{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T02:15:01Z","timestamp":1777601701449,"version":"3.51.4"},"reference-count":76,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T00:00:00Z","timestamp":1615161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2006\/00591-5"],"award-info":[{"award-number":["2006\/00591-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["BEX: 9370\/12-9"],"award-info":[{"award-number":["BEX: 9370\/12-9"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Classical Hodgkin lymphoma (cHL) is a B-cell-derived malignant neoplasia that has a unique histological distribution, in which the scarce malignant Hodgkin and Reed-Sternberg cells are surrounded by nonmalignant inflammatory cells. The interactions between the malignant and inflammatory cells are mediated by aberrantly produced cytokines, which play an important role in tumor immunopathogenesis. Single nucleotide polymorphisms (SNPs) in genes encoding cytokines and their regulatory proteins may influence the peripheral levels of these molecules and affect disease\u2019s pathobiology. In this study, we evaluate SNPs in the promoter regions of the genes encoding for two key cytokines in Hodgkin lymphoma: IL-10 (SNP\/p<jats:italic>IL10<\/jats:italic>\u2013592, rs1800872; and SNP\/p<jats:italic>IL10<\/jats:italic>\u20131082, rs1800896) and TNF-\u03b1 (SNP\/p<jats:italic>TNF<\/jats:italic> -238, rs361525; and SNP\/p<jats:italic>TNF<\/jats:italic> -862, rs1800630), as well as an SNP in the intronic region of the NF\u03baB1 gene (SNP\/i<jats:italic>NFKB1<\/jats:italic>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.ncbi.nlm.nih.gov\/projects\/SNP\/snp_ref.cgi?rs=1585215\" xlink:type=\"simple\">rs1585215<\/jats:ext-link>), an important regulator of cytokine gene expression. We then look to their possible association with clinical and laboratory features in cHL patients. Seventy-three patients with cHL are genotyped by qPCR-high resolution melting. The SNPs\u2019 genotypes are analyzed individually for each SNP, and when more than two allelic combinations are identified, the genotypes are also divided into two groups according to proposed biological relevance. By univariate analysis, patients harboring SNP\/p<jats:italic>TNF<\/jats:italic> -238 AG genotype more frequently have EBV-associated cHL compared to homozygous GG, whereas the presence of mediastinal disease (bulky and nonbulky) is more common in the p<jats:italic>IL10<\/jats:italic>\u2013592 AC\/CC group compared to the AA homozygous group. Patients with SNP\/i<jats:italic>NFKB1<\/jats:italic> AA genotype more frequently have stage IV and extranodal disease at diagnosis. These results indicate that some SNPs\u2019 genotypes for IL-10 and TNF-\u03b1 genes are associated with prognostic parameters in cHL. For the first time, the SNP\/i<jats:italic>NFKB1<\/jats:italic> is described in association with clinical features of the disease.<\/jats:p>","DOI":"10.1371\/journal.pone.0248259","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T18:26:17Z","timestamp":1615227977000},"page":"e0248259","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["SNPs in genes encoding for IL-10, TNF-\u03b1, and NF\u03baB p105\/p50 are associated with clinical prognostic factors for patients with Hodgkin lymphoma"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9480-4995","authenticated-orcid":true,"given":"Rafael Dezen","family":"Gaiolla","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcelo Padovani de Toledo","family":"Moraes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deilson Elgui","family":"de Oliveira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"pone.0248259.ref001","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1080\/10428190802163339","article-title":"Biologic features of Hodgkin lymphoma and the development of biologic prognostic factors in Hodgkin lymphoma: tumor and microenvironment","volume":"49","author":"ED Hsi","year":"2008","journal-title":"Leuk Lymphoma"},{"key":"pone.0248259.ref002","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1146\/annurev.pathol.4.110807.092209","article-title":"Pathogenesis of classical and lymphocyte-predominant Hodgkin lymphoma","volume":"4","author":"R Schmitz","year":"2009","journal-title":"Annu Rev Pathol"},{"key":"pone.0248259.ref003","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1056\/NEJMoa1000067","article-title":"Reduced treatment intensity in patients with early-stage Hodgkin\u2019s lymphoma","volume":"363","author":"A Engert","year":"2010","journal-title":"N Engl J Med"},{"key":"pone.0248259.ref004","doi-asserted-by":"crossref","first-page":"4199","DOI":"10.1200\/JCO.2010.29.8018","article-title":"Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin\u2019s lymphoma: final analysis of the German Hodgkin Study Group HD11 trial","volume":"28","author":"HT Eich","year":"2010","journal-title":"J Clin Oncol"},{"key":"pone.0248259.ref005","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1200\/JCO.2011.38.5807","article-title":"Dose-intensification in early unfavorable Hodgkin\u2019s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial","volume":"30","author":"B von Tresckow","year":"2012","journal-title":"J Clin Oncol"},{"key":"pone.0248259.ref006","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1016\/S0140-6736(11)61940-5","article-title":"Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin\u2019s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial","volume":"379","author":"A Engert","year":"2012","journal-title":"Lancet"},{"key":"pone.0248259.ref007","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1016\/S0140-6736(17)32134-7","article-title":"PET-guided treatment in patients with advanced-stage Hodgkin\u2019s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group","volume":"390","author":"P Borchmann","year":"2017","journal-title":"Lancet"},{"key":"pone.0248259.ref008","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1056\/NEJM199811193392104","article-title":"A prognostic score for advanced Hodgkin\u2019s disease. International Prognostic Factors Project on Advanced Hodgkin\u2019s Disease","volume":"339","author":"D Hasenclever","year":"1998","journal-title":"N Engl J Med"},{"key":"pone.0248259.ref009","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/bjh.12759","article-title":"Current status of prognostication in classical Hodgkin lymphoma","volume":"165","author":"G Venkataraman","year":"2014","journal-title":"Br J Haematol"},{"key":"pone.0248259.ref010","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1182\/blood-2014-07-537480","article-title":"Risk assessment in the management of newly diagnosed classical Hodgkin lymphoma","volume":"125","author":"JM Connors","year":"2015","journal-title":"Blood"},{"key":"pone.0248259.ref011","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1182\/asheducation-2016.1.323","article-title":"Long-term risk of second malignancy and cardiovascular disease after Hodgkin lymphoma treatment","volume":"2016","author":"FE van Leeuwen","year":"2016","journal-title":"Hematology"},{"key":"pone.0248259.ref012","doi-asserted-by":"crossref","first-page":"e462","DOI":"10.1016\/S2352-3026(18)30140-6","article-title":"Intensive treatment strategies in advanced-stage Hodgkin\u2019s lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials","volume":"5","author":"B von Tresckow","year":"2018","journal-title":"Lancet Haematol"},{"key":"pone.0248259.ref013","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S1470-2045(03)01320-2","article-title":"Part II: Hodgkin\u2019s lymphoma\u2014diagnosis and treatment","volume":"5","author":"V Diehl","year":"2004","journal-title":"Lancet Oncol"},{"key":"pone.0248259.ref014","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/path.2711","article-title":"The classical Hodgkin\u2019s lymphoma microenvironment and its role in promoting tumour growth and immune escape","volume":"221","author":"D Aldinucci","year":"2010","journal-title":"J Pathol"},{"key":"pone.0248259.ref015","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1200\/JCO.2010.32.8401","article-title":"Molecular Pathogenesis of Hodgkin\u2019s Lymphoma: increasing evidence of the importance of the microenvironment","volume":"29","author":"C Steidl","year":"2011","journal-title":"J Clin Oncol"},{"key":"pone.0248259.ref016","doi-asserted-by":"crossref","first-page":"2918","DOI":"10.1182\/blood.V87.7.2918.bloodjournal8772918","article-title":"Frequent expression of Interleukin-10 by Epstein-Barr virus-harboring tumor cells of Hodgkin\u2019s disease","volume":"87","author":"H Herbst","year":"1996","journal-title":"Blood"},{"key":"pone.0248259.ref017","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/1471-2164-15-S4-S2","article-title":"The structural network of Interleukin-10 and its implications in inflammation and cancer","volume":"15","author":"ES Acuner-Ozbabacan","year":"2014","journal-title":"BMC Genomics"},{"key":"pone.0248259.ref018","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1172\/JCI116977","article-title":"Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein","volume":"93","author":"Y Levy","year":"1994","journal-title":"J Clin Invest"},{"key":"pone.0248259.ref019","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1182\/blood-2002-01-0099","article-title":"The role of cytokines in classical Hodgkin lymphoma","volume":"99","author":"BF Skinnider","year":"2002","journal-title":"Blood"},{"key":"pone.0248259.ref020","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1111\/bjh.13015","article-title":"Expression of tumour necrosis factor-\u03b1 and its receptors in Hodgkin lymphoma","volume":"167","author":"S Nakayama","year":"2014","journal-title":"Br J Haematol"},{"key":"pone.0248259.ref021","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1111\/j.1365-2141.1993.tb03138.x","article-title":"Lymphotoxin, tumour necrosis factor and Interleukin-6 gene transcripts are present in Hodgkin and Reed-Sternberg cells of most Hodgkin\u2019s disease cases","volume":"84","author":"HD Foss","year":"1993","journal-title":"Br J Haematol"},{"key":"pone.0248259.ref022","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev.iy.10.040192.002211","article-title":"The pathophysiology of tumor necrosis factors","volume":"10","author":"P Vassalli","year":"1992","journal-title":"Annu Rev Immunol"},{"key":"pone.0248259.ref023","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s002770050564","article-title":"Poor clinical outcome of patients with Hodgkin\u2019s disease and elevated Interleukin-10 serum levels. Clinical significance of Interleukin-10 serum levels for Hodgkin\u2019s disease","volume":"79","author":"H Bohlen","year":"2000","journal-title":"Ann Hematol"},{"key":"pone.0248259.ref024","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/BF02826218","article-title":"Elevated pretreatment serum levels of IL-10 are associated with a poor prognosis in Hodgkin\u2019s disease, the Milan Cancer Institute experience","volume":"17","author":"S Viviani","year":"2000","journal-title":"Med Oncol"},{"key":"pone.0248259.ref025","first-page":"274","article-title":"Serum Interleukin-10 levels are an independent prognostic factor for patients with Hodgkin\u2019s lymphoma","volume":"86","author":"TP Vassilakopoulos","year":"2001","journal-title":"Haematologica"},{"key":"pone.0248259.ref026","first-page":"2114","article-title":"Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin\u2019s lymphoma: associations with presenting features, serum Interleukin 10 levels, and clinical outcome","volume":"9","author":"M Herling","year":"2003","journal-title":"Clin Cancer Res"},{"key":"pone.0248259.ref027","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1200\/JCO.2006.08.1331","article-title":"Plasma cytokine and soluble receptor signature predicts outcome of patients with classical Hodgkin\u2019s lymphoma: a study from the Groupe d\u2019Etude des Lymphomes de l\u2019Adulte","volume":"25","author":"R-O Casasnovas","year":"2007","journal-title":"J Clin Oncol"},{"key":"pone.0248259.ref028","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1038\/bjc.1998.391","article-title":"Plasma levels of tumour necrosis factor and its soluble receptors correlate with clinical features and outcome of Hodgkin\u2019s disease patients","volume":"77","author":"K Warzocha","year":"1998","journal-title":"Br J Cancer"},{"key":"pone.0248259.ref029","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1182\/blood-2018-08-870915","article-title":"Serum levels of TARC, MDC, IL-10, and soluble CD163 in Hodgkin lymphoma: a SWOG S0816 correlative study","volume":"133","author":"ED Hsi","year":"2019","journal-title":"Blood"},{"key":"pone.0248259.ref030","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/sj.gene.6363920","article-title":"Differential regulation of interleukin-10 production by genetic and environmental factors\u2014a twin study","volume":"3","author":"E Reuss","year":"2002","journal-title":"Genes Immun"},{"key":"pone.0248259.ref031","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1016\/j.leukres.2009.01.009","article-title":"Clinical significance of Interleukin-10 gene polymorphisms and plasma levels in Hodgkin lymphoma","volume":"33","author":"S Hohaus","year":"2009","journal-title":"Leuk Res"},{"key":"pone.0248259.ref032","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1093\/hmg\/8.8.1443","article-title":"A common functional polymorphism (C\u2192 A substitution at position- 863) in the promoter region of the tumour necrosis factor-\u03b1 (TNF-\u03b1) gene associated with reduced circulating levels of TNF-\u03b1","volume":"8","author":"T Skoog","year":"1999","journal-title":"Hum Mol Genet"},{"key":"pone.0248259.ref033","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1046\/j.1523-1747.2000.00001.x","article-title":"Different transcriptional activity and in vitro TNF-\u03b1 production in psoriasis patients carrying the TNF-\u03b1 238A promoter polymorphism","volume":"114","author":"W Kaluza","year":"2000","journal-title":"J Invest Dermatol"},{"key":"pone.0248259.ref034","doi-asserted-by":"crossref","first-page":"2700","DOI":"10.1182\/blood-2006-07-025809","article-title":"Aberrant NF- B signaling in lymphoma: mechanisms, consequences and therapeutic implications","volume":"109","author":"PJ Jost","year":"2007","journal-title":"Blood"},{"key":"pone.0248259.ref035","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.semcancer.2015.02.002","article-title":"Lymphomagenesis in Hodgkin lymphoma","volume":"34","author":"E Matsuki","year":"2015","journal-title":"Semin Cancer Biol"},{"key":"pone.0248259.ref036","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.tim.2010.04.001","article-title":"NF-kappa B signaling modulation by EBV and KSHV","volume":"18","author":"DE de Oliveira","year":"2010","journal-title":"Trends Microbiol"},{"key":"pone.0248259.ref037","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1101\/gad.1228704","article-title":"Signaling to NF-\u03baB","volume":"18","author":"MS Hayden","year":"2004","journal-title":"Genes Dev"},{"key":"pone.0248259.ref038","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1158\/1055-9965.EPI-08-1130","article-title":"Polymorphic variation in NFKB1 and other aspirin-related genes and risk of Hodgkin lymphoma","volume":"18","author":"ET Chang","year":"2009","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"pone.0248259.ref039","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1097\/ALN.0b013e318277a652","article-title":"The NFKB1 promoter polymorphism (-94ins\/delATTG) alters nuclear translocation of NF-\u03baB1 in monocytes after lipopolysaccharide stimulation and is associated with increased mortality in sepsis","volume":"118","author":"M Adamzik","year":"2013","journal-title":"Anesthesiology"},{"key":"pone.0248259.ref040","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.imbio.2014.03.009","article-title":"Polymorphism of the NFKB1 affects the serum inflammatory levels of IL-6 in Hashimoto thyroiditis in a Turkish population","volume":"219","author":"A Koc","year":"2014","journal-title":"Immunobiology"},{"key":"pone.0248259.ref041","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/612972","article-title":"Association between NFKB1 \u221294ins\/del ATTG promoter polymorphism and cancer susceptibility: an updated meta-analysis","volume":"2014","author":"X Yang","year":"2014","journal-title":"Int J Genomics"},{"key":"pone.0248259.ref042","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1111\/bjh.13197","article-title":"NFKB1 \u2212 94ins\/delATTG polymorphism is a novel prognostic marker in first line-treated multiple myeloma","volume":"168","author":"G Varga","year":"2015","journal-title":"Br J Haematol"},{"key":"pone.0248259.ref043","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1200\/JCO.2013.54.8800","article-title":"Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification","volume":"32","author":"BD Cheson","year":"2014","journal-title":"J Clin Oncol"},{"key":"pone.0248259.ref044","doi-asserted-by":"crossref","first-page":"3070","DOI":"10.1093\/annonc\/mdt413","article-title":"Impact of risk factors on outcomes in early-stage Hodgkin\u2019s lymphoma: an analysis of international staging definitions","volume":"24","author":"B Klimm","year":"2013","journal-title":"Ann Oncol"},{"key":"pone.0248259.ref045","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/nm0798-844","article-title":"Tissue microarrays for high-throughput molecular profiling of tumor specimens","volume":"4","author":"J Kononen","year":"1998","journal-title":"Nat Med"},{"key":"pone.0248259.ref046","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1309\/UU2JADUEHDWATVM9","article-title":"Human papillomavirus and Epstein-Barr virus infection, p53 expression, and cellular proliferation in laryngeal carcinoma","volume":"126","author":"DE de Oliveira","year":"2006","journal-title":"Am J Clin Pathol"},{"key":"pone.0248259.ref047","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.5858\/2007-131-1691-EVIASN","article-title":"Epstein-Barr virus infection and single nucleotide polymorphisms in the promoter region of interleukin 10 gene in patients with Hodgkin lymphoma","volume":"131","author":"GN Da Silva","year":"2007","journal-title":"Arch Pathol Lab Med"},{"key":"pone.0248259.ref048","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1002\/ppul.20526","article-title":"Single nucleotide polymorphisms of tumor necrosis factor-alpha and the susceptibility to bronchopulmonary dysplasia","volume":"42","author":"SS Strassberg","year":"2007","journal-title":"Pediatr Pulmonol"},{"key":"pone.0248259.ref049","doi-asserted-by":"crossref","first-page":"D617","DOI":"10.1093\/nar\/gkj151","article-title":"SNP500Cancer: a public resource for sequence validation, assay development, and frequency analysis for genetic variation in candidate genes","volume":"34","author":"BR Packer","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"pone.0248259.ref050","unstructured":"Gaiolla RD. Polimorfismos de nucleot\u00eddeo \u00fanico (SNPs) nos genes codificadores da IL-10, TNF-\u03b1 e em NFkB1 e sua associa\u00e7\u00e3o com par\u00e2metros cl\u00ednicos, laboratoriais e de seguimento de pacientes com linfoma de Hodgkin cl\u00e1ssico. Ph.D. Thesis, S\u00e3o Paulo State University. 2015. http:\/\/acervodigital.unesp.br\/handle\/11449\/139380."},{"key":"pone.0248259.ref051","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1089\/omi.2016.0063","article-title":"Consensus genome-wide expression quantitative trait loci and their relationship with human complex trait disease","volume":"20","author":"CH Yu","year":"2016","journal-title":"Omics"},{"key":"pone.0248259.ref052","doi-asserted-by":"crossref","first-page":"D869","DOI":"10.1093\/nar\/gkv1317","article-title":"GWASdb v2: an update database for human genetic variants identified by genome-wide association studies","volume":"44","author":"MJ Li","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"pone.0248259.ref053","first-page":"D807","article-title":"CAUSALdb: a database for disease\/trait causal variants identified using summary statistics of genome-wide association studies","volume":"48","author":"J Wang","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"pone.0248259.ref054","doi-asserted-by":"crossref","DOI":"10.1093\/database\/baw100","article-title":"The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins","volume":"2016","author":"AD Rouillard","year":"2016","journal-title":"Database"},{"key":"pone.0248259.ref055","doi-asserted-by":"crossref","first-page":"4851","DOI":"10.1093\/bioinformatics\/btz469","article-title":"PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations","volume":"35","author":"MA Kamat","year":"2019","journal-title":"Bioinformatics"},{"key":"pone.0248259.ref056","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2015. http:\/\/www.R-project.org."},{"key":"pone.0248259.ref057","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1634\/theoncologist.2012-0291","article-title":"Interleukin-10 gene polymorphisms are associated with freedom from treatment failure for patients with Hodgkin lymphoma","volume":"18","author":"N Schoof","year":"2013","journal-title":"Oncologist"},{"key":"pone.0248259.ref058","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/mc.20688","article-title":"Hodgkin disease risk: Role of genetic polymorphisms and gene-gene interactions in inflammation pathway genes","volume":"50","author":"CM Monroy","year":"2011","journal-title":"Mol Carcinog"},{"key":"pone.0248259.ref059","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.3109\/10428194.2013.842982","article-title":"Genetic polymorphism of tumor necrosis factor promoter region and susceptibility to develop Hodgkin lymphoma in a Mexican population","volume":"55","author":"LM Torres-Espindola","year":"2014","journal-title":"Leuk Lymphoma"},{"key":"pone.0248259.ref060","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/nrc2542","article-title":"The biology of Hodgkin\u2019s lymphoma","volume":"9","author":"R K\u00fcppers","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"pone.0248259.ref061","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/nrc1452","article-title":"Epstein\u2013Barr virus: 40 years on","volume":"4","author":"LS Young","year":"2004","journal-title":"Nat Rev Cancer"},{"key":"pone.0248259.ref062","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1023\/A:1008301602785","article-title":"Interleukin-10 levels are often elevated in serum of adults with Hodgkin\u2019s disease and are associated with inferior failure-free survival","volume":"10","author":"AH Sarris","year":"1999","journal-title":"Ann Oncol"},{"key":"pone.0248259.ref063","doi-asserted-by":"crossref","first-page":"9465","DOI":"10.1073\/pnas.95.16.9465","article-title":"Interleukin 10 secretion in relation to human IL-10 locus haplotypes","volume":"95","author":"J Eskdale","year":"1998","journal-title":"Proc Natl Acad Sci"},{"key":"pone.0248259.ref064","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1002\/1529-0131(199906)42:6<1101::AID-ANR6>3.0.CO;2-Y","article-title":"Polymorphic haplotypes of the interleukin-10 5\u2019 flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis","volume":"42","author":"E Crawley","year":"1999","journal-title":"Arthritis Rheum"},{"key":"pone.0248259.ref065","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.4049\/jimmunol.166.6.3915","article-title":"Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus","volume":"166","author":"AW Gibson","year":"2001","journal-title":"J Immunol"},{"key":"pone.0248259.ref066","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1093\/hmg\/ddh187","article-title":"Transcription of the IL10 gene reveals allele-specific regulation at the mRNA level","volume":"13","author":"FAS Kurreeman","year":"2004","journal-title":"Hum Mol Genet"},{"key":"pone.0248259.ref067","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/jlb.45.2.155","article-title":"Mechanisms of tumor necrosis factor alpha-induced lymphopenia, neutropenia, and biphasic neutrophilia: a study of lymphocyte recirculation and hematologic interactions of TNF alpha with endogenous mediators of leukocyte trafficking","volume":"45","author":"TR Ulich","year":"1989","journal-title":"J Leukoc Biol"},{"key":"pone.0248259.ref068","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1182\/blood.V94.6.2065","article-title":"Hodgkin\/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils","volume":"94","author":"F Jundt","year":"1999","journal-title":"Blood"},{"key":"pone.0248259.ref069","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1002\/ijc.24502","article-title":"Mutations of NFKBIA, encoding I\u03baB\u03b1, are a recurrent finding in classical Hodgkin lymphoma but are not a unifying feature of non-EBV-associated cases","volume":"125","author":"A Lake","year":"2009","journal-title":"Int J Cancer"},{"key":"pone.0248259.ref070","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.cancergencyto.2009.11.005","article-title":"Mutations of NFKBIA in biopsy specimens from Hodgkin lymphoma","volume":"197","author":"X Liu","year":"2010","journal-title":"Cancer Genet Cytogenet"},{"key":"pone.0248259.ref071","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1182\/blood.V99.4.1474","article-title":"Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma","volume":"99","author":"JI Martin-Subero","year":"2002","journal-title":"Blood"},{"key":"pone.0248259.ref072","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3389\/fgene.2012.00055","article-title":"The Function of Introns","volume":"3","author":"M Chorev","year":"2012","journal-title":"Front Genet"},{"key":"pone.0248259.ref073","doi-asserted-by":"crossref","first-page":"e261","DOI":"10.1016\/j.clml.2018.04.001","article-title":"Extralymphatic Disease Is an Independent Prognostic Factor in Hodgkin Lymphoma","volume":"18","author":"F Gaudio","year":"2018","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"pone.0248259.ref074","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/hon.2450","article-title":"Treatment outcomes for Hodgkin lymphoma: First report from the Brazilian Prospective Registry","volume":"36","author":"I Biasoli","year":"2018","journal-title":"Hematol Oncol"},{"key":"pone.0248259.ref075","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1080\/16078454.2019.1598678","article-title":"Clinical characteristics and prognostic factors of primary extranodal classical Hodgkin lymphoma: a retrospective study","volume":"24","author":"M Yang","year":"2019","journal-title":"Hematology"},{"key":"pone.0248259.ref076","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/sj.gene.6364055","article-title":"Is there a future for TNF promoter polymorphisms?","volume":"5","author":"J-P Bayley","year":"2004","journal-title":"Genes Immun"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0248259","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T18:27:27Z","timestamp":1615228047000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0248259"}},"subtitle":[],"editor":[{"given":"Luwen","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,3,8]]},"references-count":76,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0248259","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,8]]}}}