Vitamin D deficiency and vitamin D receptor FokI polymorphism as risk factors for COVID-19
Nancy M S Zeidan, Hanan M Abd El Lateef, Dalia M Selim, Suzan A Razek, Ghada A B Abd-Elrehim, Mohamed Nashat, Noha Elgyar, Nevin M Waked, Attia A Soliman, Ahmed A Elhewala, Mohamed M M Shehab, Ahmed A A Ibraheem, Hassan Shehata, Yousif M Yousif, Nagwa E Akeel, Mustafa I A Hashem, Amani A Ahmed, Ahmed A Emam, Mohamed M Abdelmohsen, Mohamed F Ahmed, Ahmed S E Saleh, Heba H Eltrawy, Gehan H Shahin, Rehab M Nabil, Thoraya A Hosny, Mohamed R Abdelhamed, Mona R Afify, Mohanned T Alharbi, Mohammed K Nagshabandi, Muyassar K Tarabulsi, Sherif F Osman, Amal S M Abd-Elrazek, Manal M Rashad, Sonya A A El-Gaaly, Said A B Gad, Mohamed Y Mohamed, Khalil Abdelkhalek, Aly A Yousef
Pediatric Research, doi:10.1038/s41390-022-02275-6
BACKGROUND: Given the sparse data on vitamin D status in pediatric COVID-19, we investigated whether vitamin D deficiency could be a risk factor for susceptibility to COVID-19 in Egyptian children and adolescents. We also investigated whether vitamin D receptor (VDR) FokI polymorphism could be a genetic marker for COVID-19 susceptibility. METHODS: One hundred and eighty patients diagnosed to have COVID-19 and 200 matched control children and adolescents were recruited. Patients were laboratory confirmed as SARS-CoV-2 positive by real-time RT-PCR. All participants were genotyped for VDR Fok1 polymorphism by RT-PCR. Vitamin D status was defined as sufficient for serum 25(OH) D at least 30 ng/mL, insufficient at 21-29 ng/mL, deficient at <20 ng/mL. RESULTS: Ninety-four patients (52%) had low vitamin D levels with 74 (41%) being deficient and 20 (11%) had vitamin D insufficiency. Vitamin D deficiency was associated with 2.6-fold increased risk for COVID-19 (OR = 2.6; [95% CI 1.96-4.9]; P = 0.002. The FokI FF genotype was significantly more represented in patients compared to control group (OR = 4.05; [95% CI: 1.95-8.55]; P < 0.001). CONCLUSIONS: Vitamin D deficiency and VDR Fok I polymorphism may constitute independent risk factors for susceptibility to COVID-19 in Egyptian children and adolescents.
AUTHOR CONTRIBUTIONS All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
COMPETING INTERESTS The authors declare no competing interests.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE Written informed consents were provided by parents or legal guardians for all participants. The study was performed in accordance with the Declaration of Helsinki.
ADDITIONAL INFORMATION Correspondence and requests for materials should be addressed to Ahmed A. Emam. Reprints and permission information is available at http://www.nature.com/reprints Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
Abdollahzadeh, Association of Vitamin D receptor gene polymorphisms and clinical/severe outcomes of COVID-19 patients, Infect. Genet. Evol
Abouzeid, Association of vitamin D receptor gene FokI polymorphism and susceptibility to CAP in Egyptian children: a multicenter study, Pediatr. Res
Akoğlu, Evaluation of childhood COVID-19 cases: a retrospective analysis, J. Pediatr. Infect. Dis
Alpcan, Tursun, Kandur, Vitamin D levels in children with COVID-19: a report from Turkey, Epidemiol. Infect
Apaydin, Effects of vitamin D receptor gene polymorphisms on the prognosis of COVID-19, Clin. Endocrinol
Beyazgül, How vitamin D levels of children changed during COVID-19 pandemic: a comparison of pre-pandemic and pandemic periods, J. Clin. Res. Pediatr. Endocrinol
Carpagnano, Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19, J. Endocrinol. Investig
Chen, Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus, World J. Pediatr
Chiodini, Vitamin D status and SARS-CoV-2 infection and COVID-19 clinical outcomes, Front Public Health
Dancer, Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS), Thorax
Daneshkhah, Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients, Aging Clin. Exp. Res
Darren, Vitamin D status of children with paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS), Br. J. Nutr
De Souza, Nadal, Nogueira, Pereira, Brandão, Clinical manifestations of children with COVID-19: a systematic review, Pediatr. Pulmonol
El Basha, Mohsen, Kamal, Mehaney, Association of vitamin D deficiency with severe pneumonia in hospitalized children under 5 years, Comp. Clin. Pathol
Fedirko, Pre-diagnostic 25-hydroxyvitamin D, VDR and CASR polymorphisms and survival in patients with colorectal cancer in Western European Populations, Cancer Epidemiol. Biomark. Prev
Freire-Paspuel, Analytical and clinical comparison of Viasure (CerTest Biotec) and 2019-nCoV CDC (IDT) RT-qPCR kits for SARS-CoV2 diagnosis, Virology
Grant, Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths, Nutrients
Greiller, Martineau, Modulation of the immune response to respiratory viruses by vitamin D, Nutrients
Guan, Clinical characteristics of coronavirus disease 2019 in China, N. Engl. J. Med
Han, Association of vitamin D receptor polymorphism with susceptibility to symptomatic pertussis, PLoS ONE
Hoffmann, SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell
Holick, The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention, Rev. Endocr. Metab. Disord
Huang, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet
Jurutka, The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB, Mol. Endocrinol
Kong, VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system, Mol. Endocrinol
Kresfelder, Janssen, Bont, Pretorius, Venter, 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
Li, Association between serum 25-hydroxyvitamin D concentration and pulmonary infection in children, Medicine
Li, Li, Zhang, Liu, Sunlight and vitamin D in the prevention of coronavirus disease (COVID-19) infection and mortality in the United States,
doi:10.21203/rs.3.rs-32499/v1Li, 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
Long, Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections, Nat. Med
Martineau, Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data, BMJ
Mcnally, Vitamin D deficiency in young children with severe acute lower respiratory infection, Pediatr. Pulmonol
Merzon, Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study, FEBS J
Neill, Vitamin D receptor gene expression and function in a South African population: ethnicity, vitamin D and FokI, PLoS ONE
Overbergh, 1alpha,25-dihydroxyvitamin D3 induces an autoantigenspecific T-helper 1/T-helper 2 immune shift in NOD mice immunized with GAD65 (p524-543), Diabetes
Pike, Meyer, The vitamin D receptor: new paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D(3), Endocrinol. Metab. Clin. North Am
Pinzon, Pradana, Vitamin D deficiency among patients with COVID-19: case series and recent literature review, Trop. Med. Health
Shafiek, Cytokine profile in Egyptian children and adolescents with COVID-19 pneumonia: a multicenter study, Pediatr. Pulmonol
Underwood, Bevins, Defensin-barbed innate immunity: clinical associations in the pediatric population, Pediatrics
Van Etten, The vitamin D receptor gene FokI polymorphism: functional impact on the immune system, Eur. J. Immunol
Wang, Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China, JAMA
Wang, Xi, Reilly, Liu, Fu, Quantitative assessment of the associations between four polymorphisms (FokI, ApaI, BsmI, TaqI) of vitamin D receptor gene and risk of diabetes mellitus, Mol. Biol. Rep
Yuan, 1, 25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter, J. Biol. Chem
Yılmaz, Şen, Is vitamin D deficiency a risk factor for COVID-19 in children?, Pediatr. Pulmonol
{ 'indexed': {'date-parts': [[2022, 9, 9]], 'date-time': '2022-09-09T11:45:34Z', 'timestamp': 1662723934237},
'reference-count': 45,
'publisher': 'Springer Science and Business Media LLC',
'license': [ { 'start': { 'date-parts': [[2022, 9, 9]],
'date-time': '2022-09-09T00:00:00Z',
'timestamp': 1662681600000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0'},
{ 'start': { 'date-parts': [[2022, 9, 9]],
'date-time': '2022-09-09T00:00:00Z',
'timestamp': 1662681600000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0'}],
'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False},
'abstract': '<jats:title>Abstract</jats:title><jats:sec>\n'
' <jats:title>Background</jats:title>\n'
' <jats:p>Given the sparse data on vitamin D status in pediatric COVID-19, we '
'investigated whether vitamin D deficiency could be a risk factor for susceptibility to '
'COVID-19 in Egyptian children and adolescents. We also investigated whether vitamin D '
'receptor (VDR) FokI polymorphism could be a genetic marker for COVID-19 '
'susceptibility.</jats:p>\n'
' </jats:sec><jats:sec>\n'
' <jats:title>Methods</jats:title>\n'
' <jats:p>One hundred and eighty patients diagnosed to have COVID‐19 and 200 '
'matched control children and adolescents were recruited. Patients were laboratory confirmed '
'as SARS-CoV-2 positive by real-time RT-PCR. All participants were genotyped for VDR Fok1 '
'polymorphism by RT-PCR. Vitamin D status was defined as sufficient for serum 25(OH) D at '
'least 30\u2009ng/mL, insufficient at 21–29\u2009ng/mL, deficient at <20\u2009'
'ng/mL.</jats:p>\n'
' </jats:sec><jats:sec>\n'
' <jats:title>Results</jats:title>\n'
' <jats:p>Ninety-four patients (52%) had low vitamin D levels with 74 (41%) being '
'deficient and 20 (11%) had vitamin D insufficiency. Vitamin D deficiency was associated with '
'2.6-fold increased risk for COVID-19 (OR\u2009=\u20092.6; [95% CI 1.96–4.9]; '
'<jats:italic>P</jats:italic>\u2009=\u20090.002. The FokI FF genotype was significantly more '
'represented in patients compared to control group (OR\u2009=\u20094.05; [95% CI: 1.95–8.55]; '
'<jats:italic>P</jats:italic>\u2009<\u20090.001).</jats:p>\n'
' </jats:sec><jats:sec>\n'
' <jats:title>Conclusions</jats:title>\n'
' <jats:p>Vitamin D deficiency and VDR Fok I polymorphism may constitute '
'independent risk factors for susceptibility to COVID-19 in Egyptian children and '
'adolescents.</jats:p>\n'
' </jats:sec><jats:sec>\n'
' <jats:title>Impact</jats:title>\n'
' <jats:p><jats:list list-type="bullet">\n'
' <jats:list-item>\n'
' <jats:p>Vitamin D deficiency could be a modifiable risk factor for COVID-19 '
'in children and adolescents because of its immune-modulatory action.</jats:p>\n'
' </jats:list-item>\n'
' <jats:list-item>\n'
' <jats:p>To our knowledge, ours is the first such study to investigate the '
'VDR <jats:italic>Fok</jats:italic> I polymorphism in Caucasian children and adolescents with '
'COVID-19.</jats:p>\n'
' </jats:list-item>\n'
' <jats:list-item>\n'
' <jats:p>Vitamin D deficiency and the VDR <jats:italic>Fok</jats:italic> I '
'polymorphism may constitute independent risk factors for susceptibility to COVID-19 in '
'Egyptian children and adolescents.</jats:p>\n'
' </jats:list-item>\n'
' <jats:list-item>\n'
' <jats:p>Clinical trials should be urgently conducted to test for causality '
'and to evaluate the efficacy of vitamin D supplementation for prophylaxis and treatment of '
'COVID-19 taking into account the VDR polymorphisms.</jats:p>\n'
' </jats:list-item>\n'
' </jats:list></jats:p>\n'
' </jats:sec>',
'DOI': '10.1038/s41390-022-02275-6',
'type': 'journal-article',
'created': {'date-parts': [[2022, 9, 9]], 'date-time': '2022-09-09T09:23:48Z', 'timestamp': 1662715428000},
'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy',
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Vitamin D deficiency and vitamin D receptor FokI polymorphism as risk factors for COVID-19',
'prefix': '10.1038',
'author': [ {'given': 'Nancy M. S.', 'family': 'Zeidan', 'sequence': 'first', 'affiliation': []},
{'given': 'Hanan M. Abd El', 'family': 'Lateef', 'sequence': 'additional', 'affiliation': []},
{'given': 'Dalia M.', 'family': 'Selim', 'sequence': 'additional', 'affiliation': []},
{'given': 'Suzan A.', 'family': 'Razek', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ghada A. B.', 'family': 'Abd-Elrehim', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mohamed', 'family': 'Nashat', 'sequence': 'additional', 'affiliation': []},
{'given': 'Noha', 'family': 'ElGyar', 'sequence': 'additional', 'affiliation': []},
{'given': 'Nevin M.', 'family': 'Waked', 'sequence': 'additional', 'affiliation': []},
{'given': 'Attia A.', 'family': 'Soliman', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ahmed A.', 'family': 'Elhewala', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mohamed M. M.', 'family': 'Shehab', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ahmed A. A.', 'family': 'Ibraheem', 'sequence': 'additional', 'affiliation': []},
{'given': 'Hassan', 'family': 'Shehata', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yousif M.', 'family': 'Yousif', 'sequence': 'additional', 'affiliation': []},
{'given': 'Nagwa E.', 'family': 'Akeel', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mustafa I. A.', 'family': 'Hashem', 'sequence': 'additional', 'affiliation': []},
{'given': 'Amani A.', 'family': 'Ahmed', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ahmed A.', 'family': 'Emam', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mohamed M.', 'family': 'Abdelmohsen', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mohamed F.', 'family': 'Ahmed', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ahmed S. E.', 'family': 'Saleh', 'sequence': 'additional', 'affiliation': []},
{'given': 'Heba H.', 'family': 'Eltrawy', 'sequence': 'additional', 'affiliation': []},
{'given': 'Gehan H.', 'family': 'Shahin', 'sequence': 'additional', 'affiliation': []},
{'given': 'Rehab M.', 'family': 'Nabil', 'sequence': 'additional', 'affiliation': []},
{'given': 'Thoraya A.', 'family': 'Hosny', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mohamed R.', 'family': 'Abdelhamed', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mona R.', 'family': 'Afify', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mohanned T.', 'family': 'Alharbi', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mohammed K.', 'family': 'Nagshabandi', 'sequence': 'additional', 'affiliation': []},
{'given': 'Muyassar K.', 'family': 'Tarabulsi', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sherif F.', 'family': 'Osman', 'sequence': 'additional', 'affiliation': []},
{'given': 'Amal S. M.', 'family': 'Abd-Elrazek', 'sequence': 'additional', 'affiliation': []},
{'given': 'Manal M.', 'family': 'Rashad', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sonya A. A.', 'family': 'El-Gaaly', 'sequence': 'additional', 'affiliation': []},
{'given': 'Said A. B.', 'family': 'Gad', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mohamed Y.', 'family': 'Mohamed', 'sequence': 'additional', 'affiliation': []},
{'given': 'Khalil', 'family': 'Abdelkhalek', 'sequence': 'additional', 'affiliation': []},
{'given': 'Aly A.', 'family': 'Yousef', 'sequence': 'additional', 'affiliation': []}],
'member': '297',
'published-online': {'date-parts': [[2022, 9, 9]]},
'reference': [ { 'key': '2275_CR1',
'unstructured': 'World Health Organization. WHO coronavirus (COVID-19) dashboard. '
'https://covid19.who.int (2022).'},
{ 'key': '2275_CR2',
'doi-asserted-by': 'publisher',
'first-page': '497',
'DOI': '10.1016/S0140-6736(20)30183-5',
'volume': '395',
'author': 'C Huang',
'year': '2020',
'unstructured': 'Huang, C. et al. Clinical features of patients infected with 2019 novel '
'coronavirus in Wuhan, China. Lancet 395, 497–506 (2020).',
'journal-title': 'Lancet'},
{ 'key': '2275_CR3',
'doi-asserted-by': 'publisher',
'first-page': '271.e8',
'DOI': '10.1016/j.cell.2020.02.052',
'volume': '181',
'author': 'M Hoffmann',
'year': '2020',
'unstructured': 'Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 '
'and is blocked by a clinically proven protease inhibitor. Cell 181, '
'271.e8–280.e8 (2020).',
'journal-title': 'Cell'},
{ 'key': '2275_CR4',
'doi-asserted-by': 'publisher',
'first-page': '1708',
'DOI': '10.1056/NEJMoa2002032',
'volume': '382',
'author': 'WJ Guan',
'year': '2020',
'unstructured': 'Guan, W. J. et al. Clinical characteristics of coronavirus disease 2019 '
'in China. N. Engl. J. Med. 382, 1708–1720 (2020).',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': '2275_CR5',
'doi-asserted-by': 'publisher',
'first-page': '1061',
'DOI': '10.1001/jama.2020.1585',
'volume': '323',
'author': 'D Wang',
'year': '2020',
'unstructured': 'Wang, D. et al. Clinical characteristics of 138 hospitalized patients '
'with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA '
'323, 1061–1069 (2020).',
'journal-title': 'JAMA'},
{ 'key': '2275_CR6',
'doi-asserted-by': 'publisher',
'first-page': '255',
'DOI': '10.1016/j.ecl.2010.02.007',
'volume': '39',
'author': 'JW Pike',
'year': '2010',
'unstructured': '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).',
'journal-title': 'Endocrinol. Metab. Clin. North Am.'},
{ 'key': '2275_CR7',
'unstructured': 'Martineau, A. R. et al. Vitamin D supplementation to prevent acute '
'respiratory tract infections: systematic review and meta-analysis of '
'individual participant data. BMJ 356, i6583 (2017).'},
{ 'key': '2275_CR8',
'doi-asserted-by': 'publisher',
'first-page': '617',
'DOI': '10.1136/thoraxjnl-2014-206680',
'volume': '70',
'author': 'RC Dancer',
'year': '2015',
'unstructured': 'Dancer, R. C. et al. Vitamin D deficiency contributes directly to the '
'acute respiratory distress syndrome (ARDS). Thorax 70, 617–624 (2015).',
'journal-title': 'Thorax'},
{ 'key': '2275_CR9',
'doi-asserted-by': 'publisher',
'first-page': '1237',
'DOI': '10.1542/peds.2009-3289',
'volume': '125',
'author': 'MA Underwood',
'year': '2010',
'unstructured': 'Underwood, M. A. & Bevins, C. L. Defensin-barbed innate immunity: '
'clinical associations in the pediatric population. Pediatrics 125, '
'1237–1247 (2010).',
'journal-title': 'Pediatrics'},
{ 'key': '2275_CR10',
'doi-asserted-by': 'publisher',
'first-page': '845',
'DOI': '10.1038/s41591-020-0897-1',
'volume': '26',
'author': 'QX Long',
'year': '2020',
'unstructured': 'Long, Q. X. et al. Clinical and immunological assessment of asymptomatic '
'SARS-CoV-2 infections. Nat. Med. 26, 845–848 (2020).',
'journal-title': 'Nat. Med.'},
{ 'key': '2275_CR11',
'doi-asserted-by': 'publisher',
'first-page': '988',
'DOI': '10.3390/nu12040988',
'volume': '12',
'author': 'WB Grant',
'year': '2020',
'unstructured': 'Grant, W. B. et al. Evidence that vitamin D supplementation could reduce '
'risk of influenza and COVID-19 infections and deaths. Nutrients 12, 988 '
'(2020).',
'journal-title': 'Nutrients'},
{ 'key': '2275_CR12',
'doi-asserted-by': 'publisher',
'unstructured': 'Li, Y., Li, Q., Zhang, N. & Liu, Z. Sunlight and vitamin D in the '
'prevention of coronavirus disease (COVID-19) infection and mortality in '
'the United States. Preprint at https://doi.org/10.21203/rs.3.rs-32499/v1 '
'(2020).',
'DOI': '10.21203/rs.3.rs-32499/v1'},
{ 'key': '2275_CR13',
'doi-asserted-by': 'publisher',
'first-page': '2141',
'DOI': '10.1007/s40520-020-01677-y',
'volume': '32',
'author': 'A Daneshkhah',
'year': '2020',
'unstructured': 'Daneshkhah, A. et al. Evidence for possible association of vitamin D '
'status with cytokine storm and unregulated inflammation in COVID-19 '
'patients. Aging Clin. Exp. Res. 32, 2141–2158 (2020).',
'journal-title': 'Aging Clin. Exp. Res.'},
{ 'key': '2275_CR14',
'doi-asserted-by': 'publisher',
'first-page': '9405',
'DOI': '10.1007/s11033-012-1805-7',
'volume': '39',
'author': 'Q Wang',
'year': '2012',
'unstructured': 'Wang, Q., Xi, B., Reilly, K. H., Liu, M. & Fu, M. Quantitative '
'assessment of the associations between four polymorphisms (FokI, ApaI, '
'BsmI, TaqI) of vitamin D receptor gene and risk of diabetes mellitus. '
'Mol. Biol. Rep. 39, 9405–9414 (2012).',
'journal-title': 'Mol. Biol. Rep.'},
{ 'key': '2275_CR15',
'doi-asserted-by': 'publisher',
'first-page': 'e67663',
'DOI': '10.1371/journal.pone.0067663',
'volume': '8',
'author': 'O Neill',
'year': '2013',
'unstructured': 'Neill, O. et al. Vitamin D receptor gene expression and function in a '
'South African population: ethnicity, vitamin D and FokI. PLoS ONE 8, '
'e67663 (2013).',
'journal-title': 'PLoS ONE'},
{ 'key': '2275_CR16',
'doi-asserted-by': 'publisher',
'first-page': '395',
'DOI': '10.1002/eji.200636043',
'volume': '37',
'author': 'E van Etten',
'year': '2007',
'unstructured': '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).',
'journal-title': 'Eur. J. Immunol.'},
{ 'key': '2275_CR17',
'doi-asserted-by': 'publisher',
'first-page': '3595',
'DOI': '10.1002/ppul.25106',
'volume': '55',
'author': 'K Yılmaz',
'year': '2020',
'unstructured': 'Yılmaz, K. & Şen, V. Is vitamin D deficiency a risk factor for COVID-19 '
'in children? Pediatr. Pulmonol. 55, 3595–3601 (2020).',
'journal-title': 'Pediatr. Pulmonol.'},
{ 'key': '2275_CR18',
'doi-asserted-by': 'publisher',
'first-page': 'E180',
'DOI': '10.1017/S0950268821001825',
'volume': '149',
'author': 'A Alpcan',
'year': '2021',
'unstructured': 'Alpcan, A., Tursun, S. & Kandur, Y. Vitamin D levels in children with '
'COVID-19: a report from Turkey. Epidemiol. Infect. 149, E180 (2021).',
'journal-title': 'Epidemiol. Infect.'},
{ 'key': '2275_CR19',
'doi-asserted-by': 'publisher',
'first-page': '091',
'DOI': '10.1055/s-0041-1723957',
'volume': '16',
'author': 'HA Akoğlu',
'year': '2021',
'unstructured': 'Akoğlu, H. A. et al. Evaluation of childhood COVID-19 cases: a '
'retrospective analysis. J. Pediatr. Infect. Dis. 16, 091–098 (2021).',
'journal-title': 'J. Pediatr. Infect. Dis.'},
{ 'key': '2275_CR20',
'doi-asserted-by': 'publisher',
'first-page': '240',
'DOI': '10.1007/s12519-020-00345-5',
'volume': '16',
'author': 'ZM Chen',
'year': '2020',
'unstructured': 'Chen, Z. M. et al. Diagnosis and treatment recommendations for pediatric '
'respiratory infection caused by the 2019 novel coronavirus. World J. '
'Pediatr. 16, 240–246 (2020).',
'journal-title': 'World J. Pediatr.'},
{ 'key': '2275_CR21',
'doi-asserted-by': 'publisher',
'first-page': '153',
'DOI': '10.1007/s11154-017-9424-1',
'volume': '18',
'author': 'MF Holick',
'year': '2017',
'unstructured': 'Holick, M. F. The vitamin D deficiency pandemic: approaches for '
'diagnosis, treatment and prevention. Rev. Endocr. Metab. Disord. 18, '
'153–165 (2017).',
'journal-title': 'Rev. Endocr. Metab. Disord.'},
{ 'key': '2275_CR22',
'doi-asserted-by': 'publisher',
'first-page': '154',
'DOI': '10.1016/j.virol.2020.10.010',
'volume': '553',
'author': 'B Freire-Paspuel',
'year': '2021',
'unstructured': 'Freire-Paspuel, B. et al. Analytical and clinical comparison of Viasure '
'(CerTest Biotec) and 2019-nCoV CDC (IDT) RT-qPCR kits for SARS-CoV2 '
'diagnosis. Virology 553, 154–156 (2021).',
'journal-title': 'Virology'},
{ 'key': '2275_CR23',
'doi-asserted-by': 'publisher',
'first-page': '582',
'DOI': '10.1158/1055-9965.EPI-11-1065',
'volume': '21',
'author': 'V Fedirko',
'year': '2012',
'unstructured': 'Fedirko, V. et al. Pre-diagnostic 25-hydroxyvitamin D, VDR and CASR '
'polymorphisms and survival in patients with colorectal cancer in Western '
'European Populations. Cancer Epidemiol. Biomark. Prev. 21, 582–593 '
'(2012).',
'journal-title': 'Cancer Epidemiol. Biomark. Prev.'},
{ 'key': '2275_CR24',
'doi-asserted-by': 'publisher',
'first-page': 'e9060',
'DOI': '10.1097/MD.0000000000009060',
'volume': '97',
'author': 'W Li',
'year': '2018',
'unstructured': 'Li, W. et al. Association between serum 25-hydroxyvitamin D '
'concentration and pulmonary infection in children. Medicine 97, e9060 '
'(2018).',
'journal-title': 'Medicine'},
{ 'key': '2275_CR25',
'doi-asserted-by': 'publisher',
'first-page': '981',
'DOI': '10.1002/ppul.21089',
'volume': '44',
'author': 'JD McNally',
'year': '2009',
'unstructured': 'McNally, J. D. et al. Vitamin D deficiency in young children with severe '
'acute lower respiratory infection. Pediatr. Pulmonol. 44, 981–988 '
'(2009).',
'journal-title': 'Pediatr. Pulmonol.'},
{ 'key': '2275_CR26',
'doi-asserted-by': 'publisher',
'first-page': '1247',
'DOI': '10.1007/s00580-013-1770-0',
'volume': '23',
'author': 'N El Basha',
'year': '2014',
'unstructured': '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).',
'journal-title': 'Comp. Clin. Pathol.'},
{ 'key': '2275_CR27',
'doi-asserted-by': 'publisher',
'first-page': '736665',
'DOI': '10.3389/fpubh.2021.736665',
'volume': '9',
'author': 'I Chiodini',
'year': '2021',
'unstructured': 'Chiodini, I. et al. Vitamin D status and SARS-CoV-2 infection and '
'COVID-19 clinical outcomes. Front Public Health 9, 736665 (2021).',
'journal-title': 'Front Public Health'},
{ 'key': '2275_CR28',
'doi-asserted-by': 'publisher',
'first-page': '3693',
'DOI': '10.1111/febs.15495',
'volume': '287',
'author': 'E Merzon',
'year': '2020',
'unstructured': 'Merzon, E. et al. Low plasma 25(OH) vitamin D level is associated with '
'increased risk of COVID-19 infection: an Israeli population-based study. '
'FEBS J. 287, 3693–3702 (2020).',
'journal-title': 'FEBS J.'},
{ 'key': '2275_CR29',
'doi-asserted-by': 'publisher',
'first-page': '102',
'DOI': '10.1186/s41182-020-00277-w',
'volume': '48',
'author': 'RT Pinzon',
'year': '2020',
'unstructured': 'Pinzon, R. T. & Pradana, A. W. Vitamin D deficiency among patients with '
'COVID-19: case series and recent literature review. Trop. Med. Health '
'48, 102 (2020).',
'journal-title': 'Trop. Med. Health'},
{ 'key': '2275_CR30',
'doi-asserted-by': 'publisher',
'first-page': '188',
'DOI': '10.4274/jcrpe.galenos.2022.2021-10-6',
'volume': '14',
'author': 'G Beyazgül',
'year': '2022',
'unstructured': 'Beyazgül, G. et al. How vitamin D levels of children changed during '
'COVID-19 pandemic: a comparison of pre-pandemic and pandemic periods. J. '
'Clin. Res. Pediatr. Endocrinol. 14, 188–195 (2022).',
'journal-title': 'J. Clin. Res. Pediatr. Endocrinol.'},
{ 'key': '2275_CR31',
'doi-asserted-by': 'publisher',
'first-page': '896',
'DOI': '10.1017/S0007114521001562',
'volume': '127',
'author': 'A Darren',
'year': '2022',
'unstructured': 'Darren, A. et al. Vitamin D status of children with paediatric '
'inflammatory multisystem syndrome temporally associated with severe '
'acute respiratory syndrome coronavirus 2 (PIMS-TS). Br. J. Nutr. 127, '
'896–903 (2022).',
'journal-title': 'Br. J. Nutr.'},
{ 'key': '2275_CR32',
'doi-asserted-by': 'publisher',
'first-page': '765',
'DOI': '10.1007/s40618-020-01370-x',
'volume': '44',
'author': 'GE Carpagnano',
'year': '2020',
'unstructured': 'Carpagnano, G. E. et al. Vitamin D deficiency as a predictor of poor '
'prognosis in patients with acute respiratory failure due to COVID-19. J. '
'Endocrinol. Investig. 44, 765–771 (2020).',
'journal-title': 'J. Endocrinol. Investig.'},
{ 'key': '2275_CR33',
'doi-asserted-by': 'publisher',
'first-page': '1892',
'DOI': '10.1002/ppul.24885',
'volume': '55',
'author': 'TH de Souza',
'year': '2020',
'unstructured': 'de Souza, T. H., Nadal, J. A., Nogueira, R. J. N., Pereira, R. M. & '
'Brandão, M. B. Clinical manifestations of children with COVID-19: a '
'systematic review. Pediatr. Pulmonol. 55, 1892–1899 (2020).',
'journal-title': 'Pediatr. Pulmonol.'},
{ 'key': '2275_CR34',
'doi-asserted-by': 'publisher',
'first-page': '2116',
'DOI': '10.1210/me.2013-1146',
'volume': '27',
'author': 'J Kong',
'year': '2013',
'unstructured': 'Kong, J. et al. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 '
'pathway and renin-angiotensin system. Mol. Endocrinol. 27, 2116–2125 '
'(2013).',
'journal-title': 'Mol. Endocrinol.'},
{ 'key': '2275_CR35',
'doi-asserted-by': 'publisher',
'first-page': '4240',
'DOI': '10.3390/nu7064240',
'volume': '7',
'author': 'CL Greiller',
'year': '2015',
'unstructured': 'Greiller, C. L. & Martineau, A. R. Modulation of the immune response to '
'respiratory viruses by vitamin D. Nutrients 7, 4240–4270 (2015).',
'journal-title': 'Nutrients'},
{ 'key': '2275_CR36',
'doi-asserted-by': 'publisher',
'first-page': '29821',
'DOI': '10.1074/jbc.M705495200',
'volume': '282',
'author': 'W Yuan',
'year': '2007',
'unstructured': 'Yuan, W. et al. 1, 25-dihydroxyvitamin D3 suppresses renin gene '
'transcription by blocking the activity of the cyclic AMP response '
'element in the renin gene promoter. J. Biol. Chem. 282, 29821–29830 '
'(2007).',
'journal-title': 'J. Biol. Chem.'},
{ 'key': '2275_CR37',
'doi-asserted-by': 'publisher',
'first-page': '1301',
'DOI': '10.2337/diabetes.49.8.1301',
'volume': '49',
'author': 'L Overbergh',
'year': '2000',
'unstructured': 'Overbergh, L. et al. 1alpha,25-dihydroxyvitamin D3 induces an '
'autoantigen-specific T-helper 1/T-helper 2 immune shift in NOD mice '
'immunized with GAD65 (p524-543). Diabetes 49, 1301–1307 (2000).',
'journal-title': 'Diabetes'},
{ 'key': '2275_CR38',
'doi-asserted-by': 'publisher',
'first-page': '3924',
'DOI': '10.1002/ppul.25679',
'volume': '56',
'author': 'HK Shafiek',
'year': '2021',
'unstructured': 'Shafiek, H. K. et al. Cytokine profile in Egyptian children and '
'adolescents with COVID-19 pneumonia: a multicenter study. Pediatr. '
'Pulmonol. 56, 3924–3933 (2021).',
'journal-title': 'Pediatr. Pulmonol.'},
{ 'key': '2275_CR39',
'doi-asserted-by': 'publisher',
'first-page': '1834',
'DOI': '10.1002/jmv.22179',
'volume': '83',
'author': 'TL Kresfelder',
'year': '2011',
'unstructured': '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).',
'journal-title': 'J. Med. Virol.'},
{ 'key': '2275_CR40',
'doi-asserted-by': 'publisher',
'first-page': 'e0149576',
'DOI': '10.1371/journal.pone.0149576',
'volume': '11',
'author': 'WG Han',
'year': '2016',
'unstructured': 'Han, W. G. et al. Association of vitamin D receptor polymorphism with '
'susceptibility to symptomatic pertussis. PLoS ONE 11, e0149576 (2016).',
'journal-title': 'PLoS ONE'},
{ 'key': '2275_CR41',
'doi-asserted-by': 'publisher',
'first-page': '621',
'DOI': '10.1007/s00431-014-2433-0',
'volume': '174',
'author': 'W Li',
'year': '2015',
'unstructured': '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).',
'journal-title': 'Eur. J. Pediatr.'},
{ 'key': '2275_CR42',
'doi-asserted-by': 'publisher',
'first-page': '639',
'DOI': '10.1038/s41390-018-0149-y',
'volume': '84',
'author': 'H Abouzeid',
'year': '2018',
'unstructured': 'Abouzeid, H. et al. Association of vitamin D receptor gene FokI '
'polymorphism and susceptibility to CAP in Egyptian children: a '
'multicenter study. Pediatr. Res. 84, 639–644 (2018).',
'journal-title': 'Pediatr. Res.'},
{ 'key': '2275_CR43',
'doi-asserted-by': 'publisher',
'first-page': '819',
'DOI': '10.1111/cen.14664',
'volume': '96',
'author': 'T Apaydin',
'year': '2022',
'unstructured': 'Apaydin, T. et al. Effects of vitamin D receptor gene polymorphisms on '
'the prognosis of COVID-19. Clin. Endocrinol. 96, 819–830 (2022).',
'journal-title': 'Clin. Endocrinol.'},
{ 'key': '2275_CR44',
'doi-asserted-by': 'publisher',
'first-page': '105098',
'DOI': '10.1016/j.meegid.2021.105098',
'volume': '96',
'author': 'R Abdollahzadeh',
'year': '2021',
'unstructured': 'Abdollahzadeh, R. et al. Association of Vitamin D receptor gene '
'polymorphisms and clinical/severe outcomes of COVID-19 patients. Infect. '
'Genet. Evol. 96, 105098 (2021).',
'journal-title': 'Infect. Genet. Evol.'},
{ 'key': '2275_CR45',
'doi-asserted-by': 'publisher',
'first-page': '401',
'DOI': '10.1210/mend.14.3.0435',
'volume': '14',
'author': 'PW Jurutka',
'year': '2000',
'unstructured': 'Jurutka, P. W. et al. The polymorphic N terminus in human vitamin D '
'receptor isoforms influences transcriptional activity by modulating '
'interaction with transcription factor IIB. Mol. Endocrinol. 14, 401–420 '
'(2000).',
'journal-title': 'Mol. Endocrinol.'}],
'container-title': 'Pediatric Research',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.nature.com/articles/s41390-022-02275-6.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://www.nature.com/articles/s41390-022-02275-6',
'content-type': 'text/html',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://www.nature.com/articles/s41390-022-02275-6.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 9, 9]],
'date-time': '2022-09-09T11:24:39Z',
'timestamp': 1662722679000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41390-022-02275-6'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2022, 9, 9]]},
'references-count': 45,
'alternative-id': ['2275'],
'URL': 'http://dx.doi.org/10.1038/s41390-022-02275-6',
'relation': {},
'ISSN': ['0031-3998', '1530-0447'],
'subject': ['Pediatrics, Perinatology and Child Health'],
'container-title-short': 'Pediatr Res',
'published': {'date-parts': [[2022, 9, 9]]},
'assertion': [ { 'value': '11 June 2022',
'order': 1,
'name': 'received',
'label': 'Received',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '22 July 2022',
'order': 2,
'name': 'revised',
'label': 'Revised',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '5 August 2022',
'order': 3,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '9 September 2022',
'order': 4,
'name': 'first_online',
'label': 'First Online',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': 'The authors declare no competing interests.',
'order': 1,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}},
{ 'value': 'Written informed consents were provided by parents or legal guardians for all '
'participants. The study was performed in accordance with the Declaration of '
'Helsinki.',
'order': 2,
'name': 'Ethics',
'group': { 'name': 'EthicsHeading',
'label': 'Ethics approval and consent to participate'}}]}
