Vitamin D receptor gene variations and influence on asthma control with Vitamin D3 supplementation in adults with asthma: a pilot randomised controlled trial

Asthma is a heterogenous, chronic respiratory disorder characterized by airway inflammation, expiratory airflow limitation and plethora of symptoms ranging from wheeze, chest tightness, shortness of breath and cough to episodic flare-ups or exacerbations1. Asthma affects 1-18% of the population across different nations and had an annual reported worldwide incidence of 262 million in 2019 contributing to 4,61,000 deaths2.Asthma is not only associated with patient�’specific impairment but also a significant social, mental and economic burden to the family and society. Majority of our population does not possess health insurance and high out�’of�’pocket costs may be deterring for purchase of asthma medications. Further, language and health literacy barriers may limit effectiveness of asthma self�’management education.Access to inhalers in public primary health-care facilities is also a major problem in low-income countries like India. The resulting limited adherence accounts for poor disease control and exacerbations.  Exacerbations, triggered commonly by viral respiratory infections and/or poor adherence to controller medications, may be life-threatening and primarily account for mortality associated with this disorder.

In recent era, vitamin D has been identified as an effect modifier of pulmonary function, disease severity and response to corticosteroid therapy in asthma. An important role of vitamin D in pulmonary health has been attributed to its immune-modulatory and anti-inflammatory effects. Vitamin D has been reported to decrease the airway smooth muscle cell proliferation and collagen deposition, attenuate Th2 and Th17 responses and promote IL-10 synthesis by B cells 3-5. IL-10 in turn suppresses T cell activation by inhibiting antigen presentation by macrophages and dendritic cells, also it inhibits IgE expression of peripheral B cells 6. Several observational studies have reported a direct correlation between low serum 25-hydroxy vitamin D levels and deteriorating lung function, which in turn predisposes to acute exacerbations 7-10. These findings compounded by concerns over far-flung vitamin D insufficiency in general and asthmatic population form strong rationale for vitamin D supplementation to improve outcomes in asthma.

According to a systematic review of eight RCTs including 1078 participants, vitamin D supplementation reduced the rate of asthma exacerbations requiring overall treatment with systemic corticosteroids11. Another systematic review provided inconclusive evidence regarding the utility of vitamin D supplementation in clinical practice and highlighted the need of more research in this area12.  In a randomised, double blind placebo controlled clinical trial (VIDA trial) by Castro et al, vitamin D3 supplementation did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency13. Another trial (ViDiAs trial) reported non-significant benefit of vitamin D supplementation on time to asthma exacerbation in adults with asthma compared to placebo 14.

Given the emerging data with few interventional studies claiming to confirm the benefit of vitamin D supplementation to improve asthma related outcomes in adults while others not supporting it, there is still conflicting evidence in this direction. One possible explanation for this dilemma may be genetic background influences and a possible role of genetic polymorphisms in vitamin D pathway on therapeutic response to vitamin D supplementation in asthma. Numerous genetic polymorphisms involving vitamin D metabolism (e.g. CYP2R1, CYP27B1, vitamin D binding protein) and function (vitamin D receptor) have been identified to be related with asthma severity, treatment response, changes in inflammatory markers and serum vitamin D levels 15. Among these, the gene encoding vitamin D receptor (VDR) has been most widely studied and several VDR gene single nucleotide polymorphisms (SNPs) viz. FokI, BsmI, ApaI, TaqI have been linked with prognosis in bronchial asthma. A study conducted in asthmatic patients of South Indian origin reported protective role of VDR polymorphism Fok I (rs2228570) against asthma 16. Another study by Lahmar et al reported an association of gene polymorphisms in vitamin D metabolism pathway (rs12794714 and rs10877012) with increased risk of asthma 17. Mohamed et al in a case control study observed a possible association between the FokI T allele and glucocorticoid resistance in patients with asthma 18. Martineau et al in a randomised controlled trial observed that the influence of vitamin D supplementation on the coprimary outcome of prevention of asthma exacerbationa and upper respiratory infection was not modified by different vitamin D pathway genotypes 14.

Based on conflicting evidence on benefit of vitamin D supplementation in bronchial asthma, we hypothesize a possible role of genetic polymorphisms in vitamin D pathway on therapeutic response to vitamin D supplementation in adults with asthma. The results of this study are expected to provide a theoretical basis for rational vitamin D3 supplementation in  asthmatic patients with different genetic backgrounds.

1.  References

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2.   https://www.who.int/news-room/fact-sheets/detail/asthma. Accessed August 2022.

3.   MatheuV, BackO, Mondoc E, Issazadeh-Navikas S. Dual effects of vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease. J Allergy Clin Immunol. 2003;112(3):585-592. doi:10.1016/S0091-6749(03) 01855-4

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5.   Heine G, Niesner U, Chang HD, et al. 1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells. Eur J Immunol. 2008; 38(8):2210-2218. doi:10.1002/eji.200838216.

6.   Jeffery LE, Burke F, MuraM, et al. 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol. 2009; 183(9):5458-5467. doi:10.4049/jimmunol.0803217

7.   Brehm JM, Acosta-Perez E, Klei L, et al. Vitamin D Insufficiency and Severe Asthma Exacerbations in Puerto Rican Children. Am J Respir Crit Care Med 2012; 186 (2): 140–146.

8.   Esfandiar N, Alaei F, Fallah S, et al. Vitamin D deficiency and its impact on asthma severity in asthmatic children. Italian Journal of Pediatrics. 2016; 42:108. doi: 10.1186/s13052-016-0300-5.

9.   Sharif A, Kashani HH, Sharif MR. Association of 25�’hydroxy vitamin D with asthma and its severity in children: a case–control study. Clin Mol Allergy. 2020; 18:7. doi.org/10.1186/s12948-020-00122-9.

10.Ozturk Thomas G, Tutar E, Tokuc G, et al. (March 22, 2019) 25-hydroxy Vitamin D Levels in Pediatric Asthma Patients and its Link with Asthma Severity. Cureus 11(3): e4302. DOI 10.7759/cureus.4302.

11.Jolliffe DA , Griffiths CJ, Camargo CA et al. Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. Lancet Respir Med. 2017 November ; 5(11): 881–890.

12.Martineau AR, Cates CJ, Urashima M, Jensen M, Gri­iths AP, Nurmatov U, Sheikh A, Gri­iths CJ. Vitamin D for the management of asthma. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD011511. DOI: 10.1002/14651858.CD011511.pub2.

13. Castro M, King T S, Kunselman S J, et al. Effect of Vitamin D3 on Asthma Treatment Failures in Adults With Symptomatic Asthma and Lower Vitamin D Levels: the VIDA randomised clinical trial. JAMA. 2014 May ; 311(20): 2083–2091.

14.Martineau A R,MacLaughlin B D,Hooper R L, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax 2015;70:451–457.

15. Iordanidou M, Paraskakis E, Giannakopoulou E, et al. Vitamin D Receptor ApaI a Allele Is Associated with Better Childhood Asthma Control and Improvement in Ability for Daily Activities. OMICS A Journal of Integrative Biology. 2014; 18 (11). doi: 10.1089/omi.2014.0023.

16. Rajaram M, Selvarajan S, Neelamegan R, et al. 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(6): 483–491. doi: 10.4103/lungindia.lungindia_23_19.

17. Lahmar O, Salhi M, Kaabachi W et al. Association Between Vitamin D Metabolism Gene Polymorphisms and Risk of Tunisian Adults’ Asthma. Lung 2018. https://doi.org/10.1007/s00408-018-0101-2

18. Mohamed NA, Abdel-Rehim ASM. Influence of vitamin D receptor gene FokI and ApaI polymorphisms on glucocorticoid response in patients with asthma. Int Forum Allergy Rhinol. 2019;00:1-8.