{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T14:48:09Z","timestamp":1781189289341,"version":"3.54.1"},"reference-count":33,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Tumor necrosis factor alpha (TNF-alpha) plays a key role in systemic inflammation in multiple disorders, including inflammatory bowel diseases (IBDs). Our purpose was to investigate the contribution of two promoter single-nucleotide polymorphisms (rs361525\/\u2013238G\/A and rs1800629\/\u2013308G\/A) to disease susceptibility, clinical features, and response to biologic therapy in a cohort of Romanian patients with IBDs. Methods: A total of 198 patients with IBDs, 106 with Crohn\u2019s disease (CD) and 92 with ulcerative colitis (UC), as well as 160 healthy controls, all Caucasians of Romanian origin, were genotyped using TaqMan Allelic Discrimination Assays. Phenotypical and anti-TNF treatment characteristics of the patients with IBDs were recorded. Statistical analyses were performed using OpenEpi and PLINK v1.07 software. Results: We found a significantly higher frequency of the minor allele A of rs361525 in patients with CD than in the controls (6.6% vs. 2.2%, p = 0.01, OR = 3.16). Half of the patients with extraintestinal manifestations (EIMs) had at least one copy of the rs1800629 A allele compared with approximately 10% of patients without EIM (p = 1 \u00d7 10\u22124, OR 9.58 for UC and p = 9 \u00d7 10\u22124, OR 6.60 for CD). In the whole IBD group of patients, the carriers of the minor allele (AA+GA) for both SNPs studied (rs1800629 and rs361525) were significantly more likely to have EIM associated with IBDs (p = 3 \u00d7 10\u22127, OR 7.87; p = 0.03, OR 3.02, respectively). In patients with UC, the analysis according to disease extension revealed that the frequency of the minor allele of rs1800629 was significantly higher in the subgroup with the E2 phenotype compared to the E1 and E3 phenotypes (16.6% versus 5.6%, p = 0.02, OR 3.32). Conclusions: These findings highlight the role of genetic TNF-alpha variants in disease susceptibility, phenotype, and systemic involvement, supporting their potential relevance in understanding IBD heterogeneity.<\/jats:p>","DOI":"10.3390\/jcm15031042","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T15:04:46Z","timestamp":1769612686000},"page":"1042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["TNF-alpha Promoter Single-Nucleotide Polymorphisms and Inflammatory Bowel Diseases in Romania: Association with Disease Susceptibility and Clinical Features"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5348-0341","authenticated-orcid":false,"given":"Cristian George","family":"\u021aieranu","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Gastroenterology, \u201cElias\u201d Emergency University Hospital, 011461 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3458-4692","authenticated-orcid":false,"given":"Luis Ovidiu","family":"Popa","sequence":"additional","affiliation":[{"name":"Molecular Biology Department, \u201cGrigore Antipa\u201d National Museum of Natural History, 011341 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"\u021aieranu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, \u201cMarie Sklodowska Curie\u201d Clinical Emergency Hospital for Children, 041434 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica Irina","family":"Du\u021bescu","sequence":"additional","affiliation":[{"name":"National HLA Laboratory, \u2018\u2018Prof. Dr. Constantin T. Nicolau\u2019\u2019 National Institute of Blood Transfusion, 011155 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen Monica","family":"Preda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Gastroenterology, Fundeni Clinical Institute, 022328 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei Ovidiu","family":"Olteanu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Gastroenterology, \u201cElias\u201d Emergency University Hospital, 011461 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4396-8081","authenticated-orcid":false,"given":"Cristian Valentin","family":"Toma","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Urology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"S\u0103ftoiu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Gastroenterology, \u201cElias\u201d Emergency University Hospital, 011461 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia Mihaela","family":"Popa","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Immunology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.2174\/1874259900802010050","article-title":"Single Nucleotide Polymorphisms in IL4, OCTN1 and OCTN2 Genes in Association with Inflammatory Bowel Disease Phenotypes in a Caucasian Population in Canterbury, New Zealand","volume":"2","author":"Ferguson","year":"2008","journal-title":"Open Gastroenterol. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"338","DOI":"10.3748\/wjg.14.338","article-title":"Inflammatory bowel disease: Genetic and epidemiologic considerations","volume":"14","author":"Cho","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_3","first-page":"1301","article-title":"Gene expression profile of endoscopically active and inactive ulcerative colitis: Preliminary data","volume":"58","author":"Dobre","year":"2017","journal-title":"Rom. J. Morphol. Embryol. Rev. Roum. Morphol. Embryol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"390","DOI":"10.3748\/wjg.14.390","article-title":"Immunopathogenesis of inflammatory bowel disease","volume":"14","author":"Shih","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"591704","DOI":"10.1155\/2009\/591704","article-title":"Tumor Necrosis Factor Receptor Superfamily, Member 1B Haplotypes Increase or Decrease the Risk of Inflammatory Bowel Diseases in a New Zealand Caucasian Population","volume":"2009","author":"Ferguson","year":"2009","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Padula, M.C., Padula, A.A., D\u2019Angelo, S., Lascaro, N., Radice, R.P., Martelli, G., and Leccese, P. (2023). TNF\u03b1 rs1800629 Polymorphism and Response to Anti-TNF\u03b1 Treatment in Beh\u00e7et Syndrome: Data from an Italian Cohort Study. J. Pers. Med., 13.","DOI":"10.3390\/jpm13091347"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"99","DOI":"10.4236\/ojra.2022.124011","article-title":"Analysis of Association between Interleukin-6 (IL6), Interleukin-13 (IL13) and Tumor Necrosis Factor-Alpha (TNF-alpha) Gene Polymorphisms and Genetic Susceptibility of Rheumatoid Arthritis in Kuwaiti Arab","volume":"12","author":"Haider","year":"2022","journal-title":"Open J. Rheumatol. Autoimmune Dis."},{"key":"ref_8","first-page":"164","article-title":"Preliminary Study Regarding the Association between Tumor Necrosis Factor Alpha Gene Polymorphisms and Childhood Idiopathic Nephrotic Syndrome in Romanian Pediatric Patients","volume":"12","author":"Tieranu","year":"2017","journal-title":"Maedica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.2217\/pgs.11.114","article-title":"Genetic and Genomic Predictors of Anti-TNF Response","volume":"12","author":"Prajapati","year":"2011","journal-title":"Pharmacogenomics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/1097-0029(20000801)50:3<216::AID-JEMT5>3.0.CO;2-Q","article-title":"TNF-alpha gene polymorphism: Clinical and biological implications","volume":"50","author":"Hajeer","year":"2000","journal-title":"Microsc. Res. Tech."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/j.1365-2036.2010.04340.x","article-title":"Meta-analysis: Polymorphisms in TNF-\u03b1 gene promoter and Crohn\u2019s disease","volume":"32","author":"Han","year":"2010","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3195","DOI":"10.1073\/pnas.94.7.3195","article-title":"Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation","volume":"94","author":"Wilson","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1046\/j.1365-2370.1999.00128.x","article-title":"Analysis of the polymorphism of the tumour necrosis factor (TNF) gene and promoter and of circulating TNF-alpha levels in heart-transplant patients suffering or not suffering from severe rejection","volume":"26","author":"Abdallah","year":"1999","journal-title":"Eur. J. Immunogenet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/iji.12059","article-title":"Genetic polymorphisms of tumour necrosis factor alpha (TNF-\u03b1) promoter gene and response to TNF-\u03b1 inhibitors in Spanish patients with inflammatory bowel disease","volume":"41","author":"Campillo","year":"2014","journal-title":"Int. J. Immunogenet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1038\/ejhg.2010.159","article-title":"Relationship between the polymorphism of tumor necrosis factor-\u03b1-308 G>A and susceptibility to inflammatory bowel diseases and colorectal cancer: A meta-analysis","volume":"19","author":"Wan","year":"2011","journal-title":"Eur. J. Hum. Genet. EJHG"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1002\/ibd.21845","article-title":"Genetics of inflammatory bowel disease in Asia: Systematic review and meta-analysis","volume":"18","author":"Ng","year":"2012","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1097\/00029330-200607020-00011","article-title":"Genetic susceptibility to ulcerative colitis in the Chinese Han ethnic population: Association with TNF polymorphisms","volume":"119","author":"Cao","year":"2006","journal-title":"Chin. Med. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.humimm.2004.10.004","article-title":"Association of TNF-alpha polymorphisms in Crohn disease","volume":"66","author":"Zipperlen","year":"2005","journal-title":"Hum. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5009\/gnl.2010.4.1.1","article-title":"Inflammatory Bowel Disease in Korea: Epidemiological, Genomic, Clinical, and Therapeutic Characteristics","volume":"4","author":"Kim","year":"2010","journal-title":"Gut Liver"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1097\/00054725-200409000-00022","article-title":"The epidemiology and phenotype of Crohn\u2019s disease in the Chinese population","volume":"10","author":"Leong","year":"2004","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_21","first-page":"133","article-title":"Association of tumor necrosis factor-\u03b1; and -\u03b2; gene polymorphisms in inflammatory bowel disease","volume":"9","year":"2016","journal-title":"J. Inflamm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Olteanu, A.O., Ionescu, E.M., Tieranu, C.G., Popa, L.O., Andrei, S.I., Preda, C.M., Dutescu, M.I., Bojinca, M., Tieranu, I., and Popa, O.M. (2023). Interleukin-4 Gene Polymorphisms in Romanian Patients with Inflammatory Bowel Diseases: Association with Disease Risk and Clinical Features. Diagnostics, 13.","DOI":"10.3390\/diagnostics13081465"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/ecco-jcc\/jjw168","article-title":"3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn\u2019s Disease 2016: Part 1: Diagnosis and Medical Management","volume":"11","author":"Dignass","year":"2017","journal-title":"J. Crohns Colitis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1093\/ecco-jcc\/jjx008","article-title":"Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders","volume":"11","author":"Magro","year":"2017","journal-title":"J. Crohns Colitis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1136\/gut.2005.082909","article-title":"The Montreal classification of inflammatory bowel disease: Controversies, consensus, and implications","volume":"55","author":"Satsangi","year":"2006","journal-title":"Gut"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tieranu, I., Tieranu, C.G., Dutescu, M.I., Berghea, C.E., Balgradean, M., and Popa, O.M. (2022). Genetic Variants of Interleukin-4 in Romanian Patients with Idiopathic Nephrotic Syndrome. Medicina, 58.","DOI":"10.3390\/medicina58020265"},{"key":"ref_27","unstructured":"Dean, A., Sullivan, K., and Soe, M. (2013). OpenEpi: Open Source Epidemiologic Statistics for Public Health, 3.01, OpenEpi Development Team."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15811","DOI":"10.4238\/2015.December.1.33","article-title":"Association between TNF-\u03b1 rs1799724 and rs1800629 polymorphisms and the risk of Crohn\u2019s disease","volume":"14","author":"Mao","year":"2015","journal-title":"Genet. Mol. Res. GMR"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1053\/j.gastro.2024.02.026","article-title":"Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease","volume":"167","author":"Khrom","year":"2024","journal-title":"Gastroenterology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1097\/01.mpg.0000221917.80887.9e","article-title":"Cytokine tumor necrosis factor-alpha A promoter gene polymorphism at position -308 G\u2192A and pediatric inflammatory bowel disease: Implications in ulcerative colitis and Crohn\u2019s disease","volume":"42","author":"Subrt","year":"2006","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1590\/S1807-59322011000800011","article-title":"The TNF-\u03b1-308 polymorphism may affect the severity of Crohn\u2019s disease","volume":"66","author":"Santana","year":"2011","journal-title":"Clin. Sao Paulo Braz."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Rottura, M., Pirrotta, I., Giorgi, D.A., Irrera, N., Arcoraci, V., Mannino, F., Campisi, R., Bivacqua, C., Patan\u00e8, L., and Costantino, G. (2025). Genetic Polymorphisms on TNFA, TNFRSF1A, and TNFRSF1B Genes Predict the Effectiveness of Anti-TNF-\u03b1 Treatment in Inflammatory Bowel Disease Patients. Biomedicines, 13.","DOI":"10.3390\/biomedicines13030669"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/3\/1042\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T15:30:43Z","timestamp":1769614243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/3\/1042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,28]]},"references-count":33,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["jcm15031042"],"URL":"https:\/\/doi.org\/10.3390\/jcm15031042","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,28]]}}}