Skip to main content
Top
Published in: BMC Pediatrics 1/2023

Open Access 01-12-2023 | Pneumonia | Research

Increased susceptibility to complicated pneumonia among egyptian children with FokI (rs2228570), not TaqI (rs731236), vitamin D receptor gene polymorphism in association with vitamin D deficiency: a case-control study

Authors: Mahitab Morsy Hussein, Enas Maher Mohamed, Tarek Mostafa Kamal, Tharwat Ezzat Deraz

Published in: BMC Pediatrics | Issue 1/2023

Login to get access

Abstract

Background

Determining a genetic contribution to the development of complicated community-acquired pneumonia in children may help understand underlying pathogenesis. We aimed to investigate the association between two vitamin D receptor (VDR) gene polymorphisms, FokI and TaqI, and susceptibility to complicated pneumonia in Egyptian children compared to uncomplicated pneumonia. Associations with 25 hydroxy-vitamin D serum level were studied.

Methods

This was a case-control study that included 320 participants divided into 2 groups: patients and controls. The patients’ group included 100 children hospitalized with complicated pneumonia and 100 with uncomplicated pneumonia. 120 age and sex-matched apparently healthy children served as controls. The VDR FokI and TaqI polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. 25 hydroxy-vitamin D level was estimated in serum using ELISA.

Results

Regarding FokI, homozygous CC genotype was more common in complicated (52%) than uncomplicated pneumonia (28%) and controls (10%) (OR = 65; 95%CI (5.13-822.63), p < 0.001) and (OR = 4.3; 95%CI (0.7-27.16), p = 0.003), respectively. Children carrying C allele possessed 3 higher odds for complicated than uncomplicated pneumonia (OR = 3.08; 95%CI (1.33–7.14), p < 0.001). Heterozygous CT genotype increased susceptibility to complicated pneumonia (OR = 13.7; 95%CI (4.6–40.1), p < 0.001), not uncomplicated pneumonia (OR = 1.56; 95%CI (0.86–2.85), p = 0.145). Among complicated pneumonia, vitamin D level was lower in CC (6.92 ± 2.6ng/ml) than CT (9.55 ± 3.2 ng/ml) and TT genotype carriers (13.13 ± 3.6ng/ml) (p < 0.001). There was no significant difference between patients and controls as regards TaqI genotypes and alleles.

Conclusion

In association with vitamin D deficiency, VDR gene FokI polymorphism, not TaqI, is a genetic risk factor for complicated pneumonia in Egyptian children.
Appendix
Available only for authorised users
Literature
1.
go back to reference Nasrin S, Tariqujjaman M, Sultana M, Zaman RA, Ali S, Chisti MJ, Faruque AG, Ahmed T, Fuchs GJ, Gyr N, et al. Factors associated with community acquired severe pneumonia among under five children in Dhaka, Bangladesh: a case control analysis. PLoS ONE. 2022;17(3):e0265871.CrossRefPubMedPubMedCentral Nasrin S, Tariqujjaman M, Sultana M, Zaman RA, Ali S, Chisti MJ, Faruque AG, Ahmed T, Fuchs GJ, Gyr N, et al. Factors associated with community acquired severe pneumonia among under five children in Dhaka, Bangladesh: a case control analysis. PLoS ONE. 2022;17(3):e0265871.CrossRefPubMedPubMedCentral
2.
go back to reference Benedictis FM, Kerem E, Chang AB, Colin AA, Zar HJ, Bush A. Complicated pneumonia in children. Lancet. 2020;396:786–98.CrossRefPubMed Benedictis FM, Kerem E, Chang AB, Colin AA, Zar HJ, Bush A. Complicated pneumonia in children. Lancet. 2020;396:786–98.CrossRefPubMed
3.
go back to reference Tracy MC, Mathew R. Complicated pneumonia: current concepts and state of the art. Curr Opin Pediatr. 2018;30:384–92.CrossRefPubMed Tracy MC, Mathew R. Complicated pneumonia: current concepts and state of the art. Curr Opin Pediatr. 2018;30:384–92.CrossRefPubMed
4.
go back to reference Meganathan P, Awasthi S. Predicting complicated parapneumonic effusion in community acquired pneumonia: hospitalbased case-control study. Indian J Pediatr. 2019;86(2):140–7.CrossRef Meganathan P, Awasthi S. Predicting complicated parapneumonic effusion in community acquired pneumonia: hospitalbased case-control study. Indian J Pediatr. 2019;86(2):140–7.CrossRef
5.
go back to reference Masarweh K, Gur M, Toukan Y, Bar-Yoseph R, Kassis E, Gut G, Hakim F, Nir V, Bentur L. Factors associated with complicated pneumonia in children. Pediatr Pulmonol. 2021;56:2700–6.CrossRefPubMed Masarweh K, Gur M, Toukan Y, Bar-Yoseph R, Kassis E, Gut G, Hakim F, Nir V, Bentur L. Factors associated with complicated pneumonia in children. Pediatr Pulmonol. 2021;56:2700–6.CrossRefPubMed
6.
go back to reference Muhe L, Lulseged S, Mason KE, Simoes EA. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in ethiopian children. Lancet. 1997;349:1801–4.CrossRefPubMed Muhe L, Lulseged S, Mason KE, Simoes EA. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in ethiopian children. Lancet. 1997;349:1801–4.CrossRefPubMed
7.
go back to reference Banajeh SM. Nutritional rickets and vitamin D deficiency–association with the outcomes of childhood very severe pneumonia: a prospective cohort study. Pediatr Pulmonol. 2009;44:1207–15.CrossRefPubMed Banajeh SM. Nutritional rickets and vitamin D deficiency–association with the outcomes of childhood very severe pneumonia: a prospective cohort study. Pediatr Pulmonol. 2009;44:1207–15.CrossRefPubMed
8.
go back to reference Manaseki-Holland S, Qader G, Masher MI, Bruce J, Mughal MZ, Chandramohan D, Walraven G. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med & Int Health. 2010;15(10):1148–55.CrossRef Manaseki-Holland S, Qader G, Masher MI, Bruce J, Mughal MZ, Chandramohan D, Walraven G. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med & Int Health. 2010;15(10):1148–55.CrossRef
9.
go back to reference Edelson JD, Chan S, Jassal D, Post M, Tanswell AK. Vitamin D stimulate DNA synthesis in alveolar type-II cells. Biochim Biophys Acta. 1994;1221(2):159–66.CrossRefPubMed Edelson JD, Chan S, Jassal D, Post M, Tanswell AK. Vitamin D stimulate DNA synthesis in alveolar type-II cells. Biochim Biophys Acta. 1994;1221(2):159–66.CrossRefPubMed
10.
go back to reference Dürr UH, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta. 2006;1758(9):1408–25.CrossRefPubMed Dürr UH, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta. 2006;1758(9):1408–25.CrossRefPubMed
12.
go back to reference Agrawal T, Gupta GK, Agrawal DK. Vitamin D deficiency decreases the expression of VDR and prohibitin in the lungs of mice with allergic airway inflammation. Exp Mol Pathol. 2012;93(1):74–81.CrossRefPubMedPubMedCentral Agrawal T, Gupta GK, Agrawal DK. Vitamin D deficiency decreases the expression of VDR and prohibitin in the lungs of mice with allergic airway inflammation. Exp Mol Pathol. 2012;93(1):74–81.CrossRefPubMedPubMedCentral
13.
go back to reference Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S, Inoue Y, Morita K, Takeda E, Pike JW. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol. 1997;11(8):1165–79.CrossRefPubMed Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S, Inoue Y, Morita K, Takeda E, Pike JW. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol. 1997;11(8):1165–79.CrossRefPubMed
14.
go back to reference Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004;338(2):143–56.CrossRefPubMed Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004;338(2):143–56.CrossRefPubMed
15.
go back to reference Monticielo OA, Teixeira TD, Chies JA, Brenol JC, Xavier RM. Vitamin D and polymorphisms of VDR gene in patients with systemic lupus erythematosus. Clin Rheumatol. 2012;31:1411–21.CrossRefPubMed Monticielo OA, Teixeira TD, Chies JA, Brenol JC, Xavier RM. Vitamin D and polymorphisms of VDR gene in patients with systemic lupus erythematosus. Clin Rheumatol. 2012;31:1411–21.CrossRefPubMed
16.
go back to reference Ruiz-Ballesteros AI, Merza-Merza MR, Vizmanos-Lamotte B, de la Parra-Rojas I. Cruz-Moss0 U. Association of vitamin D metabolism gene polymorphisms with autoimmunity: evidence in population genetic studies. Int J Mol Sci. 2020;17(24):9626.CrossRef Ruiz-Ballesteros AI, Merza-Merza MR, Vizmanos-Lamotte B, de la Parra-Rojas I. Cruz-Moss0 U. Association of vitamin D metabolism gene polymorphisms with autoimmunity: evidence in population genetic studies. Int J Mol Sci. 2020;17(24):9626.CrossRef
17.
go back to reference Fouad H, Yahia S, Elsaid A, Hammad A, Wahba Y, El-Gilany A, Abdel-Aziz AF. Oxidative stress and vitamin D receptor BsmI gene polymorphism in egyptian children with systemic lupus erythematosus: a single center study. Lupus. 2019;28(6):771–7.CrossRefPubMed Fouad H, Yahia S, Elsaid A, Hammad A, Wahba Y, El-Gilany A, Abdel-Aziz AF. Oxidative stress and vitamin D receptor BsmI gene polymorphism in egyptian children with systemic lupus erythematosus: a single center study. Lupus. 2019;28(6):771–7.CrossRefPubMed
18.
go back to reference Kresfelder TL, Janssen R, Bont L, 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. 2011;83:1834–40.CrossRefPubMed Kresfelder TL, Janssen R, Bont L, 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. 2011;83:1834–40.CrossRefPubMed
19.
go back to reference Leiter K, Franks K, Borland ML, Coleman L, Harris L, Le Souëf PN, Laing IA. Vitamin D receptor polymorphisms are associated with severity of wheezing illnesses and asthma exacerbations in children. J Steroid Biochem Mol Biol. 2020;5:105692.CrossRef Leiter K, Franks K, Borland ML, Coleman L, Harris L, Le Souëf PN, Laing IA. Vitamin D receptor polymorphisms are associated with severity of wheezing illnesses and asthma exacerbations in children. J Steroid Biochem Mol Biol. 2020;5:105692.CrossRef
20.
go back to reference Panda S, Tiwari A, Luthra k, Sharma SK, Singh A. Association of Fok1 VDR polymorphism with vitamin D and its associated molecules in pulmonary tuberculosis patients and their household contacts. Sci Rep. 2019;9:15251.CrossRefPubMedPubMedCentral Panda S, Tiwari A, Luthra k, Sharma SK, Singh A. Association of Fok1 VDR polymorphism with vitamin D and its associated molecules in pulmonary tuberculosis patients and their household contacts. Sci Rep. 2019;9:15251.CrossRefPubMedPubMedCentral
21.
go back to reference Awasthi N, Awasthi S, Pandey S. Role of VDR gene polymorphisms with community acquired pneumonia in north indian children: a case-control study. Int J Mol Epidemiol Genet. 2021;12(1):1–8.PubMedPubMedCentral Awasthi N, Awasthi S, Pandey S. Role of VDR gene polymorphisms with community acquired pneumonia in north indian children: a case-control study. Int J Mol Epidemiol Genet. 2021;12(1):1–8.PubMedPubMedCentral
22.
go back to reference Li W, Guo L, Li H, Sun C, Cui X, Song G, Wang J, Zhang Q. 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. 2015;174:621–9.CrossRefPubMed Li W, Guo L, Li H, Sun C, Cui X, Song G, Wang J, Zhang Q. 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. 2015;174:621–9.CrossRefPubMed
23.
go back to reference Abouzeid H, Abdelaal NM, Abdou MA, Mosabah AA, Zakaria MT, Soliman MM, Sherif AM, Hamed ME, Soliman AA, Noah MA, et al. Association of vitamin D receptor gene FokI polymorphism and susceptibility to CAP in egyptian children: a multicenter study. Pediatr Res. 2018;84:639–44.CrossRefPubMed Abouzeid H, Abdelaal NM, Abdou MA, Mosabah AA, Zakaria MT, Soliman MM, Sherif AM, Hamed ME, Soliman AA, Noah MA, et al. Association of vitamin D receptor gene FokI polymorphism and susceptibility to CAP in egyptian children: a multicenter study. Pediatr Res. 2018;84:639–44.CrossRefPubMed
25.
go back to reference British Thoracic Society of Standards of Care Committee. BTS Guidelines for the management of community acquired pneumonia in childhood. Thorax. 2011;57:1i–24i.CrossRef British Thoracic Society of Standards of Care Committee. BTS Guidelines for the management of community acquired pneumonia in childhood. Thorax. 2011;57:1i–24i.CrossRef
26.
go back to reference Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122(2):398–417.CrossRefPubMed Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122(2):398–417.CrossRefPubMed
27.
go back to reference Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004;173(5):2909–12.CrossRefPubMed Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004;173(5):2909–12.CrossRefPubMed
28.
29.
go back to reference Roth DE, Jones AB, Prosser C, Robinson JL, Vohra S. Vitamin D receptor polymorphism and the risk of Acute Lower respiratory tract infection in early childhood. J Infect Dis. 2008;197:676–80.CrossRefPubMed Roth DE, Jones AB, Prosser C, Robinson JL, Vohra S. Vitamin D receptor polymorphism and the risk of Acute Lower respiratory tract infection in early childhood. J Infect Dis. 2008;197:676–80.CrossRefPubMed
30.
go back to reference Arai H, Miyamoto K, Taketani Y, Yamamoto H, Iemori Y, Morita K et al. (1997) 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): 915–921. Arai H, Miyamoto K, Taketani Y, Yamamoto H, Iemori Y, Morita K et al. (1997) 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): 915–921.
31.
go back to reference Jurutka PW, Remus LS, Whitfield GK, Thompson PD, Hsieh JC, Zitzer H, et al. The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol. 2000;14(3):401–20.CrossRefPubMed Jurutka PW, Remus LS, Whitfield GK, Thompson PD, Hsieh JC, Zitzer H, et al. The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol. 2000;14(3):401–20.CrossRefPubMed
32.
go back to reference Van Etten E, Verlinden L, Giulietti A, Ramos-Lopez E, Branisteanu DD, Ferreira GB, Overbergh L, Verstuyf A, Bouillon R, Roep BO. The vitamin D receptor gene FokI polymorphism: functional impact on the immune system. Eur J Immunol. 2007;37:395–405.CrossRefPubMed Van Etten E, Verlinden L, Giulietti A, Ramos-Lopez E, Branisteanu DD, Ferreira GB, Overbergh L, Verstuyf A, Bouillon R, Roep BO. The vitamin D receptor gene FokI polymorphism: functional impact on the immune system. Eur J Immunol. 2007;37:395–405.CrossRefPubMed
33.
go back to reference Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med. 2010;88(5):441–50.CrossRefPubMed Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med. 2010;88(5):441–50.CrossRefPubMed
35.
go back to reference Hashemian H, Heidarzadeh A. Role of vitamin D [25(OH) D] Deficiency in Development of Pneumonia in Children. Arch Pediatr Infect Dis. 2017;5(3):e57276. Hashemian H, Heidarzadeh A. Role of vitamin D [25(OH) D] Deficiency in Development of Pneumonia in Children. Arch Pediatr Infect Dis. 2017;5(3):e57276.
36.
go back to reference Kim HJ, Jang JG, Hong KS, Park JK, Choi EY. Relationship between serum vitamin D concentrations and clinical outcome of community-acquired pneumonia. Int J Tuberc Lung Dis. 2015;19(6):729–34.CrossRefPubMed Kim HJ, Jang JG, Hong KS, Park JK, Choi EY. Relationship between serum vitamin D concentrations and clinical outcome of community-acquired pneumonia. Int J Tuberc Lung Dis. 2015;19(6):729–34.CrossRefPubMed
38.
go back to reference Mansy W, Ibrahim NH, Al-Gawhary S, Alsubaie SS, Aboulkheir MM, Fatani A, Abd Al Reheem F, El Awady H, Zakaria EA. Vitamin D status and vitamin D receptor gene polymorphism in saudi children with acute lower respiratory tract infection. Mol Biol Rep. 2019;46(2):1955–62.CrossRefPubMed Mansy W, Ibrahim NH, Al-Gawhary S, Alsubaie SS, Aboulkheir MM, Fatani A, Abd Al Reheem F, El Awady H, Zakaria EA. Vitamin D status and vitamin D receptor gene polymorphism in saudi children with acute lower respiratory tract infection. Mol Biol Rep. 2019;46(2):1955–62.CrossRefPubMed
39.
go back to reference Erlichman I, Breuer O, Shoeyov D, Cohen-Cymberknoh M, Kopelwitz B, Averbuch D, Erlichman M, Picard E, Kerem E. Complicated Community Acquired Pneumonia in Childhood: different types, clinical course, and Outcome. Pediatr Pulmonol. 2017;52:247–54.CrossRefPubMed Erlichman I, Breuer O, Shoeyov D, Cohen-Cymberknoh M, Kopelwitz B, Averbuch D, Erlichman M, Picard E, Kerem E. Complicated Community Acquired Pneumonia in Childhood: different types, clinical course, and Outcome. Pediatr Pulmonol. 2017;52:247–54.CrossRefPubMed
40.
go back to reference Ooi JM, Eg KP, Chinna K, Nathan AM, Bruyne JA, Thavagnanam S. Predictive risk factors for complicated pneumonia in malaysian children. J Paediatr Child Health. 2019;55:406–10.CrossRefPubMed Ooi JM, Eg KP, Chinna K, Nathan AM, Bruyne JA, Thavagnanam S. Predictive risk factors for complicated pneumonia in malaysian children. J Paediatr Child Health. 2019;55:406–10.CrossRefPubMed
41.
go back to reference Krenke K, Krawiec M, Kraj G, Peradzynska J, Krauze A, Kulus M. Risk factors for local complications in children with community-acquired pneumonia. Clin Respir J. 2018;12(1):253–61.CrossRefPubMed Krenke K, Krawiec M, Kraj G, Peradzynska J, Krauze A, Kulus M. Risk factors for local complications in children with community-acquired pneumonia. Clin Respir J. 2018;12(1):253–61.CrossRefPubMed
42.
go back to reference Elemraid MA, Thomas MF, Blain AP, Rushton SP, Spencer DA, Gennery AR, Clark JE. Risk factors for the development of pleural empyema in children. Pediatr Pulmonol. 2015;50(7):721–6.CrossRefPubMed Elemraid MA, Thomas MF, Blain AP, Rushton SP, Spencer DA, Gennery AR, Clark JE. Risk factors for the development of pleural empyema in children. Pediatr Pulmonol. 2015;50(7):721–6.CrossRefPubMed
Metadata
Title
Increased susceptibility to complicated pneumonia among egyptian children with FokI (rs2228570), not TaqI (rs731236), vitamin D receptor gene polymorphism in association with vitamin D deficiency: a case-control study
Authors
Mahitab Morsy Hussein
Enas Maher Mohamed
Tarek Mostafa Kamal
Tharwat Ezzat Deraz
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Pediatrics / Issue 1/2023
Electronic ISSN: 1471-2431
DOI
https://doi.org/10.1186/s12887-023-04192-x

Other articles of this Issue 1/2023

BMC Pediatrics 1/2023 Go to the issue