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.

The Association of Vitamin D Receptor Polymorphisms with COVID-19 Severity

“…Nevertheless, to the best of our knowledge, this is the first case-control study evaluating the association between 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 ].…”

“…These studies, however, did not include a control group of uninfected individuals, thus limiting the robustness and validity of those early findings by failing to assess causality, generalize results, or reduce the risk of bias within the cohort. In two recent case-control studies, TaqI and FokI polymorphisms were associated with increased susceptibility to and severity of the disease in two populations of different geographical origin: Turkey [ 15 ] and Cyprus [ 16 ]. In the study from Turkey, presenting a cohort of approximately 300 COVID-19 patients, the TaqI TT genotype was associated with a poor prognosis and increased admission to ICU [ 15 ].…”

“…In this study, the FokI f allele affected the prognosis of patients, while the ApaI aa genotype was associated with higher mortality rates [ 15 ]. In the cohort of 600 individuals (of whom 300 were SARS-CoV-2 infection positive) from Cyprus, the FokI T and TaqI C alleles were more frequently observed in SARS-CoV-2-infected patients compared to the control group ( p < 0.005), pointing to a linkage disequilibrium between these VDR variants [ 16 ]. However, this study could not confirm the potential association of FokI T and TaqI C polymorphisms with severity of COVID-19 due to lack of access to the patients’ clinical data [ 16 ].…”

“…To date, several studies have investigated the role of VDR gene polymorphisms in the outcome of COVID-19, showing inconsistent results in different ethnicities and geographical regions and in regard to various vitamin D levels [ 12 , 13 , 14 , 15 , 16 ]. The aim of the present study was to evaluate the association between the VDR gene polymorphisms FokI (rs10735810), ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410) and the severity of COVID-19 in the setting of a single tertiary centre during the period of the COVID-19 pandemic and irrespective of vitamin D levels in the serum.…”

Long-COVID-19 in Asymptomatic, Non-Hospitalized, and Hospitalized Populations: A Cross-Sectional Study

“…SARS-CoV-2 infection was diagnosed by RT-PCR performed on nasopharyngeal swab samples, utilizing Uniplex RT-qPCR SARS-CoV-2 RT-qPCR Detection Kit (IKAS Medical, Nicosia, Northern Cyprus) that is based on amplification of viral ORF1ab, N1, and N2 genes and uses human Rnase P as an internal control. SARS-CoV-2 variant analysis was conducted by using Multiplex SARS-CoV-2 VoC RT-qPCR Detection Kit (IKAS Medical, Nicosia, Northern Cyprus) that identifies variants of concern, including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), P.1 (Gamma), and B.1.1.529 (Omicron) variants, by simultaneously detecting mutations (del69/70, N501Y, K417N, T478K, Y144del, and P681R) in the Spike protein gene [ 12 , 13 ].…”