Association between Vitamin D Level, Vitamin D Receptor Gene Polymorphisms, and Cathelicidin Level to Acute Lower Respiratory Infections, and the Picture of Exon 2-Vitamin D Receptor Gene Polymorphisms in Children under 5 years old

  • Ida Bagus Subanada Department of Pediatric, School of Medicine, Universitas Udayana, Sanglah General Hospital, Denpasar, Bali, Indonesia
  • I. Made Bakta Department of Internal Medicine, School of Medicine, Universitas Udayana, Sanglah General Hospital, Denpasar, Bali, Indonesia
  • I. Wayan Bikin Suryawan Department of Pediatric, Wangaya Hospital Denpasar, Bali, Indonesia
  • Putu Astawa Department of Orthopaedic, School of Medicine, Universitas Udayana, Sanglah General Hospital Denpasar, Bali, Indonesia
  • Bagus Komang Satriyasa Department of Pharmacology, School of Medicine, Universitas Udayana Denpasar, Bali, Indonesia
Keywords: acute lower respiratory infections, vitamin D level, VDR gene polymorphism, cathelicidin level, children under five


BACKGROUND: Acute lower respiratory infections (ALRIs) are infectious diseases with high morbidity and mortality in children under five. There are several factors associated with ALRIs (bronchiolitis or pneumonia) that have been established. In recent years, Vitamin D level, Vitamin D receptor (VDR) gene polymorphism, and cathelicidin level are also associated with ALRIs. Until now, there was no VDR gene other than Fok1 identified at the exon 2-VDR gene.

OBJECTIVE: The objective of this study was to establish whether Vitamin D deficiency, ff genotype-Fok1 VDR gene polymorphism, and low levels of cathelicidin are risk factors of ALRIs and to determine the pictures of exon 2-VDR genes polymorphisms in children under five.

METHODS: A matched case–control study was conducted in children under the age of five. There were 35 subjects who suffered from bronchiolitis or pneumonia and 35 healthy subjects as a control group. These groups were matched based on age and gender, and the children originated from the same neighborhood. Level of 25(OH) D, exon 2-VDR genes sequencing, and level of cathelicidin were investigated. Data were analyzed by the Chi-square test or Fisher exact test and logistic regression with a significant level of p < 0.05.

RESULTS: This study found that Vitamin D deficiency and low levels of cathelicidin were risk factors of ALRIs (odds ratio [OR] = 5.82 [95% confidence interval [CI] = 1.71–19.89], p = 0.005 and OR = 4.07 [95% CI = 1.10–15.12], p = 0.036, respectively), while ff genotype-Fok1 VDR gene polymorphism was not (OR = 1.12 [95% CI = 0.26–4.86], p = 1.000). Fok1 VDR gene polymorphism was the picture of exon 2-VDR gene polymorphisms.

CONCLUSION: It is concluded that Vitamin D deficiency and low levels of cathelicidin are risk factors, but ff genotype-Fok1 VDR gene polymorphism is not a risk factor of ALRIs. Fok1 VDR gene polymorphism is the picture of exon 2-VDR genes polymorphisms.


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DeNicola LK, Maraqa NF, Custodio HT. Bronchiolitis. Available from: overview#a0156. [Last accessed on 2013 Dec 10].

Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, et al. Global burden of childhood pneumonia and diarrhoea. Lancet. 2013;381(9875):1405-16. s0140-6736(13)60222-6 PMid:23582727

United Nations Children’s Fund (UNICEF). Committing to Child Survival: A Promise Renewed. Progress Report; 2012. Available from: [Last accessed on 2013 Dec 01].

WHO. Pneumonia Still Responsible for One 5th of Child Deaths. Available from: world-penumonia-day-201311122/en. [Last accessed on 2014 Jul 25].

United Nations Children’s Fund (UNICEF). Pneumonia and Diarrhea: Tackling the Deadliest Disease for the World’s Poorest Children; 2012. Available from: http://www.worldpneumoniaday. org. [Last accessed on 2013 Dec 01].

Departemen Kesehatan Indonesia. Profil Kesehatan Indonesia 2012. Jakarta: Departemen Kesehatan Indonesia; 2013.

Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: Systematic review and meta-analysis. BMJ. 2011;343:d5094. PMid:21868478

Watts KD, Goodman DM. Wheezing in infant: Bronchiolitis. In: Kliegman RM, Stanton BF, Geme JW, Schor NF, Behrman RE, editors. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Saunders; 2011. p. 1456-9. b978-1-4377-0755-7.00714-4

Ali S, Plint AC, Klassen TP. Bronkiolitis. In: Wilmott RW, Chernick V, Boat TF, Deterding RR, Bush A, Ratjen F, editors. Kendig and Chernick’s Disorders of The Respiratory Tract in Children. 8th ed. Philadelphia, PA: Saunders; 2012. p. 443-52.

Crowe JE. Viral pneumonia. In: Wilmott RW, Chernick P, Boat TF, Deterding RR, Bush A, Ratjen F, editors. Kendig and Chernick’s Disorders of the Respiratory Tract in Children. 8th ed. Philadelphia, PA: Saunders; 2012. p. 453-60. https://doi. org/10.1016/b978-1-4377-1984-0.00081-4

Jackson S, Mathews KH, Pulanic D, Falconer R, Rudan I, Campbell H, et al. Risk factors for severe acute lower respiratory infection in children-a systematic review and meta-analysis. Croat Med J. 2013;54(2):110-21. cmj.2013.54.110 PMid:23630139

Marostica PJ, Stein RT. Communiy-acquired bacterial pneumonia. In: Wilmott RW, Chernick P, Boat TF, Deterding RR, Bush A, Ratjen F, editors. Kendig and Chernick’s Disorders of the Respiratory Tract in Children. 8th ed. Philadelphia, PA: Saunders; 2012. p. 461-72. b978-1-4377-1984-0.00081-4

Roth DE, Shah R, Black RE, Baqui AH. Vitamin D status and acute lower respiratory infection in early childhood in Sylhet, Bangladesh. Acta Paediatr. 2010;99(3):389-93. https://doi. org/10.1111/j.1651-2227.2009.01594.x PMid:19900174

Belderbos ME, Houben ML, Wilbrink B, Lentjes E, Bloemen EM, Kimpen JLL, et al. Cord blood Vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Pediatrics. 2011;127(6):e1513-20. PMid:21555499

Camargo CA Jr., Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, et al. Randomized trial of Vitamin D supplementation and risk of acute respiratory tract infection in Mongolia. Pediatrics. 2012;130(3):e561-7. https://doi. org/10.1542/peds.2011-3029 PMid:22908115

Leis KS, McNally JD, Montgomery MR, Sankaran K, Karunanayake C, Rosemberg AM. Vitamin D intake in young children with acute lower respiratory infection. Transl Pediatr. 2012;1(1):6-14. PMid:26835258

Roth DE, Jones AB, Prosser C, Robinson JL, Vohra S. Vitamin D status is not associated with the risk of hospitalization for acute bronchiolitis in early childhood Vitamin D status and childhood bronchiolitis. Eur J Clin Nutr. 2009;63(2):297-9. https://doi. org/10.1038/sj.ejcn.1602946 PMid:17971825

McNally JD, Leis K, Matheson LA, Karuananyake C, San- Karan K, Rosenberg AM. Vitamin D deficiency in young children with severe acute lower respiratory infection. Pediatr Pulmonol. 2009;44(10):981-8. PMid:19746437

Hewison M. An update on Vitamin D and human immunity. Clin Endocrinol (Oxf). 2012;76(3):315-25. PMid:21995874

White JH. Vitamin D signaling, infectious diseases, and regulation of innate immunity. Infect Immun. 2008;76(9):3837-43. PMid:18505808

Roth DE, Jones AB, Proser C, Robinson JL, Vobra S. Vitamin D receptor polymorphisms and the risk of acute lower respiratory tract infection in early childhood. J Infect Dis. 2008;197(5):676- 80. PMid:18266602

Bruce D, Ooi JH, Cantoma MT. Vitamin D host resistance to infection? Putting the cart infront of the horse. Exp Biol Med (Maywood). 2010;235(8):921-7. ebm.2010.010c02 PMid:20660091

Bartley J. Vitamin D, innate immunity and upper respiratory tract infection. J Laryngol Otol. 2010;124(5):465-9. https://doi. org/10.1017/s0022215109992684 PMid:20067648

Gombart AF, Bhan I, Borregaard N. Low plasma level of cathelicidin antimicrobial peptide (hCAP 18) predicts increased infectious diseases mortality in patients undergoing hemodialysis. Clin Infect Dis. 2009;48(4):418-24. https://doi. org/10.1086/596314 PMid:19133797

Albanna EA, Ali YF, Elkashnia RA. Vitamin D and LL-37 in children with pneumonia. Egypt J Pediatr Allergy Immunol. 2010;8(2):81-6.

Yildiz I, Unuvar E, Zeybek U, Toptas B, Cacina C, Toprak S, et al. The role of Vitamin D in children with recurrent tonsillopharyngitis. Ital J Pediatr. 2012;38:25. https://doi. org/10.1186/1824-7288-38-25 PMid:22682426

Leow L, Simpson T, Cursons R, Karalus N, Hancox RJ. Vitamin D, innate immunity and outcomes in community acquired pneumonia. Respirology. 2011;16(4):611-6. https://doi. org/10.1111/j.1440-1843.2011.01924.x PMid:21244571

Holick MF. Vitamin D: A millenium perspective. J Cell Biochem. 2003;88(2):296-307. PMid:12520530

Holick MF. Sunlight and Vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004;80(6):1678S-88. ajcn/80.6.1678s PMid:15585788

Uitterlinden AG, Fang Y, van Meurs JB, Pols HA, van Leeuwen JP. Genetics and biology of Vitamin D receptor polymorphism. Gene. 2004;338(2):143-56. https://doi. org/10.1016/j.gene.2004.05.014 PMid:15315818

Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of Vitamin D deficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911- 30. PMid:21646368

Ojaimi S, Skinner NA, Strauss BJ, Sundararajan V, Woolley I, Visvanathan K. Vitamin D deficiency impacts on expression of toll-like receptor-2 and cytokine profile: A pilot study. J Transl Med. 2013;11:176. PMid:23875738

Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the Vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25 dihydroxyvitamin D3. FASEB J. 2005;19(9):1067-77. PMid:15985530

Finklea JD, Grossmann RE, Tangpricha V. Vitamin D and chronic lung disease: A review of molecular mechanism and clinical studies. Adv Nutr. 2011;2(3):244-53. PMid:22332056

Deluca HF, Prahl JM, Plum LA. 1,25-dihydroxyvitamin D is not responsible for toxicity caused by Vitamin D or 25-hydroxyvitamin D. Arch Biochem Biophys. 2011;505(2):226- 30. PMid:20965147

Heaney RP. Vitamin D-baseline status and effective dose. N Engl J Med. 2012;367(1):77-8. PMid:22762324

Shin YH, Yu J, Kim KW, Ahn K, Hong SA, Lee E, et al. Association between cord blood 25-hydroxyvitamin D concentrations and respiratory tract infections in the first 6 months of age in a Korean population: A birth cohort study (COCOA). Korean J Pediatr. 2013;56(10):439-45. kjp.2013.56.10.439 PMid:24244212

Litonjua AA. Vitamin D deficiency as a risk factor for childhood allergic disease and asthma. Curr Opin Allergy Clin Immunol. 2012;12(2):179-85. aci.0b013e3283507927 PMid:22266772

Genetics Home Reference. Your Guide to Understanding Genetics Conditions. VDR-Vitamin D 1,25-dyhidroxyvitamin D3) Receptor. Available from: VDR. [Last accessed on 2014 Oct 02].

Flugge J, Krusekopf S, Goldammer M, Osswald E, Terhalle W, Malzahn U, et al. Vitamin D receptor hapotypes protect against development of colorectal cancer. Eur J Clin Pharmacol. 2007;63(11):997-1005. s00228-007-0367-4 PMid:17882409

Arai H, Miyamoto K, Taketani Y, Yamamoto H, Iemori Y, Morita K, et al. A Vitamin D receptor gene polymorphism in the translation initiation codon: Effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res. 1997;12(6):915-21. PMid:9169350

Saijo T, Naito E, Ito M, Takeda E, Hashimoto T, Kuroda Y. Therapeutic effect of sodium dichloroacetate on visual and auditory hallucinations in a patient with MELAS. Neuropediatrics. 1991;22(3):166-7. PMid:1944824

Nizet V, Gallo RL. Cathelicidins and innate defence against invasive bacterial infection. Scand J Infect. 2003;35(9):670-6. PMid:14620153

Tomasinsig L, Zanetti M. The cathelicidins. Structure, function, and evolution. Curr Protein Pept Sci. 2005;6(1):23-34. PMid:15638766

Jeng L, Yamshcchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, et al. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med. 2009;7:28. PMid:19389235

Peric M, Koglin S, Kim SM. Enhances Vitamin D-induced expression of cathelicidin antimicrobial peptide in human keratinocytes. J Immunol. 2008;181(12):8504-12. https://doi. org/10.4049/jimmunol.181.12.8504 PMid:19050268

Dixon BM, Barker T, Mckinnon T, Cuomo J, Frei B, Borregaard N, et al. Positive correlation between circulating cathelicidin antimicrobial peptide (hCAP18)/LL-37) and 25-hydroxyvitamin D levels in healthy adults. BMC Res Notes. 2012;5:575. https:// PMid:23095332

Miller EK, Gebretsadik T, Carroll KN, Dupont WD, Mohamed YA, Morin, et al. Viral etiologies of infants bronchiolitis, croup, and upper respiratory illness during four consecutive years. Pediatr Infect Des. 2013;32(9):950-5. inf.0b013e31829b7e43 PMid:23694832

Robinson J. Viral Pneumonia. Available from: http://www. infection. [Last accessed on 2016 Jan 09].

Schwalfenberg GK. A review of the critical role of Vitamin D in the functioning of the immune system and the clinical implications of Vitamin D deficiency. Mol Nutr Food Res. 2011;55(1):96-108. PMid:20824663

How to Cite
Subanada IB, Bakta IM, Suryawan IWB, Astawa P, Satriyasa BK. Association between Vitamin D Level, Vitamin D Receptor Gene Polymorphisms, and Cathelicidin Level to Acute Lower Respiratory Infections, and the Picture of Exon 2-Vitamin D Receptor Gene Polymorphisms in Children under 5 years old. Open Access Maced J Med Sci [Internet]. 2020May10 [cited 2020Oct.31];8(B):536-41. Available from: