Strong Association between Vitamin D Receptor Gene and Severe Acute Respiratory Syndrome coronavirus 2 Infectious Variants

Abstract

A coronavirus disease 2019 (COVID-19) disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created significant concern since December 2019 worldwide. The virus is known to be highly transmissible. Heterogenic clinical features even vary more among SARS-CoV-2 variants from asymptomatic forms to severe symptoms. Previous studies revealed an association between COVID-19 and vitamin D deficiency resulting from its low levels in COVID-19 patients. To our knowledge, there is no scientific investigation that evaluates the direct association between SARS-CoV-2 variants of concern and vitamin D receptor (VDR) gene markers in Cyprus. Thus, the present study aimed to identify the putative impact of VDR gene polymorphisms on SARS-CoV-2 infection among different variants.
The nasopharyngeal swabs were taken from a total number of 600 patients who were admitted to Near East University Hospital COVID-19 Polymerase Chain Reaction (PCR) Diagnosis Laboratory for routine SARS-CoV-2 real-time quantitative reverse transcription PCR (RT-qPCR) test. The RT-qPCR negative resulting samples were taken as control samples (n = 300). On the contrary, the case group consisted of patients who were SARS-CoV-2 RT-qPCR positive, infected with either SARS-CoV-2 Alpha (n = 100), Delta (n = 100), or Omicron (n = 100) variants. Two VDR gene polymorphisms, TaqI-rs731236 T > C and FokI-rs10735810 C > T, were genotyped by polymerase chain reaction-restriction fragment length polymorphism.
The mean age of the COVID-19 patient's ± standard deviation was 46.12 ± 12.36 and 45.25 ± 12.71 years old for the control group (p > 0.05). The gender distribution of the patient group was 48.3% female and 51.7% male and for the control group 43% female and 57% male (p > 0.05). Significant differences were observed in genotype frequencies of FokI and TaqI variants between SARS-CoV-2 patients compared to the control group (p < 0.005). Furthermore, the risk alleles, FokI T allele and TaqI C, were found to be statistically significant (odds ratio [OR] = 1.80, 95% confidence interval [CI] = 1.42-2.29, OR = 1.62, 95% CI = 1.27-2.05, respectively) in COVID-19 patients. The highest number of patients with wild-type genotype was found in the control group, which is 52.9% compared with 17.5% in the case group. Moreover, most of the COVID-19 patients had heterozygous/homozygous genotypes, reaching 82.5%, while 47.1% of the control group patients had heterozygous/homozygous genotypes.
Our results suggested that patients with FokI and TaqI polymorphisms might tend to be more susceptible to getting infected with SARS-CoV-2. Overall, findings from this study provided evidence regarding vitamin D supplements recommendation in individuals with vitamin D deficiency/insufficiency in the peri- or post-COVID-19 pandemic.

Keywords

COVID-19 / VDR / polymorphism / FokI / TaqI

References

[1] Rauf A, Abu-Izneid T, Olatunde A, et al. COVID-19 pandemic: epidemiology, etiology, conventional and non-conventional therapies. Int J Environ Res Public Health 2020;17(21):8155

[2] WHO Coronavirus (COVID-19) Dashboard, 2022. Accessed January 23, 01 2023 at: https://covid19.who.int/

[3] Raman R, Patel KJ, Ranjan K. COVID-19: unmasking emerging SARS-CoV-2 variants, vaccines and therapeutic strategies. Biomolecules 2021;11(07):993

[4] Safari I, Elahi E. Evolution of the SARS-CoV-2 genome and emergence of variants of concern. Arch Virol 2022;167(02): 293-305

[5] Shahhosseini N, Babuadze GG, Wong G, Kobinger GP. Mutation signatures and in silico docking of novel SARS-CoV-2 variants of concern. Microorganisms 2021;9(05):926

[6] Holick MF. The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord 2017;18(02):153-165

[7] Gallagher J.(12 June 2021). “COVID: is there a limit to how much worse variants can get?”. BBC. Archived from the original on 15 June 2021. Retrieved 12 June 2021.

[8] Yi Y, Lagniton PNP, Ye S, Li E, Xu RH. COVID-19: what has been learned and to be learned about the novel coronavirus disease. Int J Biol Sci 2020;16(10):1753-1766

[9] Carpagnano GE, Di Lecce V, Quaranta VN, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest 2021;44(04):765-771

[10] Weir EK, Thenappan T, Bhargava M, Chen Y. Does vitamin D deficiency increase the severity of COVID-19? Clin Med (Lond) 2020;20(04):e107-e108

[11] Krawiec M, Dominiak M. The role of vitamin D in the human body with a special emphasis on dental issues: literature review. Dent Med Probl 2018;55(04):419-424

[12] Charoenngam N, Holick MF. Immunologic effects of vitamin D on human health and disease. Nutrients 2020;12(07):2097

[13] Wang H, Chen W, Li D, et al. Vitamin D and chronic diseases. Aging Dis 2017;8(03):346-353

[14] Kandemiş E, Tuncel G, Fahrioğlu U, Temel ŞG, Mocan G, Ergören MÇ Natural selection at work? Vitamin D deficiency rates and rising health problems in young Turkish Cypriot professionals. Cent Eur J Public Health 2021;29(02):130-133

[15] Tuncel G, Temel SG, Ergoren MC. Strong association between VDR FokI (rs2228570) gene variant and serum vitamin D levels in Turkish Cypriots. Mol Biol Rep 2019;46(03):3349-3355

[16] Li L, Wu B, Liu J-Y, Yang L-B. Vitamin D receptor gene polymorphisms and type 2 diabetes: a meta-analysis. Arch Med Res 2013;44(03):235-241

[17] Lee YH, Bae S-C, Choi SJ, Ji JD, Song GG. Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a metaanalysis. Mol Biol Rep 2011;38(06):3643-3651

[18] Abdollahzadeh R, Shushizadeh MH, Barazandehrokh M, et al. Association of Vitamin D receptor gene polymorphisms and clinical/severe outcomes of COVID-19 patients. Infect Genet Evol 2021;96:105098

[19] Al-Anouti F, Mousa M, Karras SN, et al. Associations between genetic variants in the vitamin D metabolism pathway and severity of COVID-19 among UAE residents. Nutrients 2021;13(11):3680

[20] Raoult D, Zumla A, Locatelli F, Ippolito G, Kroemer G. Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses. Cell Stress 2020;4(04):66-75

[21] Aranow C. Vitamin D and the immune system. J Investig Med 2011;59(06):881-886

[22] Mamani M, Muceli N, Ghasemi Basir HR, Vasheghani M, Poorolajal J. Association between serum concentration of 25-hydroxyvitamin D and community-acquired pneumonia: a case-control study. Int J Gen Med 2017;10:423-429

[23] Laplana M, Royo JL, Fibla J, Vitamin D. Vitamin D Receptor polymorphisms and risk of enveloped virus infection: a meta-analysis. Gene 2018;678:384-394

[24] Peralta EM, Rosales YZ, Mesa TC, et al. TaqI polymorphism of the VDR gene: aspects related to the clinical behavior of COVID-19 in Cuban patients. Egypt J Med Hum Genet 2021;22(01):83

[25] Martineau AR, Jolliffe DA, Greenberg L, et al. Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technol Assess 2019;23(02):1-44

[26] Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, et al. “Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”. J Steroid Biochem Mol Biol 2020;203:105751

[27] Freitas AT, Calhau C, Antunes G, et al. Vitamin D-related polymorphisms and vitamin D levels as risk biomarkers of COVID-19 disease severity. Sci Rep 2021;11(01):20837

[28] Annweiler G, Corvaisier M, Gautier J, et al. Vitamin D supplementation associated to better survival in hospitalized frail elderly COVID-19 patients: the GERIA-COVID quasi-experimental study. Nutrients 2020;12(11):3377

[29] Apaydin T, Polat H, Dincer Yazan C, et al. Effects of vitamin D receptor gene polymorphisms on the prognosis of COVID-19. Clin Endocrinol (Oxf) 2022;96(06):819-830

[30] Dror AA, Morozov N, Daoud A, et al. Pre-infection 25-hydroxyvitamin D3 levels and associationwith severity of COVID-19 illness. PLoS One 2022;17(02):e0263069

RIGHTS & PERMISSIONS

2023 Global Medical Genetics