Population Study Article | Published:

Association of vitamin D receptor gene FokI polymorphism and susceptibility to CAP in Egyptian children: a multicenter study



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.


To evaluate the association of the VDR gene Fok I polymorphism with susceptibility to CAP in Egyptian children.


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.


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.


The VDR gene Fok I (rs2228570) polymorphism confers susceptibility to CAP in Egyptian children.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Wardlaw, T., Salama, P., Johansson, E. W. & Mason, E. Pneumonia: the leading killer of children. Lancet 368, 1048–1050 (2006).

  2. 2.

    Solé- Violán, J. et al. Genetic variability in the severity and outcome of community-acquired pneumonia. Respir. Med. 104, 440–447 (2010).

  3. 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. 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. 5.

    Underwood, M. A. & Bevins, C. L. Defensin-barbed innate immunity: clinical associations in the pediatric population. Pediatrics 125, 1237–1247 (2010).

  6. 6.

    Hossein-nezhad, A. & Holick, M. F. Vitamin D for health: a global perspective. Mayo Clin. Proc. 88, 720–755 (2013).

  7. 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. 8.

    Khoo, A. L. et al. Translating the role of vitamin D3 in infectious diseases. Crit. Rev. Microbiol. 38, 122–135 (2012).

  9. 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. 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. 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. 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. 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. 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. 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. 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. http://www.who.int/iris/handle/10665/66956

  17. 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. 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. 19.

    Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007).

  20. 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).

  21. 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).

  22. 22.

    Salimpour, R. Rickets in Tehran. Study of 200 cases. Arch. Dis. Child. 50, 63–66 (1975).

  23. 23.

    Hughes, D. A. & Norton, R. Vitamin D and respiratory health. Clin. Exp. Immunol. 158, 20–25 (2009).

  24. 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).

  25. 25.

    Raloff, J. The antibiotic vitamin: deficiency in vitamin D may predispose people to infection. Sci. News 170, 312–317 (2006).

  26. 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).

  27. 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).

  28. 28.

    Han, W. G. et al. Association of vitamin D receptor polymorphism with susceptibility to symptomatic pertussis. PLoS ONE 11, e0149576 (2016).

  29. 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).

  30. 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).

  31. 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).

  32. 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).

  33. 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).

  34. 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).

  35. 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).

  36. 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).

  37. 37.

    Liu, P. T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).

  38. 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).

  39. 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. 40.

    Aird, W. C. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101, 3765–3777 (2003).

  41. 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. 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).

Download references


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

Correspondence to Heba Abouzeid.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading

Fig. 1