Pneumonia in Egyptian Children 3.6 X more likely if poor Vitamin D Receptor
Association of vitamin D receptor gene FokI polymorphism and susceptibility to CAP in Egyptian children: a multicenter study
Pediatric Research (2018) https://doi.org/10.1038/s41390-018-0149-y
Heba Abouzeid, NourEldin M. Abdelaal, Mohammed A. Abdou, Amira A. A. Mosabah, Mervat T. Zakaria, Mohammed M. Soliman, Ashraf M. Sherif, Mohammed E. Hamed, Attia A. Soliman, Maha A. Noah, Atef M. Khalil, Mohamed S. Hegab, Alsayed Abdel-Aziz, Shaimaa S. A. Elashkar, Rehab M. Nabil, Adel M. Abdou, Ghada M. Al-Akad & Hany A. A. Elbasyouni
Background
Community-acquired pneumonia (CAP) is the leading cause of child deaths around the world. Recently, the vitamin D receptor (VDR) gene has emerged as a susceptibility gene for CAP.
Objectives
To evaluate the association of the VDR gene Fok I polymorphism with susceptibility to CAP in Egyptian children.
Methods
This was a multicenter case-control study of 300 patients diagnosed with CAP, and 300 well-matched healthy control children. The VDR Fok I (rs2228570) polymorphism was genotyped by PCR-restriction fragment length polymorphism (RFLP), meanwhile serum 25-hydroxy vitamin D (25D) level was assessed using ELISA method.
Results
The frequencies of the VDR FF genotype and F allele were more common in patients with CAP than in our control group (OR = 3.6; (95% CI: 1.9–6.7) for the FF genotype; P = 0.001) and (OR: 1.8; (95% CI: 1.4–2.3) for the F allele; P = 0.01). Patients carrying the VDR FF genotype had lower serum (25D) level (mean; 14.8 ± 3.6 ng/ml) than Ff genotype (20.6 ± 4.5 ng/ml) and the ff genotype (24.5 ± 3.7 ng/ml); P < 0.01.
Conclusion
The VDR gene Fok I (rs2228570) polymorphism confers susceptibility to CAP in Egyptian children.
References
- Wardlaw, T., Salama, P., Johansson, E. W. & Mason, E. Pneumonia: the leading killer of children. Lancet 368, 1048–1050 (2006).
2. Solé- Violán, J. et al. Genetic variability in the severity and outcome of community-acquired pneumonia. Respir. Med. 104, 440–447 (2010).
3. Patwari, P. P. et al. Interleukin-1 receptor antagonist intron 2 variable number of tandem repeats polymorphism and respiratory failure in children with community-acquired pneumonia. Pediatr. Crit. Care. Med. 9, 553–559 (2008).
4. Pike, J. W. & Meyer, M. B. The vitamin D receptor: new paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D(3). Endocrinol. Metab. Clin. North. Am. 39, 255–269 (2010).
5. Underwood, M. A. & Bevins, C. L. Defensin-barbed innate immunity: clinical associations in the pediatric population. Pediatrics 125, 1237–1247 (2010).
6. Hossein-nezhad, A. & Holick, M. F. Vitamin D for health: a global perspective. Mayo Clin. Proc. 88, 720–755 (2013).
7. Liu, P. T., Stenger, S., Tang, D. H. & Modlin, R. L. Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J. Immunol. 179, 2060–2063 (2007).
8. Khoo, A. L. et al. Translating the role of vitamin D3 in infectious diseases. Crit. Rev. Microbiol. 38, 122–135 (2012).
9. Muhe, L., Lulseged, S., Mason, K. E. & Simoes, E. A. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet 349, 1801–1804 (1997).
10. Banajeh, S. M. Nutritional rickets and vitamin D deficiency–association with the outcomes of childhood very severe pneumonia: a prospective cohort study. Pediatr. Pulmonol. 44, 1207–1215 (2009).
11. Manaseki-Holland, S. et al. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop. Med. Int. Health 15, 1148–1155 (2010).
12. O Neill, V., Asani, F. F., Jeffery, T. J., Saccone, D. S. & Bornman, L. Vitamin D receptor gene expression and function in a South African population: ethnicity, vitamin D and FokI. PLoS ONE 8, e67663 (2013).
13. Nejentsev, S. et al. Comparative high-resolution analysis of linkage disequilibrium and tag single nucleotide polymorphisms between populations in the vitamin D receptor gene. Hum. Mol. Genet. 13, 1633–1639 (2004).
14. van Etten, E. et al. The vitamin D receptor gene FokI polymorphism: functional impact on the immune system. Eur. J. Immunol. 37, 395–405 (2007).
15. Neuman, M. I., Monuteaux, M. C., Scully, K. J. & Bachur, R. G. Prediction of pneumonia in a pediatric emergency department. Pediatrics 128, 246–253 (2011).
16. World Health Organization: Standardization of interpretation of chest radiographs for the diagnosis of pneumonia in children. In WHO/V&B;/01.35. Pneumonia Vaccine Trials Investigator’s Group. Geneva: World Health Organization; 2001:32.
17. British Thoracic Society of Standards of Care Committee. BTS Guidelines for the management of community acquired pneumonia in childhood. Thorax 57, 1i–24i (2011).
18. Goldstein, B., Giroir, B. & Randolph, A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr. Crit. Care. Med. 6, 2–8 (2005).
19. Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007).
20. Mory, D. B. et al. Prevalence of vitamin D receptor gene polymorphisms FokI and BsmI in Brazilian individuals with type 1 diabetes and their relation to beta-cell autoimmunity and to remaining beta-cell function. Hum. Immunol. 70, 447–451 (2009).
Show context for reference 20
Google Scholar
21. Harris, M. et al. British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011. Thorax 66(Suppl 2), ii1–ii23 (2011).
Show context for reference 21
Google Scholar
22. Salimpour, R. Rickets in Tehran. Study of 200 cases. Arch. Dis. Child. 50, 63–66 (1975).
Show context for reference 22
Google Scholar
23. Hughes, D. A. & Norton, R. Vitamin D and respiratory health. Clin. Exp. Immunol. 158, 20–25 (2009).
Show context for reference 23
Google Scholar
24. Dürr, U. H., Sudheendra, U. S. & Ramamoorthy, A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim. Biophys. Acta 1758, 1408–1425 (2006).
Show context for reference 24
Google Scholar
25. Raloff, J. The antibiotic vitamin: deficiency in vitamin D may predispose people to infection. Sci. News 170, 312–317 (2006).
Show context for reference 25
Google Scholar
26. Edelson, J. D., Chan, S., Jassal, D., Post, M. & Tanswell, A. K. Vitamin D stimulates DNA synthesis in alveolar type-II cells. Biochim. Biophys. Acta 1221, 159–166 (1994).
Show context for reference 26
Google Scholar
27. Gao, L., Tao, Y., Zhang, L. & Jin, Q. Vitamin D receptor genetic polymorphisms and tuberculosis: updated systematic review and meta-analysis. Int. J. Tuberc. Lung. Dis. 14, 15–23 (2010).
Show context for reference 27
Google Scholar
28. Han, W. G. et al. Association of vitamin D receptor polymorphism with susceptibility to symptomatic pertussis. PLoS ONE 11, e0149576 (2016).
Show context for reference 28
Google Scholar
29. Kresfelder, T. L., Janssen, R., Bont, L., Pretorius, M. & Venter, M. Confirmation of an association between single nucleotide polymorphisms in the VDR gene with respiratory syncytial virus related disease in South African children. J. Med. Virol. 83, 1834–1840 (2011).
Show context for reference 29
Google Scholar
30. Li, W. et al. Polymorphism rs2239185 in vitamin D receptor gene is associated with severe community-acquired pneumonia of children in Chinese Han population: a case–control study. Eur. J. Pediatr. 174, 621–629 (2015).
Show context for reference 30
Google Scholar
31. Roth, D. E., Jones, A. D., Prosser, C., Robinson, J. L. & Vohra, S. Vitamin D receptor polymorphism and the risk of acute lower respiratory tract infection in early childhood. J. Infect. Dis. 197, 676–680 (2008).
Show context for reference 31
Google Scholar
32. El Basha, N., Mohsen, M., Kamal, M. & Mehaney, D. Association of vitamin D deficiency with severe pneumonia in hospitalized children under 5 years. Comp. Clin. Pathol. 23, 1247–1252 (2014).
Show context for reference 32
Google Scholar
33. Inamo, Y. et al. Serum vitamin D concentrations and associated severity of acute lower respiratory tract infections in Japanese hospitalized children. Pediatr. Int. 53, 199–201 (2011).
Show context for reference 33
Google Scholar
34. Monticielo, O. A. et al. The role of BsmI and FokI vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D in Brazilian patients with systemic lupus erythematosus. Lupus 21, 43–52 (2012).
Show context for reference 34
Google Scholar
35. Das, B., Patra, S., Behera, C. & Suar, M. Genotyping of vitamin D receptor gene polymorphisms using mismatched amplification mutation assay in neonatal sepsis patients of Odisha, eastern India. Infect. Genet. Evol. 45, 40–47 (2016).
Show context for reference 35
Google Scholar
36. Møller, S., Laigaard, F., Olgaard, K. & Hemmingsen, C. Effect of 1,25-dihydroxy-vitamin D3 in experimental sepsis. Int. J. Med. Sci. 4, 190–195 (2007).
Show context for reference 36
Google Scholar
37. Liu, P. T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).
Show context for reference 37
Google Scholar
38. Jeng, L. et al. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J. Transl. Med. 7, 28 (2009).
Show context for reference 38
Google Scholar
39. Lee, P., Nair, P., Eisman, J. A. & Center, J. R. Vitamin D deficiency in the intensive care unit: an invisible accomplice to morbidity and mortality? Intensive Care Med. 35, 2028–2032 (2009).
40. Aird, W. C. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101, 3765–3777 (2003).
41. Kamen, D. L. & Tangpricha, V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J. Mol. Med. 88, 441–450 (2010).
42. Yorita, K. L. et al. Severe bronchiolitis and respiratory syncytial virus among young children in Hawaii. Pediatr. Infect. Dis. J. 26, 1081–1088 (2007).
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Acknowledgements
We thank the staff of Pediatric Pulmonology and Outpatient Clinics in Zagazig University, Ain-Shams and Cairo University hospitals for their collaboration in sampling as well as our patients who participated in the study.
Author contributions
H.A.Z. submitted the manuscript. M.A.A. designed the study. A.M.K. collected clinical data and coordinated the sample collection (Zagazig University). N.M.A. collected clinical data and coordinated the sample collection (Ain-Shams University). M.M.S. collected clinical data and coordinated the sample collection (Cairo University). M.S.H. and H.A.A.E. performed the statistical analysis. M.A.N. and A.A.S. helped to draft the manuscript. A.M.S., A.A.M., and M.E.H. wrote the manuscript. A.A.A., M.T.Z., and S.S.A.E. critically revised the final version. A.M.A., R.M.N., and G.M.A. performed laboratory analysis and genotyping. All authors read and approved all the manuscript.
Author information
Affiliations
Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
Heba Abouzeid, Mohammed A. Abdou, Mohammed E. Hamed, Attia A. Soliman, Maha A. Noah, Atef M. Khalil, Mohamed S. Hegab, Alsayed Abdel-Aziz & Shaimaa S. A. Elashkar
Department of Pediatrics, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
NourEldin M. Abdelaal
Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
Amira A. A. Mosabah, Mervat T. Zakaria, Mohammed M. Soliman & Ashraf M. Sherif
Department of Clinical pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
Rehab M. Nabil & Ghada M. Al-Akad
Department of Clinical pathology, Al Azhar Faculty of Medicine, Cairo, Egypt
Adel M. Abdou
Department of Internal Medicine, Faculty of Medicine, Menoufia University, Monufia, Egypt
Hany A. A. Elbasyouni
Competing interests
The authors declare no competing interests.
Corresponding author
Correspondence to Heba Abouzeid.