Associations between Genetic Variants in the Vitamin D Metabolism Pathway and Severity of COVID-19 among UAE Residents
Abstract
:1. Introduction
2. Materials and Methods
2.1. Participants and Collecting Samples
2.2. Collecting Demographic Data
2.3. DNA Extracting and Genotyping
2.4. Measuring Serum 25(OH)D Levels
2.5. Statistical Analysis
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- WHO Coronavirus (COVID-19) Dashboard. Available online: https://covid19.who.int/ (accessed on 7 April 2021).
- Del Valle, D.M.; Kim-Schulze, S.; Huang, H.-H.; Beckmann, N.D.; Nirenberg, S.; Wang, B.; Lavin, Y.; Swartz, T.H.; Madduri, D.; Stock, A.; et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 2020, 26, 1636–1643. [Google Scholar] [CrossRef]
- de Lucena, T.M.C.; da Silva Santos, A.F.; de Lima, B.R.; de Albuquerque Borborema, M.E.; de Azevêdo Silva, J. Mechanism of inflammatory response in associated comorbidities in COVID-19. Diabetes Metab. Syndr. Clin. Res. Rev. 2020, 14, 597–600. [Google Scholar] [CrossRef]
- Gasmi, A.; Tippairote, T.; Mujawdiya, P.K.; Peana, M.; Menzel, A.; Dadar, M.; Gasmi Benahmed, A.; Bjørklund, G. Micronutrients as immunomodulatory tools for COVID-19 management. Clin. Immunol. 2020, 220, 108545. [Google Scholar] [CrossRef]
- Evans, R.M.; Lippman, S.M. Shining Light on the COVID-19 Pandemic: A Vitamin D Receptor Checkpoint in Defense of Unregulated Wound Healing. Cell Metab. 2020, 32, 704–709. [Google Scholar] [CrossRef] [PubMed]
- Luciani, F.; Caroleo, M.C.; Cannataro, R.; Mirra, D.; D’Agostino, B.; Gallelli, L.; Cione, E. Immunological Response to SARS-CoV-2 Is Sustained by Vitamin D: A Case Presentation of One-Year Follow-Up. Reports 2021, 4, 18. [Google Scholar] [CrossRef]
- Glinsky, G.V. Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin, D.; Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells. Biomedicines 2020, 8, 129. [Google Scholar]
- Kotur, N.; Skakic, A.; Klaassen, K.; Gasic, V.; Zukic, B.; Skodric-Trifunovic, V.; Stjepanovic, M.; Zivkovic, Z.; Ostojic, O.; Stevanovic, G.; et al. Association of Vitamin, D, Zinc and Selenium Related Genetic Variants With COVID-19 Disease Severity. Front. Nutr. 2021, 8, 289. [Google Scholar] [CrossRef]
- AlSafar, H.; Grant, W.B.; Hijazi, R.; Uddin, M.; Alkaabi, N.; Tay, G.; Mahboub, B.; Al Anouti, F. COVID-19 disease severity and death in relation to vitamin D status among SARS-CoV-2-positive UAE residents. Nutrients 2021, 13, 1714. [Google Scholar] [CrossRef]
- Rahmadhani, R.; Zaharan, N.L.; Mohamed, Z.; Moy, F.M.; Jalaludin, M.Y. The associations between VDR BsmI polymorphisms and risk of vitamin D deficiency, obesity and insulin resistance in adolescents residing in a tropical country. PLoS ONE 2017, 12, e0178695. [Google Scholar] [CrossRef] [Green Version]
- Di Maria, E.; Latini, A.; Borgiani, P.; Novelli, G. Genetic variants of the human host influencing the coronavirus-associated phenotypes (SARS, MERS and COVID-19): Rapid systematic review and field synopsis. Hum. Genom. 2020, 14, 30. [Google Scholar] [CrossRef]
- Weiss, P.; Murdoch, D.R. Clinical course and mortality risk of severe COVID-19. Lancet 2020, 395, 1014–1015. [Google Scholar] [CrossRef]
- Sattar, N.; McInnes, I.B.; McMurray, J.J. Obesity is a risk factor for severe COVID-19 infection: Multiple potential mechanisms. Circulation 2020, 142, 4–6. [Google Scholar] [CrossRef]
- Castillo, M.E.; Costa, L.M.E.; Barrios, J.M.V.; Díaz, J.F.A.; Miranda, J.L.; Bouillon, R.; Gomez, J.M.Q. 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. [Google Scholar] [CrossRef]
- Charoenngam, N.; Shirvani, A.; Reddy, N.; Vodopivec, D.M.; Apovian, C.M.; Holick, M.F. Association of Vitamin D Status with Hospital Morbidity and Mortality in adult hospitalized patients with COVID-19. Endocr. Pract. 2021, 27, 271–278. [Google Scholar] [CrossRef]
- Mercola, J.; Grant, W.B.; Wagner, C.L. Evidence regarding vitamin D and risk of COVID-19 and its severity. Nutrients 2020, 12, 3361. [Google Scholar] [CrossRef]
- Grant, W.B.; Lahore, H.; McDonnell, S.L.; Baggerly, C.A.; French, C.B.; Aliano, J.L.; Bhattoa, H.P. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020, 12, 988. [Google Scholar] [CrossRef] [Green Version]
- Hossein-Nezhad, A.; Spira, A.; Holick, M.F. Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: A randomized double-blind clinical trial. PLoS ONE 2013, 8, e58725. [Google Scholar] [CrossRef] [Green Version]
- Al Anouti, F.; Chehadeh, S.E.H.; Osman, E.; ElGhazali, G.; Al Safar, H. Investigating the association of vitamin D metabolism genes CYP2R1, CYP24A1 and CYP27B1 with vitamin D status in young adult Emiratis. J. Food Nutr. Res. 2017, 5, 15–21. [Google Scholar]
- Al Safar, H.; Chehadeh, S.E.H.; Abdel-Wareth, L.; Haq, A.; Jelinek, H.F.; ElGhazali, G.; Al Anouti, F. Vitamin D receptor gene polymorphisms among Emirati patients with type 2 diabetes mellitus. J. Steroid Biochem. Mol. Biol. 2018, 175, 119–124. [Google Scholar] [CrossRef] [PubMed]
- Chehadeh, S.E.H.; Osman, W.; Nazar, S.; Jerman, L.; Alghafri, A.; Sajwani, A.; Alawlaqi, M.; AlObeidli, M.; Jelinek, H.F.; AlAnouti, F. Implication of genetic variants in overweight and obesity susceptibility among the young Arab population of the United Arab Emirates. Gene 2020, 739, 144509. [Google Scholar] [CrossRef] [PubMed]
- Enlund-Cerullo, M.; Koljonen, L.; Holmlund-Suila, E.; Hauta-alus, H.; Rosendahl, J.; Valkama, S.; Helve, O.; Hytinantti, T.; Viljakainen, H.; Andersson, S.; et al. Genetic Variation of the Vitamin D Binding Protein Affects Vitamin D Status and Response to Supplementation in Infants. J. Clin. Endocrinol. Metab. 2019, 104, 5483–5498. [Google Scholar] [CrossRef]
- Zhao, X.; Hu, Y.; Wang, R.; Mao, D.; Chen, J.; Zhang, H.; Shan, X.; Yang, L. Relationship between rs7041 polymorphism of GC gene and serum vitamin D status in Chinese women of childbearing age. Wei Sheng Yan Jiu= J. Hyg. Res. 2021, 50, 192–209. [Google Scholar]
- Xie, Z.; Wang, X.; Bikle, D.D. Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions. Front. Endocrinol. 2020, 11, 40. [Google Scholar] [CrossRef] [PubMed]
- Jolliffe, D.A.; Greiller, C.L.; Mein, C.A.; Hoti, M.; Bakhsoliani, E.; Telcian, A.G.; Simpson, A.; Barnes, N.C.; Curtin, J.A.; Custovic, A. Vitamin D receptor genotype influences risk of upper respiratory infection. Br. J. Nutr. 2018, 120, 891–900. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McNally, J.D.; Sampson, M.; Matheson, L.A.; Hutton, B.; Little, J. Vitamin D receptor (VDR) polymorphisms and severe RSV bronchiolitis: A systematic review and meta-analysis. Pediatric Pulmonol. 2014, 49, 790–799. [Google Scholar] [CrossRef]
- Karcioglu Batur, L.; Hekim, N. The role of DBP gene polymorphisms in the prevalence of new coronavirus disease 2019 infection and mortality rate. J. Med Virol. 2021, 93, 1409–1413. [Google Scholar] [CrossRef]
- Holick, M. Vitamin D: Photobiology, metabolism, and clinical application. Endocrinology 1995, 990, 1013. [Google Scholar]
- Ahn, J.; Yu, K.; Stolzenberg-Solomon, R.; Simon, K.C.; McCullough, M.L.; Gallicchio, L.; Jacobs, E.J.; Ascherio, A.; Helzlsouer, K.; Jacobs, K.B. Genome-wide association study of circulating vitamin D levels. Hum. Mol. Genet. 2010, 19, 2739–2745. [Google Scholar] [CrossRef]
- Bouillon, R. Genetic and environmental determinants of vitamin D status. Lancet 2010, 376, 148–149. [Google Scholar] [CrossRef]
- Zhu, J.G.; Ochalek, J.T.; Kaufmann, M.; Jones, G.; DeLuca, H.F. CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. Proc. Natl. Acad. Sci. USA 2013, 110, 15650–15655. [Google Scholar] [CrossRef] [Green Version]
- Elkum, N.; Alkayal, F.; Noronha, F.; Ali, M.M.; Melhem, M.; Al-Arouj, M.; Bennakhi, A.; Behbehani, K.; Alsmadi, O.; Abubaker, J. Vitamin D insufficiency in Arabs and South Asians positively associates with polymorphisms in GC and CYP2R1 genes. PLoS ONE 2014, 9, e113102. [Google Scholar] [CrossRef] [PubMed]
- Gallelli, L.; Michniewicz, A.; Cione, E.; Squillace, A.; Colosimo, M.; Pelaia, C.; Fazio, A.; Zampogna, S.; Peltrone, F.; Iannacchero, R. 25-Hydroxy Vitamin D detection using different analytic methods in patients with migraine. J. Clin. Med. 2019, 8, 895. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Variable | Noncritical, n = 453 (%) | Critical, n = 193 (%) | p |
---|---|---|---|
Age | <0.001 | ||
<33 | 155 (34.2) | 12 (6.2) | |
34–43 | 138 (30.5) | 31 (16.1) | |
44–55 | 92 (20.3) | 60 (31.1) | |
>56 | 68 (15.0) | 90 (46.6) | |
Sex | 0.217 | ||
Male | 305 (77.2) | 70 (83.3) | |
Female | 90 (22.8) | 14 (16.7) | |
Body mass index (kg/m2 of body surface area) | 0.001 | ||
<18.50 | 9 (2.3) | 1 (0.5) | |
18.51–24.90 | 115 (29.4) | 38 (19.7) | |
24.91–29.99 | 168 (43.0) | 77 (39.9) | |
>30.00 | 99 (25.3) | 77 (39.9) | |
Country of origin | 0.004 | ||
Middle Eastern | 40 (30.9) | 80 (41.5) | |
Asian | 290 (64.0) | 103 (53.4) | |
African | 18 (4.0) | 3 (1.6) | |
European | 2 (0.4) | 5 (2.6) | |
American | 3 (0.7) | 2 (1.0) | |
History of comorbid condition | <0.001 | ||
No | 263 (65.1) | 75 (40.3) | |
Yes | 141 (34.9) | 111 (59.7) | |
Diabetes | <0.001 | ||
No | 279 (75.4) | 78 (47.3) | |
Yes | 91 (24.6) | 87 (52.7) | |
Immunosuppressive condition | 0.20 | ||
No | 250 (93.6) | 117 (90.0) | |
Yes | 17 (6.4) | 13 (10.0) | |
Liver disease | 0.01 | ||
No | 323 (99.4) | 128 (96.2) | |
Yes | 2 (0.6) | 5 (3.8) | |
Metabolic disease | <0.001 | ||
No | 318 (95.8) | 112 (83.0) | |
Yes | 14 (4.2) | 23 (17.0) | |
Neurological disorder | 0.03 | ||
No | 320 (98.8) | 126 (95.5) | |
Yes | 4 (1.2) | 6 (4.5) | |
Renal disease | <0.001 | ||
No | 312 (94.8) | 111 (78.7) | |
Yes | 17 (5.2) | 30 (21.3) | |
Cardiac condition | <0.001 | ||
No | 312 (91.5) | 111 (76.0) | |
Yes | 29 (8.5) | 35 (24.0) | |
Chronic lung condition | <0.001 | ||
No | 318 (97.2) | 113 (86.3) | |
Yes | 9 (2.8) | 18 (13.7) |
25(OH)D Status (ng/mL) | Noncritical, n = 322 (%) | Critical, n = 155 (%) | p | Unadjusted OR (95% CI) | p | Adjusted OR (95% CI) | p |
---|---|---|---|---|---|---|---|
Normal (>20) | 90 (28.0) | 56 (36.1) | 0.02 | 1.00 | 1.00 | ||
Deficient (<20) | 142 (44.1) | 47 (30.3) |
0.54 (0.35–0.89) | 0.008 |
1.28 (0.62–2.65) | 0.49 | |
Severely deficient (<12) | 90 (28.0) | 52 (33.5) |
0.95 (0.59–1.51) | 0.93 |
4.37 (2.06–9.29) | <0.001 |
Gene | SNP | Genotype | Noncritical, n = 453 (%) | Critical, n = 193 (%) | Genetic Model | Unadjusted OR (95% CI) | p | Adjusted OR (95% CI) | p |
---|---|---|---|---|---|---|---|---|---|
GC | rs59241277 | AA AG GG | 363 (80.1) 86 (19.0) 4 (0.9) | 174 (90.2) 18 (9.3) 1 (0.5) | AA vs. AG + GG | 0.47 (0.28–0.77) | 0.003 | 0.43 (0.24–0.77) | 0.005 |
rs113574864 | CC CT TT | 350 (77.3) 96 (21.2) 7 (1.5) | 168 (87.0) 23 (11.9) 2 (1.1) | CC vs. CT + TT | 0.47 (0.29–078) | 0.003 | 0.43 (0.24–0.78) | 0.005 | |
rs182901986 | GG GA AA | 354 (78.1) 93 (20.5) 6 (1.3) | 171 (88.6) 20 (10.4) 2 (1.0) | GG vs. GA + AA | 0.50 (0.31–0.80) | 0.003 | 0.49 (0.29–0.84) | 0.01 | |
rs60349934 | TT TC CC | 359 (79.2) 91 (20.1) 3 (0.7) | 170 (88.1) 22 (11.4) 1 (0.5) | TT vs. TC + CC | 0.55 (0.34–0.87) | 0.011 | 0.50 (0.28–0.86) | 0.01 | |
rs113876500 | GG GT TT | 350 (77.3) 96 (21.2) 7 (1.5) | 168 (87.1) 23 (11.9) 2 (1.0) | GG vs. GT + TT | 0.54 (0.35–0.84) | 0.006 | 0.53 (0.31–0.88) | 0.02 | |
NADSYN1 | rs4944076 | AA AG GG | 148 (32.7) 198 (43.7) 107 (23.6) | 78 (40.4) 93 (48.2) 22 (11.4) | AA vs. AG + GG | 0.66 (0.51–0.84) | 0.001 | 0.66 (0.49–0.90) | 0.008 |
rs4944997 | GG GA AA | 144 (31.8) 199 (43.9) 110 (24.3) | 73 (37.8) 95 (49.2) 25 (13.0) | GG vs. GA + AA | 0.69 (0.54–0.89) | 0.004 | 0.69 (0.51–0.93) | 0.02 | |
rs4944998 | GG GC CC | 144 (31.8) 200 (44.2) 109 (24.1) | 73 (37.8) 95 (49.2) 25 (13.0) | GG vs. GC + CC | 0.70 (0.55–0.89) | 0.004 | 0.70 (0.51–0.94) | 0.02 | |
rs4944979 | GG GT TT | 146 (32.2) 197 (43.5) 110 (24.3) | 74 (38.3) 94 (48.7) 25 (13.0) | GG vs. GT + TT | 0.69 (0.54–0.89) | 0.004 | 0.70 (0.52–0.94) | 0.02 | |
rs10898210 | AA AG GG | 157 (34.7) 196 (45.2) 100 (22.1) | 85 (44.0) 87 (45.1) 21 (10.9) | AA vs. AG + GG | 0.64 (0.50–0.82) | 0.0005 | 0.67 (0.50–0.90) | 0.009 | |
VDR | rs11574018 | TT TC CC | 438 (96.7) 15 (3.3) 0 (0.0) | 192 (99.5) 1 (0.5) 0 (0.0) | TT vs. TC + CC | 0.15 (0.02–1.17) | 0.051 | 0.10 (0.01–0.86) | 0.04 |
rs11574024 | GG GT TT | 440 (97.1) 13 (2.9) 0 (0.0) | 190 (98.4) 3 (1.6) 0 (0.0) | GG vs. GT + TT | 0.53 (0.15–1.89) | 0.328 | 0.20 (0.04–0.91) | 0.04 | |
rs116886958 | CC CA AA | 428 (94.5) 25 (5.5) 0 (0.0) | 187 (96.9) 6 (3.1) 0 (0.0) | CC vs. CA + AA | 0.55 (0.22–1.36) | 0.195 | 0.37 (0.13–1.04) | 0.06 | |
rs10875694 | TT TA AA | 359 (79.2) 90 (19.9) 4 (0.9) | 158 (81.9) 32 (16.6) 3 (1.6) | TT vs. TA + AA | 0.90 (0.60–1.33) | 0.602 | 0.63 (0.13–1.02) | 0.06 | |
rs2239181 | AA AC CC | 429 (94.7) 24 (5.3) 0 (0.0) | 176 (91.2) 15 (7.8) 2 (1.0) | AA + AC vs. CC | 1.00 (0.71–1.41) | 0.996 | 1.44 (0.95–2.18) | 0.08 | |
CYP2R1 | rs11023373 | GG GC CC | 426 (94.0) 23 (5.1) 4 (0.9) | 188 (97.4) 5 (2.6) 0 (0.0) | GG vs. GC + CC | 0.37 (0.14–0.95) | 0.034 | 0.39 (0.13–1.15) | 0.09 |
rs11023374 | TT TC CC | 284 (62.7) 147 (32.5) 22 (4.9) | 130 (67.4) 55 (28.5) 8 (4.1) | TT vs. TC + CC | 0.84 (0.62–1.14) | 0.271 | 0.73 (0.51–1.05) | 0.09 | |
rs10500804 | TT TG GG | 165 (36.4) 209 (46.1) 79 (17.4) | 78 (40.4) 83 (43.0) 32 (16.6) | TT vs. TG + GG | 0.90 (0.70–1.15) | 0.415 | 0.83 (0.61–1.11) | 0.22 | |
rs1993116 | GG GA AA | 192 (42.4) 205 (45.3) 56 (12.4) | 75 (38.9) 91 (47.2) 27 (14.0) | GG + GA vs. AA | 1.11 (0.87–1.43) | 0.377 | 1.24 (0.92–1.69) | 0.15 | |
rs7935792 | AA AC CC | 362 (79.9) 84 (18.5) 7 (1.5) | 157 (81.3) 33 (17.1) 3 (1.6) | AA vs. AC + CC | 0.92 (0.62–1.37) | 0.703 | 1.00 (0.61–1.65) | 0.99 |
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Al-Anouti, F.; Mousa, M.; Karras, S.N.; Grant, W.B.; Alhalwachi, Z.; Abdel-Wareth, L.; Uddin, M.; Alkaabi, N.; Tay, G.K.; Mahboub, B.; et al. Associations between Genetic Variants in the Vitamin D Metabolism Pathway and Severity of COVID-19 among UAE Residents. Nutrients 2021, 13, 3680. https://doi.org/10.3390/nu13113680
Al-Anouti F, Mousa M, Karras SN, Grant WB, Alhalwachi Z, Abdel-Wareth L, Uddin M, Alkaabi N, Tay GK, Mahboub B, 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. https://doi.org/10.3390/nu13113680
Chicago/Turabian StyleAl-Anouti, Fatme, Mira Mousa, Spyridon N. Karras, William B. Grant, Zainab Alhalwachi, Laila Abdel-Wareth, Maimunah Uddin, Nawal Alkaabi, Guan K. Tay, Bassam Mahboub, and et al. 2021. "Associations between Genetic Variants in the Vitamin D Metabolism Pathway and Severity of COVID-19 among UAE Residents" Nutrients 13, no. 11: 3680. https://doi.org/10.3390/nu13113680