Association of Endothelial Nitric Oxide Synthase Polymorphisms with Clinical Severity in Patients with COVID-19

DOI record: { "DOI": "10.3390/jcm14061931", "ISSN": [ "2077-0383" ], "URL": "http://dx.doi.org/10.3390/jcm14061931", "abstract": "<jats:p>Background/Objectives: To elucidate the factors that contribute to individual variability in the progression of COVID-19, experiments on endothelial nitric oxide synthase polymorphisms have been reported. Nitric oxide synthase (NOS3) is located in the endothelium and is involved in the regulation of inflammation and vascular homeostasis. In this study, we investigated the association between COVID-19 severity and NOS3 G894T and NOS3 27-bp VNTR 4b/a genetic polymorphisms. Methods: Patients with COVID-19 (n = 178) were divided into Group 1 (mild disease) and Group 2 (severe disease) based on oxygen saturation levels in room air (Group 1, SpO2 ≥ 93%, n = 107; and Group 2, SpO2 &lt; 93%, n = 73) and hospitalization requirements. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: Overall, genotype and allele frequencies of the NOS3 genetic polymorphisms were similar across the two study groups (p &gt; 0.05). However, the subgroup analysis showed a notable trend for the 4b/4a allele distribution between Groups 1 and 2. In the younger subgroup of patients (≤50 years old) without chronic obstructive pulmonary disease, Group 2 tended to have a higher frequency of the 4b allele than Group 1 (97.4% vs. 85.4% p = 0.06) and a higher occurrence of 4b/4b genotype (94.7% vs. 74.0%, p = 0.05). Additionally, a rarely observed 4c allele was detected only in two subjects within Group 2 but not in Group 1. Conclusions: These findings suggest a trend of association between COVID-19 severity and NOS3 27-bp VNTR 4b/a genetic polymorphism. Genetic analysis may reveal patient susceptibility to disease, prognosis risk factors, and drug responsiveness.</jats:p>", "alternative-id": [ "jcm14061931" ], "author": [ { "ORCID": "https://orcid.org/0000-0002-5750-1223", "affiliation": [ { "name": "Department of Chest Diseases, Faculty of Medicine, Hacettepe University, Ankara 06230, Türkiye" } ], "authenticated-orcid": false, "family": "İdikut", "given": "Aytekin", "sequence": "first" }, { "affiliation": [ { "name": "Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara 06230, Türkiye" } ], "family": "Değer", "given": "İlter", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Chest Diseases, Faculty of Medicine, Hacettepe University, Ankara 06230, Türkiye" } ], "family": "Göktaş", "given": "Gamze", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Bioistatistics, Faculty of Medicine, Hacettepe University, Ankara 06230, Türkiye" } ], "family": "Karahan", "given": "Sevilay", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Chest Diseases, Faculty of Medicine, Hacettepe University, Ankara 06230, Türkiye" } ], "family": "Sarınç", "given": "Sevinç", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-8374-3691", "affiliation": [ { "name": "Department of Chest Diseases, Faculty of Medicine, Hacettepe University, Ankara 06230, Türkiye" } ], "authenticated-orcid": false, "family": "Köksal", "given": "Deniz", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara 06230, Türkiye" } ], "family": "Babaoğlu", "given": "Melih O.", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Chest Diseases, Faculty of Medicine, Hacettepe University, Ankara 06230, Türkiye" } ], "family": "Babaoğlu", "given": "Elif", "sequence": "additional" } ], "container-title": "Journal of Clinical Medicine", "container-title-short": "JCM", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2025, 3, 13 ] ], "date-time": "2025-03-13T10:53:00Z", "timestamp": 1741863180000 }, "deposited": { "date-parts": [ [ 2025, 3, 13 ] ], "date-time": "2025-03-13T12:19:59Z", "timestamp": 1741868399000 }, "indexed": { "date-parts": [ [ 2025, 3, 14 ] ], "date-time": "2025-03-14T04:19:09Z", "timestamp": 1741925949976, "version": "3.38.0" }, "is-referenced-by-count": 0, "issue": "6", "issued": { "date-parts": [ [ 2025, 3, 13 ] ] }, "journal-issue": { "issue": "6", "published-online": { "date-parts": [ [ 2025, 3 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 3, 13 ] ], "date-time": "2025-03-13T00:00:00Z", "timestamp": 1741824000000 } } ], "link": [ { "URL": "https://www.mdpi.com/2077-0383/14/6/1931/pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1968", "original-title": [], "page": "1931", "prefix": "10.3390", "published": { "date-parts": [ [ 2025, 3, 13 ] ] }, "published-online": { "date-parts": [ [ 2025, 3, 13 ] ] }, "publisher": "MDPI AG", "reference": [ { "DOI": "10.1056/NEJMcp2009575", "article-title": "Severe COVID-19", "author": "Berlin", "doi-asserted-by": "crossref", "first-page": "2451", "journal-title": "N. Engl. J. Med.", "key": "ref_1", "volume": "383", "year": "2020" }, { "DOI": "10.1016/j.jiph.2020.07.014", "article-title": "COVID-19 and comorbidities: Deleterious impact on infected patients", "author": "Ejaz", "doi-asserted-by": "crossref", "first-page": "1833", "journal-title": "J. Infect. Public Health", "key": "ref_2", "volume": "13", "year": "2020" }, { "DOI": "10.1016/j.stem.2020.11.010", "article-title": "Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response", "author": "Purkayastha", "doi-asserted-by": "crossref", "first-page": "869", "journal-title": "Cell Stem Cell", "key": "ref_3", "volume": "27", "year": "2020" }, { "DOI": "10.1186/s40246-020-00290-4", "article-title": "Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity", "author": "Anastassopoulou", "doi-asserted-by": "crossref", "first-page": "40", "journal-title": "Hum. Genom.", "key": "ref_4", "volume": "14", "year": "2020" }, { "DOI": "10.1056/NEJMoa2020283", "doi-asserted-by": "crossref", "key": "ref_5", "unstructured": "Severe COVID-19 GWAS Group, Ellinghaus, D., Degenhardt, F., Bujanda, L., Buti, M., Albillos, A., Invernizzi, P., Fernández, J., Prati, D., and Baselli, G. (2020). Genomewide association study of severe COVID-19 with respiratory failure. N. Engl. J. Med., 383, 1522–1534." }, { "DOI": "10.3389/fcimb.2022.963239", "doi-asserted-by": "crossref", "key": "ref_6", "unstructured": "Ji, X.S., Chen, B., Ze, B., and Zhou, W.H. (2022). Human genetic basis of severe or critical illness in COVID-19. Front. Cell. Infect. Microbiol., 12." }, { "key": "ref_7", "unstructured": "Delgado-Wicke, P., Fernández de Córdoba-Oñate, S., Roy-Vallejo, E., Alegría-Carrasco, E., Rodríguez-Serrano, D.A., Lamana, A., Montes, N., Nicolao-Gómez, A., Carracedo-Rodríguez, R., and Marcos-Jiménez, A. (2024). Genetic Variants Regulating the Immune Response Improve the Prediction of COVID-19 Severity Provided by Clinical Variables. Sci. Rep., 14." }, { "article-title": "Pathogenesis of SARS-CoV-2 and immune response in COVID-19", "author": "Demirci", "first-page": "183", "journal-title": "Turk. Mikrobiyol. Cem. Derg.", "key": "ref_8", "volume": "50", "year": "2020" }, { "DOI": "10.1016/j.trsl.2021.03.002", "article-title": "COVID-19 and cytokine storm syndrome: Are there lessons from macrophage activation syndrome?", "author": "Ombrello", "doi-asserted-by": "crossref", "first-page": "1", "journal-title": "Transl. Res.", "key": "ref_9", "volume": "232", "year": "2021" }, { "DOI": "10.1155/2021/6643333", "doi-asserted-by": "crossref", "key": "ref_10", "unstructured": "Khan, M., Shah, N., Mushtaq, H., and Jehanzeb, V. (2021). Profiling laboratory biomarkers associated with COVID-19 disease progression: A single-center experience. Int. J. Microbiol., 2021." }, { "DOI": "10.1080/10408363.2020.1770685", "article-title": "Biomarkers associated with COVID-19 disease progression", "author": "Ponti", "doi-asserted-by": "crossref", "first-page": "389", "journal-title": "Crit. Rev. Clin. Lab. Sci.", "key": "ref_11", "volume": "57", "year": "2020" }, { "DOI": "10.1111/j.1742-7843.2010.00637.x", "article-title": "Functional effects of endothelial nitric oxide synthase genetic polymorphisms on haemorheological parameters in healthy human individuals", "author": "Babaoglu", "doi-asserted-by": "crossref", "first-page": "171", "journal-title": "Basic Clin. Pharmacol. Toxicol.", "key": "ref_12", "volume": "108", "year": "2011" }, { "article-title": "Nitric oxide", "author": "Moncada", "first-page": "S35", "journal-title": "J. Hypertens. Suppl.", "key": "ref_13", "volume": "12", "year": "1994" }, { "DOI": "10.1002/jgm.3323", "article-title": "Variants in TNF and NOS3 (NOS3) genes associated with sepsis in adult patients", "author": "Sener", "doi-asserted-by": "crossref", "first-page": "e3323", "journal-title": "J. Gene Med.", "key": "ref_14", "volume": "23", "year": "2021" }, { "DOI": "10.1111/j.1476-5381.2010.01196.x", "article-title": "Therapeutic effect of enhancing endothelial nitric oxide synthase (NOS3) expression and preventing NOS3 uncoupling", "author": "Li", "doi-asserted-by": "crossref", "first-page": "213", "journal-title": "Br. J. Pharmacol.", "key": "ref_15", "volume": "164", "year": "2011" }, { "DOI": "10.1016/S0163-7258(97)00051-X", "article-title": "Role of vascular nitric oxide in physiological and pathological conditions", "doi-asserted-by": "crossref", "first-page": "111", "journal-title": "Pharmacol. Ther.", "key": "ref_16", "volume": "75", "year": "1997" }, { "DOI": "10.1006/mgme.2000.3033", "article-title": "Endothelial nitric oxide synthase gene sequence variations and vascular disease", "author": "Wang", "doi-asserted-by": "crossref", "first-page": "241", "journal-title": "Mol. Genet. Metab.", "key": "ref_17", "volume": "70", "year": "2000" }, { "DOI": "10.1111/j.1527-3466.2007.00017.x", "article-title": "The functional consequence of the Glu298Asp polymorphism of the endothelial nitric oxide synthase gene in young healthy volunteers", "author": "Godfrey", "doi-asserted-by": "crossref", "first-page": "280", "journal-title": "Cardiovasc. Drug Rev.", "key": "ref_18", "volume": "25", "year": "2007" }, { "DOI": "10.5152/balkanmedj.2016.16566", "article-title": "NOS3 Glu298Asp polymorphism and endothelial dysfunction in patients with and without end-stage renal disease", "author": "Kaman", "doi-asserted-by": "crossref", "first-page": "128", "journal-title": "Balkan Med. J.", "key": "ref_19", "volume": "33", "year": "2016" }, { "DOI": "10.4103/0028-3886.266231", "article-title": "The correlation of endothelial nitric oxide synthase (NOS3) polymorphism and other risk factors with aneurysmal subarachnoid hemorrhage: A case-control study", "author": "Konar", "doi-asserted-by": "crossref", "first-page": "1006", "journal-title": "Neurol. India", "key": "ref_20", "volume": "67", "year": "2019" }, { "DOI": "10.1155/2014/549747", "article-title": "Association between NOS3 4b/a polymorphism and the risk of diabetic retinopathy in type 2 diabetes mellitus: A meta-analysis", "author": "Ma", "doi-asserted-by": "crossref", "first-page": "549747", "journal-title": "J. Diabetes Res.", "key": "ref_21", "volume": "2014", "year": "2014" }, { "DOI": "10.1155/2011/419708", "article-title": "Association of endothelial dysfunction with endothelin, nitric oxide and NOS3 Glu298Asp gene polymorphism in coronary artery disease", "author": "Saini", "doi-asserted-by": "crossref", "first-page": "215", "journal-title": "Dis. Markers", "key": "ref_22", "volume": "31", "year": "2011" }, { "DOI": "10.1186/s12872-021-02192-2", "doi-asserted-by": "crossref", "key": "ref_23", "unstructured": "Shi, J., Liu, S., Guo, Y., Liu, S., Xu, J., Pan, L., Hu, Y., Liu, Y., and Cheng, Y. (2021). Association between NOS3 rs1799983 polymorphism and hypertension: A meta-analysis involving 14,185 cases and 13,407 controls. BMC Cardiovasc. Disord., 21." }, { "DOI": "10.1371/journal.pone.0270627", "doi-asserted-by": "crossref", "key": "ref_24", "unstructured": "Dieter, C., Brondani, L.A., Leitão, C.B., Gerchman, F., Lemos, N.E., and Crispim, D. (2022). Genetic Polymorphisms Associated with Susceptibility to COVID-19 Disease and Severity: A Systematic Review and Meta-Analysis. PLoS ONE, 17." }, { "DOI": "10.1016/j.genrep.2021.101062", "article-title": "Mutations and polymorphisms in genes involved in the infections by COVID-19: A Review", "author": "Kaltoum", "doi-asserted-by": "crossref", "first-page": "101062", "journal-title": "Gene Rep.", "key": "ref_25", "volume": "23", "year": "2021" }, { "DOI": "10.1016/j.genrep.2023.101814", "article-title": "The Association of PON1 and NOS3 Genetic Variants with the Severity of COVID-19", "author": "Eid", "doi-asserted-by": "crossref", "first-page": "101814", "journal-title": "Gene Rep.", "key": "ref_26", "volume": "33", "year": "2023" }, { "DOI": "10.1097/00008571-200207000-00008", "article-title": "Effects of endothelial nitric oxide synthase gene polymorphisms on platelet function, nitric oxide release, and interactions with estradiol", "author": "Desai", "doi-asserted-by": "crossref", "first-page": "407", "journal-title": "Pharmacogenetics", "key": "ref_27", "volume": "12", "year": "2002" }, { "DOI": "10.1038/s41401-022-00998-0", "article-title": "Endothelial dysfunction in COVID-19: An overview of evidence, biomarkers, mechanisms and potential therapies", "author": "Xu", "doi-asserted-by": "crossref", "first-page": "695", "journal-title": "Acta Pharmacol. Sin.", "key": "ref_28", "volume": "44", "year": "2023" }, { "DOI": "10.1016/j.atherosclerosis.2020.10.014", "article-title": "Endothelial dysfunction in COVID-19: Current findings and therapeutic implications", "author": "Haubner", "doi-asserted-by": "crossref", "first-page": "58", "journal-title": "Atherosclerosis", "key": "ref_29", "volume": "314", "year": "2020" }, { "DOI": "10.1016/j.cell.2020.04.026", "article-title": "Imbalanced host response to SARS-CoV-2 drives development of COVID-19", "author": "Liu", "doi-asserted-by": "crossref", "first-page": "1036", "journal-title": "Cell", "key": "ref_30", "volume": "181", "year": "2020" }, { "DOI": "10.1016/S0140-6736(20)30183-5", "article-title": "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China", "author": "Huang", "doi-asserted-by": "crossref", "first-page": "497", "journal-title": "Lancet", "key": "ref_31", "volume": "395", "year": "2020" }, { "DOI": "10.3390/nu14194001", "doi-asserted-by": "crossref", "key": "ref_32", "unstructured": "Ohno, M., and Dzúrová, D. (2022). Body mass index and risk for COVID-19-related hospitalization in adults aged 50 and older in Europe. Nutrients, 14." }, { "DOI": "10.1002/jcla.24713", "article-title": "The importance of using routine laboratory tests in the diagnosis and prognosis of patients with coronavirus disease 2019: Shedding light on clinical laboratory data in COVID-19", "author": "Khosravi", "doi-asserted-by": "crossref", "first-page": "e24713", "journal-title": "J. Clin. Lab. Anal.", "key": "ref_33", "volume": "36", "year": "2022" }, { "DOI": "10.1128/JVI.79.3.1966-1969.2005", "article-title": "Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus", "author": "Leijon", "doi-asserted-by": "crossref", "first-page": "1966", "journal-title": "J. Virol.", "key": "ref_34", "volume": "79", "year": "2005" }, { "DOI": "10.1016/j.arr.2020.101201", "article-title": "Does NOS3 derived nitric oxide protect the young from severe COVID-19 complications?", "author": "Guan", "doi-asserted-by": "crossref", "first-page": "101201", "journal-title": "Ageing Res. Rev.", "key": "ref_35", "volume": "64", "year": "2020" }, { "DOI": "10.1016/j.cmet.2019.08.011", "article-title": "Hallmarks of endothelial cell metabolism in health and disease", "author": "Li", "doi-asserted-by": "crossref", "first-page": "414", "journal-title": "Cell Metab.", "key": "ref_36", "volume": "30", "year": "2019" }, { "DOI": "10.1378/chest.107.4.1107", "article-title": "Efficacy of inhaled nitric oxide in patients with severe ARDS", "author": "Rossaint", "doi-asserted-by": "crossref", "first-page": "1107", "journal-title": "Chest", "key": "ref_37", "volume": "107", "year": "1995" }, { "DOI": "10.1002/eji.201646789", "article-title": "Pathogen interactions with endothelial cells and the induction of innate and adaptive immunity", "author": "Konradt", "doi-asserted-by": "crossref", "first-page": "1607", "journal-title": "Eur. J. Immunol.", "key": "ref_38", "volume": "48", "year": "2018" }, { "DOI": "10.1016/j.cbi.2022.109834", "doi-asserted-by": "crossref", "key": "ref_39", "unstructured": "Papadopoulos, K.I., Sutheesophon, W., and Aw, T.-C. (2022). The influence of renin angiotensin aldosterone system (RAAS), endothelial nitric oxide synthase (NOS3) and erythropoietin (EPO) on COVID-19 complications. Chem. Biol. Interact., 354." }, { "DOI": "10.1016/j.gene.2015.09.061", "article-title": "Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms", "author": "Lacchini", "doi-asserted-by": "crossref", "first-page": "584", "journal-title": "Gene", "key": "ref_40", "volume": "575", "year": "2016" }, { "DOI": "10.1097/00003246-200204000-00020", "article-title": "Increased bone resorption in the critically ill: Association with sepsis and increased nitric oxide production", "author": "Smith", "doi-asserted-by": "crossref", "first-page": "837", "journal-title": "Crit. Care Med.", "key": "ref_41", "volume": "30", "year": "2002" }, { "DOI": "10.1080/17425255.2020.1804857", "article-title": "Clinically relevant endothelial nitric oxide synthase polymorphisms and their impact on drug response", "author": "Lacchini", "doi-asserted-by": "crossref", "first-page": "927", "journal-title": "Expert Opin. Drug Metab. Toxicol.", "key": "ref_42", "volume": "16", "year": "2020" }, { "DOI": "10.1016/j.humimm.2008.03.001", "article-title": "Intron 4 a/b polymorphism of the endothelial nitric oxide synthase gene is associated with both type 1 and type 2 diabetes in a genetically homogeneous population", "author": "Galanakis", "doi-asserted-by": "crossref", "first-page": "279", "journal-title": "Hum. Immunol.", "key": "ref_43", "volume": "69", "year": "2008" }, { "DOI": "10.1038/ijo.2010.146", "article-title": "NOS3 haplotype associated with hypertension in obese children and adolescents", "author": "Belo", "doi-asserted-by": "crossref", "first-page": "387", "journal-title": "Int. J. Obes.", "key": "ref_44", "volume": "35", "year": "2011" }, { "DOI": "10.3171/2014.5.JNS131572", "article-title": "Association of the NOS3 intron-4 VNTR polymorphism with aneurysmal subarachnoid hemorrhage", "author": "Edsen", "doi-asserted-by": "crossref", "first-page": "587", "journal-title": "J. Neurosurg.", "key": "ref_45", "volume": "121", "year": "2014" }, { "DOI": "10.1111/j.1447-0756.2011.01606.x", "article-title": "Endothelial nitric oxide synthase gene polymorphisms in preeclampsia with or without eclampsia in a Turkish population", "author": "Ozturk", "doi-asserted-by": "crossref", "first-page": "1778", "journal-title": "J. Obstet. Gynaecol. Res.", "key": "ref_46", "volume": "37", "year": "2011" }, { "DOI": "10.1007/s43032-021-00632-0", "article-title": "Association between endothelial nitric oxide synthase (NOS3) −786 T/C and 27-bp VNTR 4b/a polymorphisms and preeclampsia development", "author": "Nikolic", "doi-asserted-by": "crossref", "first-page": "3529", "journal-title": "Reprod. Sci.", "key": "ref_47", "volume": "28", "year": "2021" }, { "DOI": "10.1016/j.bbrc.2005.07.108", "article-title": "Novel allele of the endothelial nitric oxide synthase gene polymorphism in Caucasian asthmatics", "author": "Yanamandra", "doi-asserted-by": "crossref", "first-page": "545", "journal-title": "Biochem. Biophys. Res. Commun.", "key": "ref_48", "volume": "335", "year": "2005" }, { "DOI": "10.1016/j.trsl.2012.05.004", "article-title": "Endothelial nitric oxide gene haplotype reduces the effect of a single bout of exercise on the vascular reactivity in healthy subjects", "author": "Silva", "doi-asserted-by": "crossref", "first-page": "15", "journal-title": "Transl. Res.", "key": "ref_49", "volume": "161", "year": "2013" }, { "DOI": "10.1101/2022.03.02.22271779", "doi-asserted-by": "crossref", "key": "ref_50", "unstructured": "Alshaikh, F.S., Godman, B., Sindi, O.N., Seaton, R.A., and Kurdi, A. (2022). Prevalence of bacterial coinfection and patterns of antibiotics prescribing in patients with COVID-19: A systematic review and meta-analysis. PLoS ONE, 17." } ], "reference-count": 50, "references-count": 50, "relation": {}, "resource": { "primary": { "URL": "https://www.mdpi.com/2077-0383/14/6/1931" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Association of Endothelial Nitric Oxide Synthase Polymorphisms with Clinical Severity in Patients with COVID-19", "type": "journal-article", "volume": "14" }