The Association of Vitamin D Receptor Polymorphisms with COVID-19 Severity
Nikolaos Tentolouris, Charoula Achilla, Ioanna A Anastasiou, Ioanna Eleftheriadou, Anastasios Tentolouris, Dimitrios Basoulis, Ourania Kosta, Alexandros Lambropoulos, Maria P Yavropoulou, Anthoula Chatzikyriakidou, Edward B Jude
Nutrients, doi:10.3390/nu16050727
Background: Association studies of vitamin D receptor (VDR) polymorphisms with COVID-19 severity have produced inconsistent results in different populations. Herein we examined VDR gene polymorphisms in a Caucasian Greek cohort of COVID-19 patients. Methods: This was a case-control study in a tertiary university hospital in Greece including 137 COVID-19 patients with varying disease severities and 72 healthy individuals. In total 209 individuals were genotyped for the FokI (rs10735810), ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410) single-nucleotide polymorphisms (SNP) of the VDR gene by polymerase chain reaction and restriction fragment length polymorphism analysis (PCR-RFLPs). Statistical analyses were performed to determine the association between genotype and disease severity, adjusting for various confounding factors. Results: Genotype distribution of the studied VDR SNPs in the control group was in Hardy-Weinberg equilibrium. The TaqI variant was differentially distributed between controls and COVID-19 patients according to the additive model (p = 0.009), and the CC genotype was significantly associated with an increased risk for severe COVID-19 according to the recessive model [OR: 2.52, 95%CI:1.2-5.29, p = 0.01]. Multivariate analysis demonstrated a robust association of COVID-19 severity and TaqI polymorphism in the recessive model even after adjusting for multiple confounders, including age, sex and CRP levels [Adj.OR:3.23, 95%CI:1.17-8.86, p = 0.023]. The distribution of FokI, ApaI and BsmI genotypes was similar between COVID-19 patients and controls. Conclusions: The CC genotype of TaqI polymorphism is significantly associated with an increased risk for severe COVID-19 independently of age, sex or degree of inflammation.
VDR polymorphisms and infection susceptibility. Finally, interethnic differences in the prevalence of infectious diseases and pathogen exposure patterns can influence the selective pressures acting on VDR and other immune-related genes among populations. These factors collectively highlight the importance of considering population-specific factors when studying the association between VDR polymorphisms and infection susceptibility [27, 28] . It is worth mentioning that our study has some limitations. First, this was a relatively small-sized study restricted to the broader urban area of Attiki in Greece. Second, no data were available regarding medication of COVID-19 patients in order to adjust for possible confounders in the outcomes of severe COVID-19. Third, the genetic analysis was restricted to four genetic variants of VDR, and no other genes that regulate or are related to vitamin D metabolism were assessed. Nevertheless, to the best of our knowledge, this is the first case-control study evaluating the association VDR polymorphisms and severity of COVID-19 in the Greek population. Our findings are in line with other studies showing a positive association of the TaqI C allele with COVID-19 morbidity [16, 29] . COVID-19 remains an important public health concern worldwide, and studies that investigate the impact of VDR polymorphisms in the severity of the disease across different populations are needed in order to pave the way towards a more patient-centric and..
References
Abdollahzadeh, Shushizadeh, Barazandehrokh, Choopani, Azarnezhad et al., Association of Vitamin D receptor gene polymorphisms and clinical/severe outcomes of COVID-19 patients, Infect. Genet. Evol,
doi:10.1016/j.meegid.2021.105098Albu-Mohammed, Anvari, Fateh, Evaluating the Role of BglI rs739837 and TaqI rs731236 Polymorphisms in Vitamin D Receptor with SARS-CoV-2 Variants Mortality Rate, Genes,
doi:10.3390/genes13122346Amin, Drenos, No evidence that vitamin D is able to prevent or affect the severity of COVID-19 in individuals with European ancestry: A Mendelian randomisation study of open data, BMJ Nutr. Prev. Health,
doi:10.1136/bmjnph-2020-000151Apaydin, Polat, Dincer Yazan, Ilgin, Elbasan et al., Effects of vitamin D receptor gene polymorphisms on the prognosis of COVID-19, Clin. Endocrinol,
doi:10.1111/cen.14664Bassatne, Basbous, Chakhtoura, El Zein, Rahme et al., The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis, Metabolism,
doi:10.1016/j.metabol.2021.154753Butler-Laporte, Nakanishi, Mooser, Morrison, Abdullah et al., Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study, PLoS Med,
doi:10.1371/journal.pmed.1003605Cao, Wang, Cao, Cheng, Association of Vitamin D receptor gene TaqI polymorphisms with tuberculosis susceptibility: A meta-analysis, Int. J. Clin. Exp. Med
Castillo, Entrenas Costa, Vaquero Barrios, Alcala Diaz, Lopez Miranda 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,
doi:10.1016/j.jsbmb.2020.105751Freitas, Calhau, Antunes, Araujo, Bandeira et al., Vitamin D-related polymorphisms and vitamin D levels as risk biomarkers of COVID-19 disease severity, Sci. Rep,
doi:10.1038/s41598-021-99952-zHustmyer, Deluca, Peacock, Apai, BsmI, EcoRV and TaqI polymorphisms at the human vitamin D receptor gene locus in Caucasians, blacks and Asians, Hum. Mol. Genet,
doi:10.1093/hmg/2.4.487Lee, Song, Vitamin D receptor gene FokI, TaqI, BsmI, and ApaI polymorphisms and susceptibility to pulmonary tuberculosis: A meta-analysis, Genet. Mol. Res,
doi:10.4238/2015.August.7.21Lewis, Baker, Davey Smith, Meta-analysis of vitamin D receptor polymorphisms and pulmonary tuberculosis risk, Int. J. Tuberc. Lung Dis
Mamurova, Akan, Mogol, Turgay, Tuncel et al., Strong Association between Vitamin D Receptor Gene and Severe Acute Respiratory Syndrome coronavirus 2 Infectious Variants, Glob. Med. Genet,
doi:10.1055/s-0043-1761924Mcnally, Sampson, Matheson, Hutton, Little, Vitamin D receptor (VDR) polymorphisms and severe RSV bronchiolitis: A systematic review and meta-analysis, Pediatr. Pulmonol,
doi:10.1002/ppul.22877Mora, Iwata, Von Andrian, Vitamin effects on the immune system: Vitamins A and D take centre stage, Nat. Rev. Immunol,
doi:10.1038/nri2378Murai, Fernandes, Sales, Pinto, Goessler et al., Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients with Moderate to Severe COVID-19: A Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2020.26848Nejentsev, Godfrey, Snook, Rance, Nutland 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,
doi:10.1093/hmg/ddh169Peralta, Rosales, Mesa, González, Pérez 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,
doi:10.1186/s43042-021-00206-4Ross, Manson, Abrams, Aloia, Brannon et al., The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know, J. Clin. Endocrinol. Metab,
doi:10.1210/jc.2010-2704Roth, Jones, Prosser, Robinson, Vohra, Vitamin D receptor polymorphisms and the risk of acute lower respiratory tract infection in early childhood, J. Infect. Dis,
doi:10.1086/527488Tsitsilonis, Paraskevis, Lianidou, Terpos, Akalestos et al., SARS-CoV-2 Infection Is Asymptomatic in Nearly Half of Adults with Robust Anti-Spike Protein Receptor-Binding Domain Antibody Response, Vaccines,
doi:10.3390/vaccines9030207Veldman, Cantorna, Deluca, Expression of 1,25-dihydroxyvitamin D3 receptor in the immune system, Arch. Biochem. Biophys,
doi:10.1006/abbi.1999.1605Wilkinson, Llewelyn, Toossi, Patel, Pasvol et al., Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: A case-control study, Lancet,
doi:10.1016/S0140-6736(99)02301-6Wu, Mcgoogan, Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases from the Chinese Center for Disease Control and Prevention, JAMA,
doi:10.1001/jama.2020.2648Zacharioudaki, Messaritakis, Galanakis, Vitamin D receptor, vitamin D binding protein and CYP27B1 single nucleotide polymorphisms and susceptibility to viral infections in infants, Sci. Rep,
doi:10.1038/s41598-021-93243-3
