Retinol and retinol binding protein 4 levels and COVID-19: a Mendelian randomization study

DOI record: { "DOI": "10.1186/s12890-024-03013-w", "ISSN": [ "1471-2466" ], "URL": "http://dx.doi.org/10.1186/s12890-024-03013-w", "abstract": "<jats:title>Abstract</jats:title><jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>The Corona Virus Disease 2019 (COVID-19) pandemic has struck globally. Whether the related proteins of retinoic acid (RA) signaling pathway are causally associated with the risk of COVID-19 remains unestablished. We conducted a two-sample Mendelian randomization (MR) study to assess the associations of retinol, retinol binding protein 4 (RBP4), retinol dehydrogenase 16 (RDH16) and cellular retinoic acid binding protein 1 (CRABP1) with COVID-19 in European population.</jats:p>\n </jats:sec><jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>The outcome utilized the summary statistics of COVID-19 from the COVID-19 Host Genetics Initiative. The exposure data were obtained from public genome wide association study (GWAS) database. We extracted SNPs from exposure data and outcome data. The inverse variance weighted (IVW), MR-Egger and Wald ratio methods were employed to assess the causal relationship between exposure and outcome. Sensitivity analyses were performed to ensure the validity of the results.</jats:p>\n </jats:sec><jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>The MR estimates showed that retinol was associated with lower COVID-19 susceptibility using IVW (OR: 0.69, 95% CI: 0.53–0.90, P: 0.0065), whereas the associations between retinol and COVID-19 hospitalization or severity were not significant. RBP4 was associated with lower COVID-19 susceptibility using the Wald ratio (OR: 0.83, 95% CI: 0.72–0.95, P: 0.0072). IVW analysis showed RDH16 was associated with increased COVID-19 hospitalization (OR: 1.10, 95% CI: 1.01–1.18, P: 0.0199). CRABP1 was association with lower COVID-19 susceptibility (OR: 0.95, 95% CI: 0.91–0.99, P: 0.0290) using the IVW.</jats:p>\n </jats:sec><jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>We found evidence of possible causal association of retinol, RBP4, RDH16 and CRABP1 with the susceptibility, hospitalization and severity of COVID-19. Our study defines that retinol is significantly associated with lower COVID-19 susceptibility, which provides a reference for the prevention of COVID-19 with vitamin A supplementation.</jats:p>\n </jats:sec>", "alternative-id": [ "3013" ], "article-number": "206", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "21 October 2023" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "15 April 2024" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "26 April 2024" }, { "group": { "label": "Declarations", "name": "EthicsHeading" }, "name": "Ethics", "order": 1 }, { "group": { "label": "Ethical approval and informed consent", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "Not applicable." }, { "group": { "label": "Consent to publish", "name": "EthicsHeading" }, "name": "Ethics", "order": 3, "value": "Not applicable." }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 4, "value": "The authors have no relevant financial or non-financial interests to disclose." } ], "author": [ { "affiliation": [], "family": "Wang", "given": "Haixia", "sequence": "first" }, { "affiliation": [], "family": "Zhang", "given": "Zhiyun", "sequence": "additional" }, { "affiliation": [], "family": "Xie", "given": "Li", "sequence": "additional" }, { "affiliation": [], "family": "Lu", "given": "Kongli", "sequence": "additional" }, { "affiliation": [], "family": "Zhang", "given": "Shuyi", "sequence": "additional" }, { "affiliation": [], "family": "Xing", "given": "Shunpeng", "sequence": "additional" } ], "container-title": "BMC Pulmonary Medicine", "container-title-short": "BMC Pulm Med", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2024, 4, 26 ] ], "date-time": "2024-04-26T05:01:47Z", "timestamp": 1714107707000 }, "deposited": { "date-parts": [ [ 2024, 4, 26 ] ], "date-time": "2024-04-26T05:02:06Z", "timestamp": 1714107726000 }, "funder": [ { "award": [ "No: 2020078" ], "name": "the Shanghai Talent Development Fund" }, { "award": [ "SHDC12023601" ], "name": "Shanghai Hospital Development Center Foundation" } ], "indexed": { "date-parts": [ [ 2024, 4, 27 ] ], "date-time": "2024-04-27T00:27:25Z", "timestamp": 1714177645835 }, "is-referenced-by-count": 0, "issue": "1", "issued": { "date-parts": [ [ 2024, 4, 26 ] ] }, "journal-issue": { "issue": "1", "published-online": { "date-parts": [ [ 2024, 12 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2024, 4, 26 ] ], "date-time": "2024-04-26T00:00:00Z", "timestamp": 1714089600000 } }, { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2024, 4, 26 ] ], "date-time": "2024-04-26T00:00:00Z", "timestamp": 1714089600000 } } ], "link": [ { "URL": "https://link.springer.com/content/pdf/10.1186/s12890-024-03013-w.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/article/10.1186/s12890-024-03013-w/fulltext.html", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/content/pdf/10.1186/s12890-024-03013-w.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1186", "published": { "date-parts": [ [ 2024, 4, 26 ] ] }, "published-online": { "date-parts": [ [ 2024, 4, 26 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1208/s12248-020-00532-2", "author": "J Majumder", "doi-asserted-by": "publisher", "first-page": "14", "issue": "1", "journal-title": "AAPS J", "key": "3013_CR1", "unstructured": "Majumder J, Minko T. Recent developments on therapeutic and diagnostic approaches for COVID-19. AAPS J. 2021;23(1):14.", "volume": "23", "year": "2021" }, { "DOI": "10.1016/j.biopha.2021.112015", "author": "SU Rehman", "doi-asserted-by": "publisher", "first-page": "112015", "journal-title": "Biomed Pharmacotherapy = Biomedecine Pharmacotherapie", "key": "3013_CR2", "unstructured": "Rehman SU, Rehman SU, Yoo HH. COVID-19 challenges and its therapeutics. Biomed Pharmacotherapy = Biomedecine Pharmacotherapie. 2021;142:112015.", "volume": "142", "year": "2021" }, { "DOI": "10.1136/bmj.2.3537.691", "author": "HN Green", "doi-asserted-by": "publisher", "first-page": "691", "issue": "3537", "journal-title": "Br Med J", "key": "3013_CR3", "unstructured": "Green HN, Mellanby E. Vitamin a as an anti-infective Agent. Br Med J. 1928;2(3537):691–6.", "volume": "2", "year": "1928" }, { "DOI": "10.1017/S0007114521000246", "author": "CB Stephensen", "doi-asserted-by": "publisher", "first-page": "1663", "issue": "11", "journal-title": "Br J Nutr", "key": "3013_CR4", "unstructured": "Stephensen CB, Lietz G. Vitamin A in resistance to and recovery from infection: relevance to SARS-CoV2. Br J Nutr. 2021;126(11):1663–72.", "volume": "126", "year": "2021" }, { "DOI": "10.1038/nri2378", "author": "JR Mora", "doi-asserted-by": "publisher", "first-page": "685", "issue": "9", "journal-title": "Nat Rev Immunol", "key": "3013_CR5", "unstructured": "Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008;8(9):685–98.", "volume": "8", "year": "2008" }, { "DOI": "10.3390/cells9122660", "doi-asserted-by": "crossref", "key": "3013_CR6", "unstructured": "Szymanski L, Skopek R, Palusinska M, Schenk T, Stengel S, Lewicki S et al. Retinoic acid and its derivatives in skin. Cells. 2020;9(12)." }, { "DOI": "10.1016/j.bmc.2013.11.025", "author": "BC Das", "doi-asserted-by": "publisher", "first-page": "673", "issue": "2", "journal-title": "Bioorg Med Chem", "key": "3013_CR7", "unstructured": "Das BC, Thapa P, Karki R, Das S, Mahapatra S, Liu TC, et al. Retinoic acid signaling pathways in development and diseases. Bioorg Med Chem. 2014;22(2):673–83.", "volume": "22", "year": "2014" }, { "DOI": "10.3390/ijms24054980", "doi-asserted-by": "crossref", "key": "3013_CR8", "unstructured": "Nhieu J, Milbauer L, Lerdall T, Najjar F, Wei CW, Ishida R et al. Targeting Cellular Retinoic Acid binding protein 1 with retinoic acid-like compounds to mitigate Motor Neuron Degeneration. Int J Mol Sci. 2023;24(5)." }, { "DOI": "10.1242/dev.167502", "doi-asserted-by": "crossref", "key": "3013_CR9", "unstructured": "Ghyselinck NB, Duester G. Retinoic acid signaling pathways. Development. 2019;146(13)." }, { "DOI": "10.3390/nu14102007", "doi-asserted-by": "crossref", "key": "3013_CR10", "unstructured": "Vollenberg R, Tepasse PR, Fobker M, Husing-Kabar A. Significantly reduced Retinol binding protein 4 (RBP4) levels in critically ill COVID-19 patients. Nutrients. 2022;14(10)." }, { "DOI": "10.1016/j.cellsig.2021.110121", "author": "AR Sarohan", "doi-asserted-by": "publisher", "first-page": "110121", "journal-title": "Cell Signal", "key": "3013_CR11", "unstructured": "Sarohan AR, Kizil M, Inkaya AC, Mahmud S, Akram M, Cen O. A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder. Cell Signal. 2021;87:110121.", "volume": "87", "year": "2021" }, { "DOI": "10.26719/emhj.22.064", "author": "M Rohani", "doi-asserted-by": "publisher", "first-page": "673", "issue": "9", "journal-title": "East Mediterr Health J", "key": "3013_CR12", "unstructured": "Rohani M, Mozaffar H, Mesri M, Shokri M, Delaney D, Karimy M. Evaluation and comparison of vitamin A supplementation with standard therapies in the treatment of patients with COVID-19. East Mediterr Health J. 2022;28(9):673–81.", "volume": "28", "year": "2022" }, { "DOI": "10.3390/nu12092550", "doi-asserted-by": "crossref", "key": "3013_CR13", "unstructured": "Jovic TH, Ali SR, Ibrahim N, Jessop ZM, Tarassoli SP, Dobbs TD et al. Could vitamins help in the fight against COVID-19? Nutrients. 2020;12(9)." }, { "DOI": "10.1136/bmj.n2233", "author": "VW Skrivankova", "doi-asserted-by": "publisher", "first-page": "n2233", "journal-title": "BMJ", "key": "3013_CR14", "unstructured": "Skrivankova VW, Richmond RC, Woolf BAR, Davies NM, Swanson SA, VanderWeele TJ, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ. 2021;375:n2233.", "volume": "375", "year": "2021" }, { "DOI": "10.1038/s41586-018-0175-2", "author": "BB Sun", "doi-asserted-by": "publisher", "first-page": "73", "issue": "7708", "journal-title": "Nature", "key": "3013_CR15", "unstructured": "Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, et al. Genomic atlas of the human plasma proteome. Nature. 2018;558(7708):73–9.", "volume": "558", "year": "2018" }, { "DOI": "10.1038/s41431-020-0636-6", "author": "C-HG Initiative", "doi-asserted-by": "publisher", "first-page": "715", "issue": "6", "journal-title": "Eur J Hum Genet", "key": "3013_CR16", "unstructured": "Initiative C-HG. The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. Eur J Hum Genet. 2020;28(6):715–8.", "volume": "28", "year": "2020" }, { "DOI": "10.1038/s41586-021-03767-x", "author": "C-HG Initiative", "doi-asserted-by": "publisher", "first-page": "472", "issue": "7889", "journal-title": "Nature", "key": "3013_CR17", "unstructured": "Initiative C-HG. Mapping the human genetic architecture of COVID-19. Nature. 2021;600(7889):472–7.", "volume": "600", "year": "2021" }, { "DOI": "10.1093/bioinformatics/btz469", "author": "MA Kamat", "doi-asserted-by": "publisher", "first-page": "4851", "issue": "22", "journal-title": "Bioinformatics", "key": "3013_CR18", "unstructured": "Kamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics. 2019;35(22):4851–3.", "volume": "35", "year": "2019" }, { "DOI": "10.1093/ije/dyr036", "author": "S Burgess", "doi-asserted-by": "publisher", "first-page": "755", "issue": "3", "journal-title": "Int J Epidemiol", "key": "3013_CR19", "unstructured": "Burgess S, Thompson SG, Collaboration CCG. Avoiding bias from weak instruments in mendelian randomization studies. Int J Epidemiol. 2011;40(3):755–64.", "volume": "40", "year": "2011" }, { "DOI": "10.1002/gepi.21758", "author": "S Burgess", "doi-asserted-by": "publisher", "first-page": "658", "issue": "7", "journal-title": "Genet Epidemiol", "key": "3013_CR20", "unstructured": "Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658–65.", "volume": "37", "year": "2013" }, { "DOI": "10.1007/s10654-017-0255-x", "author": "S Burgess", "doi-asserted-by": "publisher", "first-page": "377", "issue": "5", "journal-title": "Eur J Epidemiol", "key": "3013_CR21", "unstructured": "Burgess S, Thompson SG. Interpreting findings from mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32(5):377–89.", "volume": "32", "year": "2017" }, { "DOI": "10.1038/s41588-018-0099-7", "author": "M Verbanck", "doi-asserted-by": "publisher", "first-page": "693", "issue": "5", "journal-title": "Nat Genet", "key": "3013_CR22", "unstructured": "Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8.", "volume": "50", "year": "2018" }, { "DOI": "10.1002/sim.9133", "author": "E Sanderson", "doi-asserted-by": "publisher", "first-page": "5434", "issue": "25", "journal-title": "Stat Med", "key": "3013_CR23", "unstructured": "Sanderson E, Spiller W, Bowden J. Testing and correcting for weak and pleiotropic instruments in two-sample multivariable mendelian randomization. Stat Med. 2021;40(25):5434–52.", "volume": "40", "year": "2021" }, { "DOI": "10.3390/nu13072173", "doi-asserted-by": "crossref", "key": "3013_CR24", "unstructured": "Tepasse PR, Vollenberg R, Fobker M, Kabar I, Schmidt H, Meier JA et al. Vitamin A plasma levels in COVID-19 patients: a prospective Multicenter Study and Hypothesis. Nutrients. 2021;13(7)." }, { "DOI": "10.1196/annals.1443.020", "author": "T Kawai", "doi-asserted-by": "publisher", "first-page": "1", "journal-title": "Ann N Y Acad Sci", "key": "3013_CR25", "unstructured": "Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci. 2008;1143:1–20.", "volume": "1143", "year": "2008" }, { "DOI": "10.1073/pnas.90.1.30", "author": "G Allenby", "doi-asserted-by": "publisher", "first-page": "30", "issue": "1", "journal-title": "Proc Natl Acad Sci USA", "key": "3013_CR26", "unstructured": "Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, et al. Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci USA. 1993;90(1):30–4.", "volume": "90", "year": "1993" }, { "DOI": "10.1146/annurev-immunol-042617-053309", "author": "KT Chow", "doi-asserted-by": "publisher", "first-page": "667", "journal-title": "Annu Rev Immunol", "key": "3013_CR27", "unstructured": "Chow KT, Gale M Jr., Loo YM. RIG-I and other RNA sensors in antiviral immunity. Annu Rev Immunol. 2018;36:667–94.", "volume": "36", "year": "2018" }, { "DOI": "10.1016/j.mehy.2020.110250", "author": "AR Sarohan", "doi-asserted-by": "publisher", "first-page": "110250", "journal-title": "Med Hypotheses", "key": "3013_CR28", "unstructured": "Sarohan AR. COVID-19: endogenous retinoic acid theory and retinoic acid depletion syndrome. Med Hypotheses. 2020;144:110250.", "volume": "144", "year": "2020" }, { "DOI": "10.1111/1440-1681.13354", "author": "SE Trasino", "doi-asserted-by": "publisher", "first-page": "1765", "issue": "10", "journal-title": "Clin Exp Pharmacol Physiol", "key": "3013_CR29", "unstructured": "Trasino SE. A role for retinoids in the treatment of COVID-19? Clin Exp Pharmacol Physiol. 2020;47(10):1765–7.", "volume": "47", "year": "2020" }, { "DOI": "10.1002/anie.202015639", "doi-asserted-by": "crossref", "key": "3013_CR30", "unstructured": "Shoemark DK, Colenso CK, Toelzer C, Gupta K, Sessions RB, Davidson AD et al. Molecular simulations suggest vitamins, retinoids and steroids as ligands of the free fatty acid Pocket of the SARS-CoV-2 spike Protein*. Angewandte Chemie (International ed in English). 2021;60(13):7098–110." }, { "DOI": "10.3389/fphys.2021.659977", "author": "JS Steinhoff", "doi-asserted-by": "publisher", "first-page": "659977", "journal-title": "Front Physiol", "key": "3013_CR31", "unstructured": "Steinhoff JS, Lass A, Schupp M. Biological functions of RBP4 and its relevance for Human diseases. Front Physiol. 2021;12:659977.", "volume": "12", "year": "2021" }, { "DOI": "10.3945/an.116.014167", "author": "LP Rubin", "doi-asserted-by": "publisher", "first-page": "197", "issue": "2", "journal-title": "Adv Nutr", "key": "3013_CR32", "unstructured": "Rubin LP, Ross AC, Stephensen CB, Bohn T, Tanumihardjo SA. Metabolic effects of inflammation on vitamin A and carotenoids in humans and animal models. Adv Nutr. 2017;8(2):197–212.", "volume": "8", "year": "2017" }, { "DOI": "10.3390/v13112209", "doi-asserted-by": "crossref", "key": "3013_CR33", "unstructured": "Kumar N, Zuo Y, Yalavarthi S, Hunker KL, Knight JS, Kanthi Y et al. SARS-CoV-2 spike protein S1-Mediated endothelial Injury and pro-inflammatory state is amplified by Dihydrotestosterone and prevented by Mineralocorticoid antagonism. Viruses. 2021;13(11)." }, { "DOI": "10.1111/hepr.13432", "author": "YH Zhu", "doi-asserted-by": "publisher", "first-page": "110", "issue": "1", "journal-title": "Hepatol Res", "key": "3013_CR34", "unstructured": "Zhu YH, Li JB, Wu RY, Yu Y, Li X, Li ZL, et al. Clinical significance and function of RDH16 as a tumor-suppressing gene in hepatocellular carcinoma. Hepatol Res. 2020;50(1):110–20.", "volume": "50", "year": "2020" } ], "reference-count": 34, "references-count": 34, "relation": {}, "resource": { "primary": { "URL": "https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-024-03013-w" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Retinol and retinol binding protein 4 levels and COVID-19: a Mendelian randomization study", "type": "journal-article", "update-policy": "http://dx.doi.org/10.1007/springer_crossmark_policy", "volume": "24" }