{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T01:40:27Z","timestamp":1785894027674,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science, Technological Development, and Innovation of the Republic of Serbia","award":["451-03-66\/2024-03\/200110"],"award-info":[{"award-number":["451-03-66\/2024-03\/200110"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Secondary peritonitis (SP) remains a major clinical challenge due to its high complication rates and it often results in sepsis and multi-organ dysfunction. This study investigated the association between four nitric oxide synthase (NOS) single-nucleotide polymorphisms (SNPs)\u2014NOS3 c.-786T&gt;C (rs2070744), NOS3 c.894G&gt;T (rs1799983), NOS3 27 bp variable number tandem repeat (VNTR) (rs61722009), and NOS2 (rs2297518)\u2014and sepsis-related complications in 202 patients with SP. Demographic and baseline clinical characteristics, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, Mannheim Peritonitis Index, and complications (multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF), acute respiratory distress syndrome (ARDS), and sepsis) were analyzed for associations with the NOS gene variants. Haplotype analysis was also performed. No SNP showed an association with in-hospital mortality. However, the NOS3 c.-786T&gt;C TT genotype was significantly associated with an increased risk of MOF (p = 0.008), and remained independently associated after multivariate adjustment (pMOF = 0.006). The T4bG haplotype was significantly more frequent among patients with MODS (p = 0.026), MOF (p = 0.048), and sepsis (p = 0.018). These findings suggest that NOS gene variants, particularly NOS3 c.-786T&gt;C and the T4bG haplotype, may potentially serve as biomarkers for risk stratification in critically ill patients.<\/jats:p>","DOI":"10.3390\/ijms262110306","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T09:44:30Z","timestamp":1761212670000},"page":"10306","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Association of NOS Gene Polymorphisms with Sepsis-Related Complications in Secondary Peritonitis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3269-7872","authenticated-orcid":false,"given":"Milica","family":"Rasic","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5815-573X","authenticated-orcid":false,"given":"Nela","family":"Maksimovic","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7534-9608","authenticated-orcid":false,"given":"Milka","family":"Grk","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3564-2623","authenticated-orcid":false,"given":"Marija","family":"Dusanovic Pjevic","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-4381","authenticated-orcid":false,"given":"Petar","family":"Rasic","sequence":"additional","affiliation":[{"name":"Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia \u201cDr. Vukan Cupic\u201d, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milos","family":"Svircev","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, General Hospital Pancevo, 23000 Pancevo, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatjana","family":"Damnjanovic","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1077-2373","authenticated-orcid":false,"given":"Dijana","family":"Perovic","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8144-4433","authenticated-orcid":false,"given":"Ana","family":"Djuranovic Uklein","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasa","family":"Stojanovski","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milica","family":"Pesic","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Novakovic","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krstina","family":"Doklestic Vasiljev","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"},{"name":"Clinic for Emergency Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"k1407","DOI":"10.1136\/bmj.k1407","article-title":"Secondary Peritonitis: Principles of Diagnosis and Intervention","volume":"361","author":"Ross","year":"2018","journal-title":"BMJ"},{"key":"ref_2","first-page":"e41724","article-title":"The Role of Serum and Peritoneal Biomarkers in Predicting Sepsis and Septic Multiorgan Failure in Patients with Secondary Peritonitis","volume":"15","author":"Dumitrascu","year":"2023","journal-title":"Cureus"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1177\/1457496920984078","article-title":"Secondary Peritonitis and Intra-Abdominal Sepsis: An Increasingly Global Disease in Search of Better Systemic Therapies","volume":"110","author":"Clements","year":"2021","journal-title":"Scand. J. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"456","DOI":"10.3390\/epidemiologia5030032","article-title":"The Global Burden of Sepsis and Septic Shock","volume":"5","author":"Sangiorgio","year":"2024","journal-title":"Epidemiologia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA\u2014J. Am. Med. Assoc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s10528-016-9785-2","article-title":"Early Prediction of Sepsis Incidence in Critically Ill Patients Using Specific Genetic Polymorphisms","volume":"55","author":"David","year":"2017","journal-title":"Biochem. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/cc2863","article-title":"Bench-to-Bedside Review: Understanding Genetic Predisposition to Sepsis","volume":"8","author":"Villar","year":"2004","journal-title":"Crit. Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1186\/s13054-017-1782-2","article-title":"Markers of Nitric Oxide Are Associated with Sepsis Severity: An Observational Study","volume":"21","author":"Winkler","year":"2017","journal-title":"Crit. Care"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.niox.2014.09.004","article-title":"Endothelial (NOS3 E298D) and Inducible (NOS2 Exon 22) Nitric Oxide Synthase Polymorphisms, as Well as Plasma NOx, Influence Sepsis Development","volume":"42","author":"Martin","year":"2014","journal-title":"Nitric Oxide\u2014Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e3323","DOI":"10.1002\/jgm.3323","article-title":"Variants in TNF and NOS3 (ENOS) Genes Associated with Sepsis in Adult Patients","volume":"23","author":"Sener","year":"2021","journal-title":"J. Gene Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s40635-019-0274-x","article-title":"Bench to Bedside Review: Therapeutic Modulation of Nitric Oxide in Sepsis\u2014An Update","volume":"7","author":"Lambden","year":"2019","journal-title":"Intensive Care Med. Exp."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s00439-012-1253-4","article-title":"A Non-Synonymous SNP in the NOS2 Associated with Septic Shock in Patients with Sepsis in Chinese Populations","volume":"132","author":"Wang","year":"2013","journal-title":"Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Raia, L., and Zafrani, L. (2022). Endothelial Activation and Microcirculatory Disorders in Sepsis. Front. Med., 9.","DOI":"10.3389\/fmed.2022.907992"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"289","DOI":"10.3109\/07853890.2015.1029967","article-title":"Novel Relationships between Oxidative Stress and Angiogenesis-Related Factors in Sepsis: New Biomarkers and Therapies","volume":"47","author":"Vera","year":"2015","journal-title":"Ann. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/nature08494","article-title":"Finding the Missing Heritability of Complex Diseases","volume":"461","author":"Manolio","year":"2009","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Agnello, L., and Ciaccio, M. (2023). Biomarkers of Sepsis. Diagnostics, 13.","DOI":"10.3390\/diagnostics13030435"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"R15","DOI":"10.1186\/cc8872","article-title":"Sepsis Biomarkers: A Review","volume":"14","author":"Pierrakos","year":"2010","journal-title":"Crit. Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1007\/s00134-022-06956-y","article-title":"How to Use Biomarkers of Infection or Sepsis at the Bedside: Guide to Clinicians","volume":"49","author":"Coelho","year":"2023","journal-title":"Intensive Care Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"584","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","volume":"575","author":"Lacchini","year":"2016","journal-title":"Gene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1006\/bbrc.1998.8267","article-title":"Evidence of Association of the EcNOS Gene Polymorphism with Plasma NO Metabolite Levels in Humans","volume":"245","author":"Tsukada","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.niox.2006.06.005","article-title":"The NOS3 (27-Bp Repeat, Intron 4) Polymorphism Is Associated with Susceptibility to Osteomyelitis","volume":"16","author":"Asensi","year":"2007","journal-title":"Nitric Oxide\u2014Biol. Chem."},{"key":"ref_22","first-page":"872","article-title":"Endothelial Nitric Oxide Synthase 894G\u2192T but Not -786T\u2192C Gene Polymorphism Is Associated with Organ Dysfunction and Increased Mortality in Patients with Severe Sepsis","volume":"71","author":"Ma","year":"2011","journal-title":"J. Trauma\u2014Inj. Infect. Crit. Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1097\/SHK.0b013e318188e58e","article-title":"Endothelial Nitric Oxide Synthase G894T (GLU298ASP) Polymorphism Is Associated with Hypotension in Patients with E. Coli Bacteremia but Not in Bacteremia Caused by a Gram-Positive Organism","volume":"31","author":"Huttunen","year":"2009","journal-title":"Shock"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1007\/s00251-007-0255-1","article-title":"Influence of the Inducible Nitric Oxide Synthase Gene (NOS2A) on Inflammatory Bowel Disease Susceptibility","volume":"59","author":"Martinez","year":"2007","journal-title":"Immunogenetics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e46","DOI":"10.1038\/ctg.2013.17","article-title":"Higher Activity of the Inducible Nitric Oxide Synthase Contributes to Very Early Onset Inflammatory Bowel Disease","volume":"5","author":"Dhillon","year":"2014","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1186\/s13054-022-04075-0","article-title":"A New Perspective on NO Pathway in Sepsis and ADMA Lowering as a Potential Therapeutic Approach","volume":"26","author":"Singh","year":"2022","journal-title":"Crit. Care"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1186\/s13054-014-0511-3","article-title":"Endothelial Dysfunction Is a Potential Contributor to Multiple Organ Failure and Mortality in Aged Mice Subjected to Septic Shock: Preclinical Studies in a Murine Model of Cecal Ligation and Puncture","volume":"18","author":"Coletta","year":"2014","journal-title":"Crit. Care"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1093\/ndt\/gfp415","article-title":"Nitric Oxide Synthase Isoforms Play Distinct Roles during Acute Peritonitis","volume":"25","author":"Ni","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1152\/physrev.00029.2006","article-title":"Nitric Oxide and Peroxynitrite in Health and Disease","volume":"87","author":"Pacher","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.niox.2019.04.011","article-title":"Targeting Nitric Oxide as a Key Modulator of Sepsis, Arthritis and Pain","volume":"89","author":"Spiller","year":"2019","journal-title":"Nitric Oxide\u2014Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Srdi\u0107, T., \u0110ura\u0161evi\u0107, S., Laki\u0107, I., Ru\u017ei\u010di\u0107, A., Vujovi\u0107, P., Jev\u0111ovi\u0107, T., Daki\u0107, T., \u0110or\u0111evi\u0107, J., Tosti, T., and Glumac, S. (2024). From Molecular Mechanisms to Clinical Therapy: Understanding Sepsis-Induced Multiple Organ Dysfunction. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147770"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/cc7706","article-title":"Bench-to-Bedside Review: Nitric Oxide in Critical Illness\u2014Update 2008","volume":"13","author":"Hollenberg","year":"2009","journal-title":"Crit. Care"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.intimp.2018.07.024","article-title":"Prognostic Value of the Biomarkers Serum Amyloid A and Nitric Oxide in Patients with Sepsis","volume":"62","author":"Yu","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"tkae006","DOI":"10.1093\/burnst\/tkae006","article-title":"Genetic Polymorphisms, Biomarkers and Signaling Pathways Associated with Septic Shock: From Diagnosis to Therapeutic Targets","volume":"12","author":"Jiang","year":"2024","journal-title":"Burn. Trauma"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.freeradbiomed.2007.06.012","article-title":"Modulation of Nitric Oxide Formation by Endothelial Nitric Oxide Synthase Gene Haplotypes","volume":"43","author":"Metzger","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1097\/SHK.0b013e3181818518","article-title":"Nitric Oxide and Vascular Reactivity in Sepsis","volume":"30","author":"Fernandes","year":"2008","journal-title":"Shock"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1093\/eurheartj\/ehr304","article-title":"Nitric Oxide Synthases: Regulation and Function","volume":"33","author":"Sessa","year":"2012","journal-title":"Eur. Heart J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1001\/archsurg.136.1.55","article-title":"Risk Stratification in Emergency Surgical Patients","volume":"136","author":"Koperna","year":"2001","journal-title":"Arch. Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1007\/s00134-003-1662-x","article-title":"2001 SCCM\/ESICM\/ACCP\/ATS\/SIS International Sepsis Definitions Conference","volume":"29","author":"Levy","year":"2003","journal-title":"Intensive Care Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"243","DOI":"10.11138\/gchir\/2016.37.6.243","article-title":"Mannheim Peritonitis Index (MPI) and Elderly Population: Prognostic Evaluation in Acute Secondary Peritonitis","volume":"27","author":"Salamone","year":"2016","journal-title":"G. Chir.\u2014J. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","article-title":"A Simple Salting out Procedure for Extracting DNA from Human Nucleated Cells","volume":"16","author":"Miller","year":"1988","journal-title":"Nucleic Acids Res."},{"key":"ref_42","unstructured":"(2025, October 16). Carbocation Corporation False Discovery Rate Online Calculator. Available online: https:\/\/tools.carbocation.com\/FDR."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/bioinformatics\/bth457","article-title":"Haploview: Analysis and Visualization of LD and Haplotype Maps","volume":"21","author":"Barrett","year":"2005","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10306\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T09:46:14Z","timestamp":1761212774000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10306"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,23]]},"references-count":43,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110306"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110306","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,23]]}}}