to be transcriptionally regulated by Vitamin D (IL10, IL1RL1, CD28, CD86, IL8, SKIIP, etc.) as well as various environmental factors need to be studied. Second, the compliance to ICS was not supervised in our study. Third, there was a significant difference in the distribution of age according to baseline serum 25(OH)D levels in both asthma patients and healthy volunteers, keeping in mind that the effect of VDR system in immune responses might depend on age. Moreover, in the present study, the asthmatic patients had a significantly higher serum 25(OH)D level than the healthy controls. This could be attributed to the inclusion of healthy controls, mostly working indoors, unlike the patients. Similarly, nonresponders had higher serum 25(OH)D level than the responders. However, based on our findings, we would like to hypothesize this to genetic polymorphisms resulting in lower Vitamin D action irrespective of higher Vitamin D level among nonresponders and responders compared to healthy controls. However, this needs to be proven in a larger study by including sufficient number of patients in all the three Vitamin D-related genetic polymorphisms mentioned. Although these were conflicting findings in converse to our hypothesis, we are not very sure about the explanations given, since all cases and controls had Vitamin D level in insufficiency range irrespective of the significant difference. There is also a possibility that this could be a common finding since Vitamin D deficiency is known to prevail all over the country even among healthy people irrespective of their exposure to sunlight.
Notwithstanding these limitations, this study is a stepping stone in examining the potential associations of genetic polymorphisms involved in Vitamin D mechanism of actions as well as metabolic pathways with asthma control to ICS in a South Indian population. The findings indicate the potential value of additional pharmacogenetic testing and gene–gene interaction studies that can be in epistasis with genes involved in Vitamin D metabolism in asthma patients.
| Conclusion|| |
This study conducted in South Indian population has shown that a SNP in the VDR gene (rs2228570, C > T), that is involved in the genomic actions of Vitamin D, is protective for bronchial asthma while the SNPs (CYP24A1 [rs2248137, C > G] and CYP2R1 [rs10766197, G > A]) in the genes involved in the Vitamin D metabolism pathway have no associations with the disease. Further studies are required in a larger Indian population on all the polymorphisms in the genes involved in Vitamin D pathway.
Financial support and sponsorship
Intramural research grant, JIPMER, Puducherry, was obtained for this work.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]