Epidemiological And Genetic Characteristics Associated With The Severity Of Acute Viral Bronchiolitis By Respiratory Syncytial Virus

Objective: to assess the epidemiological and genetic factors associated with severity of acute viral bronchiolitis (AVB) by respiratory syncytial virus (RSV). Data source: the key words "bronchiolitis", "risk factor", "genetics" and "respiratory syncytial virus", and all combinations among them were used to perform a search in the PubMed, SciELO, and Lilacs databases, of articles published after the year 2000 that included individuals younger than 2 years of age. Data synthesis: a total of 1,259 articles were found, and their respective summaries were read. Of these, 81 were selected, which assessed risk factors for the severity of AVB, and were read in full; the 60 most relevant studies were included. The epidemiologic factors associated with AVB severity by RSV were prematurity, passive smoking, young age, lack of breastfeeding, chronic lung disease, congenital heart disease, male gender, ethnicity, viral coinfection, low weight at admission, maternal smoking during pregnancy, atopic dermatitis, mechanical ventilation in the neonatal period, maternal history of atopy and/or asthma during pregnancy, season of birth, low socioeconomic status, Down syndrome, environmental pollution, living at an altitude > 2,500 meters above sea level, and cesarean section birth. Conversely, some children with severe AVB did not present any of these risk factors. In this regard, recent studies have verified the influence of genetic factors on the severity of AVB by RSV. Polymorphisms of the TLRs, RANTES, JUN, IFNA5, NOS2, CX3CR1, ILs, and VDR genes have been shown to be associated with more severe evolution of AVB by RSV. Conclusion: the severity of AVB by RSV is a phenomenon that depends on the varying degrees of interaction among epidemiological, environmental, and genetic variables. © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.896531543Chávez-Bueno, S., Mejías, A., Welliver, R.C., Respiratory syncytial virus bronchiolitis: Current and future strategies for treatment and prophylaxis (2006) Treat Respir Med, 5, pp. 483-494Ogra, P.L., Respiratory syncytial virus: The virus, the disease and the immune response (2004) Paediatr Respir Rev, 5, pp. 119-S126Stockman, L.J., Curns, A.T., Anderson, L.J., Fischer-Langley, G., Respiratory syncytial virus-associated hospitalizations among infants and young children in the United States, 1997-2006 (2012) Pediatr Infect Dis J, 31, pp. 5-9Leader, S., Kohlhase, K., Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000 (2003) J Pediatr, 143, pp. 127-S132Ranmuthugala, G., Brown, L., Lidbury, B.A., Respiratory syncytial virus - The unrecognised cause of health and economic burden among young children in Australia (2011) Commun Dis Intell, 35, pp. 177-184Simões, E.A., Carbonell-Estrany, X., Impact of severe disease caused by respiratory syncytial virus in children living in developed countries (2003) Pediatr Infect Dis J, 22, pp. 13-S18. , discussion S18-20Albernaz, E.P., Menezes, A.M., César, J.A., Victora, C.G., Barros, F.C., Halpern, R., Risk factors associated with hospitalization for bronchiolitis in the post-neonatal period (2003) Rev Saude Publica, 37, pp. 485-493Deshpande, S.A., Northern, V., The clinical and health economic burden of respiratory syncytial virus disease among children under 2 years of age in a defined geographical area (2003) Arch Dis Child, 88, pp. 1065-1069Fryzek, J.P., Martone, W.J., Groothuis, J.R., Trends in chronologic age and infant respiratory syncytial virus hospitalization: An 8-year cohort study (2011) Adv Ther, 28, pp. 195-201Sung, C.C., Chi, H., Chiu, N.C., Huang, D.T., Weng, L.C., Wang, N.Y., Viral etiology of acute lower respiratory tract infections in hospitalized young children in Northern Taiwan (2011) J Microbiol Immunol Infect, 44, pp. 184-190García, M.L., Ordobás Gabin, M., Calvo Reya, C., González Alvarez, M., Aguilar Ruiz, J., Arregui Sierra, A., Viral infection of the lower respiratory tract in hospitalized infants: Etiology, clinical features and risk factors (2001) An Esp Pediatr, 55, pp. 101-107Riccetto, A.G., Ribeiro, J.D., Silva, M.T., Almeida, R.S., Arns, C.W., Baracat, E.C., Respiratory syncytial virus (RSV) in infants hospitalized for acute lower respiratory tract disease: Incidence and associated risks (2006) Braz J Infect Dis, 10, pp. 357-361Salomão Junior, J.B., Gardinassi, L.G., Simas, P.V., Bittar, C.O., Souza, F.P., Rahal, P., Human respiratory syncytial virus in children hospitalized for acute lower respiratory infection (2011) J Pediatr (Rio J), 87, pp. 219-224Sly, P.D., Jones, C.M., Viral co-detection in infants hospitalized with respiratory disease: Is it important to detect? (2011) J Pediatr (Rio J), 87, pp. 277-280Miller, E.K., Williams, J.V., Gebretsadik, T., Carroll, K.N., Dupont, W.D., Mohamed, Y.A., Host and viral factors associated with severity of human rhinovirus-associated infant respiratory tract illness (2011) J Allergy Clin Immunol, 127, pp. 883-891Nascimento, M.S., Souza, A.V., Ferreira, A.V., Rodrigues, J.C., Abramovici, S., Silva Filho, L.V., High rate of viral identification and coinfections in infants with acute bronchiolitis (2010) Clinics (Sao Paulo), 65, pp. 1133-1137Groothuis, J.R., Fryzek, J.P., Makari, D., Steffey, D., Martone, W.J., Respiratory syncytial virus hospitalization trends in infants with chronic lung disease of infancy, 1998-2008 (2011) Clin Epidemiol, 3, pp. 245-250Gouyon, J.B., Rozé, J.C., Guillermet-Fromentin, C., Glorieux, I., Adamon, L., Di Maio, M., Hospitalizations for respiratory syncytial virus bronchiolitis in preterm infants at < 33 weeks gestation without bronchopulmonary dysplasia: The CASTOR study (2012) Epidemiol Infect, 15, pp. 1-11Semple, M.G., Taylor-Robinson, D.C., Lane, S., Smyth, R.L., Household tobacco smoke and admission weight predict severe bronchiolitis in infants independent of deprivation: Prospective cohort study (2011) PLoS One, 6, p. 22425Koehoorn, M., Karr, C.J., Demers, P.A., Lencar, C., Tamburic, L., Brauer, M., Descriptive epidemiological features of bronchiolitis in a population-based cohort (2008) Pediatrics, 122, pp. 1196-1203Ochoa Sangrador, C., González De Dios, J., Idoneidad y Adecuación). Consensus conference on acute bronchiolitis (VI): Prognosis of acute bronchiolitis. Review of scientific evidence (2010) An Pediatr (Barc), 72 (354), pp. e1-3634. , Grupo de Revisión del Proyecto aBREVIADo (BRonquiolitis-Estudio de VariabilidadGrimwood, K., Cohet, C., Rich, F.J., Cheng, S., Wood, C., Redshaw, N., Risk factors for respiratory syncytial virus bronchiolitis hospital admission in New Zealand (2008) Epidemiol Infect, 136, pp. 1333-1341López Guinea, A., Casado Flores, J., Martín Sobrino, M.A., Espínola Docio, B., De La Calle Cabrera, T., Serrano, A., García Teresa, M.A., Severe bronchiolitis. Epidemiology and clinical course of 284 patients (2007) An Pediatr (Barc), 67, pp. 116-122Chan, P.W., Lok, F.Y., Khatijah, S.B., Risk factors for hypoxemia and respiratory failure in respiratory syncytial virus bronchiolitis (2002) Southeast Asian J Trop Med Public Health, 33, pp. 806-810Garcia, C.G., Bhore, R., Soriano-Fallas, A., Trost, M., Chason, R., Ramilo, O., Mejias, A., Risk factors in children hospitalized with RSV bronchiolitis versus non-RSV bronchiolitis (2010) Pediatrics, 126, pp. 1453-e1460Chatzimichael, A., Tsalkidis, A., Cassimos, D., Gardikis, S., Tripsianis, G., Deftereos, S., The role of breastfeeding and passive smoking on the development of severe bronchiolitis in infants (2007) Minerva Pediatr, 59, pp. 199-206Jones, L.L., Hashim, A., McKeever, T., Cook, D.G., Britton, J., Leonardi-Bee, J., Parental and household smoking and the increased risk of bronchitis, bronchiolitis and other lower respiratory infections in infancy: Systematic review and meta-analysis (2011) Respir Res, 12, p. 5Bradley, J.P., Bacharier, L.B., Bonfiglio, J., Schechtman, K.B., Strunk, R., Storch, G., Severity of respiratory syncytial virus bronchiolitis is affected by cigarette smoke exposure and atopy (2005) Pediatrics, 115, pp. 7-e14Hervás, D., Reina, J., Yañez, A., Del Valle, J.M., Figuerola, J., Hervás, J.A., Epidemiology of hospitalization for acute bronchiolitis in children: Differences between RSV and non-RSV bronchiolitis (2012) Eur J Clin Microbiol Infect Dis, 31, pp. 1975-1981Oñoro, G., Pérez Suárez, E., Iglesias Bouzas, M.I., Serrano, A., Martínez De Azagra, A., Severe bronchiolitis. Changes in epidemiology and respiratory support (2011) An Pediatr (Barc), 74, pp. 371-376Damore, D., Mansbach, J.M., Clark, S., Ramundo, M., Camargo Jr., C.A., Prospective multicenter bronchiolitis study: Predicting intensive care unit admissions (2008) Acad Emerg Med, 15, pp. 887-894Papoff, P., Moretti, C., Cangiano, G., Bonci, E., Roggini, M., Pierangeli, A., Incidence and predisposing factors for severe disease in previously healthy term infants experiencing their first episode of bronchiolitis (2011) Acta Paediatr, 100, pp. 17-e23Vidaurreta, S.M., Marcone, D.N., Ellis, A., Ekstrom, J., Cukier, D., Videla, C., Acute viral respiratory infection in children under 5 years: Epidemiological study in two centers in Buenos Aires, Argentina (2011) Arch Argent Pediatr, 109, pp. 296-304Dornelles, C.T., Piva, J.P., Marostica, P.J., Nutritional status, breastfeeding, and evolution of infants with acute viral bronchiolitis (2007) J Health Popul Nutr, 25, pp. 336-343Al-Shehri, M.A., Sadeq, A., Quli, K., Bronchiolitis in Abha, Southwest Saudi Arabia: Viral etiology and predictors for hospital admission (2005) West Afr J Med, 24, pp. 299-304Che, D., Nicolau, J., Bergounioux, J., Perez, T., Bitar, D., Bronchiolitis among infants under 1 year of age in France: Epidemiology and factors associated with mortality (2012) Arch Pediatr, 19, pp. 700-706Fjaerli, H.O., Farstad, T., Bratlid, D., Hospitalisations for respiratory syncytial virus bronchiolitis in Akershus, Norway, 1993-2000: A population-based retrospective study (2004) BMC Pediatr, 4, p. 25Meissner, H.C., Selected populations at increased risk from respiratory syncytial virus infection (2003) Pediatr Infect Dis J, 22, pp. 40-S45Riccetto, A.G., Silva, L.H., Spilki, F.R., Morcillo, A.M., Arns, C.W., Baracat, E.C., Genotypes and clinical data of respiratory syncytial virus and metapneumovirus in Brazilian infants: A new perspective (2009) Braz J Infect Dis, 13, pp. 35-39D'Elia, C., Siqueira, M.M., Portes, S.A., Sant'Anna, C.C., Respiratory syncytial virus - Associated lower respiratory tract infections in hospitalized infants (2005) Rev Soc Bras Med Trop, 38, pp. 7-10Weigl, J.A., Puppe, W., Schmitt, H.J., Variables explaining the duration of hospitalization in children under two years of age admitted with acute airway infections: Does respiratory syncytial virus have a direct impact? (2004) Klin Padiatr, 216, pp. 7-15Brand, H.K., De Groot, R., Galama, J.M., Brouwer, M.L., Teuwen, K., Hermans, P.W., Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis (2012) Pediatr Pulmonol, 47, pp. 393-400De Paulis, M., Gilio, A.E., Ferraro, A.A., Ferronato, A.E., Do Sacramento, P.R., Botosso, V.F., Severity of viral coinfection in hospitalized infants with respiratory syncytial virus infection (2011) J Pediatr (Rio J), 87, pp. 307-313Jartti, T., Söderlund-Venermo, M., Hedman, K., Ruuskanen, O., Mäkelä, M.J., New molecular virus detection methods and their clinical value in lower respiratory tract infections in children (2013) Paediatr Respir Rev, 14, pp. 38-45Carroll, K.N., Gebretsadik, T., Griffin, M.R., Dupont, W.D., Mitchel, E.F., Wu, P., Maternal asthma and maternal smoking are associated with increased risk of bronchiolitis during infancy (2007) Pediatrics, 119, pp. 1104-1112Bloemers, B.L., Van Furth, A.M., Weijerman, M.E., Gemke, R.J., Broers, C.J., Van Den Ende, K., Down syndrome: A novel risk factor for respiratory syncytial virus bronchiolitis - A prospective birth-cohort study (2007) Pediatrics, 120, pp. 1076-e1081Karr, C., Lumley, T., Schreuder, A., Davis, R., Larson, T., Ritz, B., Effects of subchronic and chronic exposure to ambient air pollutants on infant bronchiolitis (2007) Am J Epidemiol, 165, pp. 553-560Choudhuri, J.A., Ogden, L.G., Ruttenber, A.J., Thomas, D.S., Todd, J.K., Simoes, E.A., Effect of altitude on hospitalizations for respiratory syncytial virus infection (2006) Pediatrics, 117, pp. 349-356Moore, H.C., De Klerk, N., Holt, P., Richmond, P.C., Lehmann, D., Hospitalisation for bronchiolitis in infants is more common after elective caesarean delivery (2012) Arch Dis Child, 97, pp. 410-414Thomsen, S.F., Stensballe, L.G., Skytthe, A., Kyvic, K.O., Backer, V., Bisgaard, H., Increased concordance of severe respiratory syncytial virus infection in identical twins (2008) Pediatrics, 121, pp. 493-496Tal, G., Mandelberg, A., Dalal, I., Cesar, K., Somekh, E., Tal, A., Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease (2004) J Infect Dis, 189, pp. 2057-2063Douville, R.N., Lissitsyn, Y., Hirschfeld, A.F., Becker, A.B., Kozyrskyj, A.L., Liem, J., TLR4 Asp299Gly and Thr399Ile polymorphisms: No impact on human immune responsiveness to LPS or respiratory syncytial virus (2010) PLoS One, 5, p. 12087Löfgren, J., Marttila, R., Renko, M., Rämet, M., Hallman, M., Toll-like receptor 4 Asp299Gly polymorphism in respiratory syncytial virus epidemics (2010) Pediatr Pulmonol, 45, pp. 687-692Mandelberg, A., Tal, G., Naugolny, L., Cesar, K., Oron, A., Houri, S., Lipopolysaccharide hyporesponsiveness as a risk factor for intensive care unit hospitalization in infants with respiratory syncitial virus bronchiolitis (2006) Clin Exp Immunol, 144, pp. 48-52Puthothu, B., Forster, J., Heinzmann, A., Krueger, M., TLR-4 and CD14 polymorphisms in respiratory syncytial virus associated disease (2006) Dis Markers, 22, pp. 303-308Mailaparambil, B., Krueger, M., Heinze, J., Forster, J., Heinzmann, A., Polymorphisms of toll like receptors in the genetics of severe RSV associated diseases (2008) Dis Markers, 25, pp. 59-65Amanatidou, V., Sourvinos, G., Apostolakis, S., Neonaki, P., Tsilimigaki, A., Krambovitis, E., RANTES promoter gene polymorphisms and susceptibility to severe respiratory syncytial virus-induced bronchiolitis (2008) Pediatr Infect Dis J, 27, pp. 38-42Kresfelder, T.L., Janssen, R., Bont, L., Venter, M., Confirmation of an association between single nucleotide polymorphisms in the VDR gene with respiratory syncytial virus related disease in South African children (2011) J Med Virol, 83, pp. 1834-1840Janssen, R., Bont, L., Siezen, C.L., Hodemaekers, H.M., Ermers, M.J., Doornbos, G., Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes (2007) J Infect Dis, 196, pp. 826-834Amanatidou, V., Sourvinos, G., Apostolakis, S., Tsilimigaki, A., Spandidos, D.A., T280 M variation of the CX3C receptor gene is associated with increased risk for severe respiratory syncytial virus bronchiolitis (2006) Pediatr Infect Dis J, 25, pp. 410-414Ampuero, S., Luchsinger, V., Tapia, L., Palomino, M.A., Larrañaga, C.E., SP-A1, SP-A2 and SP-D gene polymorphisms in severe acute respiratory syncytial infection in Chilean infants (2011) Infect Genet Evol, 11, pp. 1368-1377Mulet, J.F., Rodríguez De Torres, B.O., Viral induced bronchiolitis and genetics (2010) An Pediatr (Barc), 73, pp. 159-16

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Prevalence Of δf508 Mutation In The Cystic Fibrosis Transmembrane Conductance Regulator Gene Among Cystic Fibrosis Patients From A Brazilian Referral Center [prevalência Da Mutação δf508 No Gene Cystic Fibrosis Transmembrane Conductance Regulator Em Pacientes Com Fibrose Cística Em Um Centro De Referência No Brasil]

Objective: To verify the presence of δF508 mutation in the cystic fibrosis transmembrane conductance regulator gene among patients with cystic fibrosis diagnosed by the sweat test for sodium and chlorine and followed at the Pediatric Pneumology Outpatient Clinic of Universidade Estadual de Campinas, Brazil, a referral center for the treatment of cystic fibrosis. Methods: The study analyzed 167 DNA samples from cystic fibrosis patients. Patients' genotype was determined by polymerase chain reaction, and allele and genotype frequencies of δF508 mutation were calculated. Results: The genotype frequencies found for -/-, δF508/-, and δF508/δF508 genotypes were respectively: 43.7% (73 patients), 32.9% (55 patients), and 23.4% (39 patients). Of the 334 alleles analyzed, we observed a frequency of 201 (60.18%) alleles for the absence of δF508 mutation and of 133 (39.82%) for the presence of δF508 mutation. Hardy-Weinberg equilibrium was calculated, obtaining a chi-square value = 16.34 (p ≤ 0.001). The study population was out of equilibrium. The expected values for -/-, δF508/-, and δF508/δF508 genotypes were respectively: 32.22% (60.48 patients), 47.93% (80.04 patients), and 15.86% (26.48 patients). Conclusions: In the analyzed population, δF508 mutation was less prevalent than the allele without this mutation. The frequency observed in this study was similar to that from other areas in Brazil and in the world, mainly due to the predominantly Caucasian origin of the population included in the study. Copyright © 2012 by Sociedade Brasileira de Pediatria.886531534Okay, T.S., Oliveira, W.P., Raiz-Júnior, R., Rodrigues, J.C., Del Negro, G.M., Frequency of the deltaF508 mutation in 108 cystic fibrosis patients in Sao Paulo: Comparison with reported Brazilian data (2005) Clinics (Sao Paulo), 60, pp. 131-134Riordan, J.R., Rommens, J.M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA (1989) Science, 245, pp. 1066-1073Rommens, J.M., Iannuzzi, M.C., Kerem, B., Drumm, M.L., Melmer, G., Dean, M., Identification of the cystic fibrosis gene: Chromosome walking and jumping (1989) Science, 245, pp. 1059-1065Kerem, B., Rommens, J.M., Buchanan, J.A., Markiewicz, D., Cox, T.K., Chakravarti, A., Identification of the cystic fibrosis gene: Genetic analysis (1989) Science, 245, pp. 1073-1080(2011) Cystic Fibrosis Mutation Database, , www.genet.sickkids.on.ca/cftr/, online). Acesso: 20/11/Ko, Y.H., Thomas, P.J., Delannoy, M.R., Pedersen, P.L., The cystic fibrosis transmembrane conductance regulator. Overexpression, purification, and characterization of wild type and delta F508 mutant forms of the first nucleotide binding fold in fusion with the maltose-binding protein (1993) J Biol Chem, 268, pp. 24330-24338Alvarez, A.E., Ribeiro, A.F., Hessel, G., Bertuzzo, C.S., Ribeiro, J.D., Fibrose cística em um centro de referência no Brasil: Características clínicas e laboratoriais de 104 pacientes e sua associação com o genótipo e a gravidade da doença (2004) J Pediatr (Rio J), 80, pp. 371-379Mickle, J.E., Cutting, G.R., Genotype-phenotype relationships in cystic fibrosis (2000) Med Clin North Am, 84, pp. 597-607Bernardino, A.L., Ferri, A., Passos-Bueno, M.R., Kim, C.E., Nakaie, C.M., Gomes, C.E., Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations (2000) Genet Test, 4, pp. 69-74(2011) Statistical Package for Social Science (SPSS), , SPSS 17.0 for Windows (computer program). Release Version 17.0.1. Chicago, IL: SPSS IncorporationMartins, C.S., Ribeiro, F., Costa, F.F., Frequency of the cystic fibrosis delta F 508 mutation in a population from São Paulo State, Brazil (1993) Braz J Med Biol Res, 26, pp. 1037-1040Vidigal, P.V., Reis, F.J., Boson, W.L., De Marco, L.A., Brasileiro-Filho, G., P.F508del in a heterogeneous cystic fibrosis population from Minas Gerais, Brazil (2008) Braz J Med Biol Res., 41, pp. 643-647Oliveira, Y.A., (2008) Fibrose Quística [Dissertação], , Covilhã, Portugal: Universidade da Beira Interior

Thymidylate Synthase Gene (tyms) Polymorphisms In Sporadic And Hereditary Breast Cancer

Background: Breast cancer (BC) is a genetic disorder characterized by growth and proliferation of breast cells in a disorderly. In Brazil, there are approximately 49.240 new cases of BC, every year. The BC etiology is still poorly understood. The BC can be sporadic (SBC) or hereditary (HBC). Recent studies have correlated gene polymorphisms with the BC, such as alterations in thymidylate synthase gene (TYMS), which are used to improve diagnosis and prevention of the disease. Polymorphisms in the TYMS gene 5'-UTR region, usually present reps double (2R) and/or triple (3R). Studies have shown that homozygous 3R/3R is overexpressed compared with 2R/2R genotype, and these polymorphic variations may contribute to individual susceptibility to the development of BC. In this context, the objective of this study was to evaluate the frequency of the TYMS 2R and 3R polymorphisms, comparing genotypic and allelic distribution with SBC and HBC patients. Methods. In this study we included a total of 204 subjects, 70 with BC (33 with SBC, and 37 with HBC) and 134 healthy subjects (controls). The Polymerase Chain Reaction was the method used. Results: Results demonstrated a high frequency of the 3R allele at BC, SBC, and HBC groups. The frequency of genotype 2R/3R was significantly higher in BC group. This work showed association between the 2R/3R variants (OR = 4.14, CI95% = 1.77-9.71) in the development of SBC, and 2R/2R (OR = 0.233, CI95% = 1.63-7.65) and 2R/3R (OR = 3.53, CI95% = 0.06-0.81) for developing HBC. To BC, there was association with the genotype 2R/3R (OR: 3.79, CI95% = 2.03-7.08). Conclusion: Our results show relation to the development of BC in association with the analyzed polymorphisms. © 2012 Junior et al.; licensee BioMed Central Ltd.5(2011) Cancer, , http://www.who.int/cancer/en/, World Health Organization WHO [Acess: 2011 Jul. 27]Zou, Y.F., Wang, F., Feng, X.L., The association between two polymorphisms in the TYMS gene and breast cancer risk: Appraisal of a recent meta-analysis (2011) Breast Cancer Res Treat, 128 (1), pp. 289-290. , 10.1007/s10549-011-1390-9 21327463Henríquez-Hernández, L.A., Murias-Rosales, A., Hernández González, A., Cabrera De León, A., Díaz-Chico, B.N., Mori De Santiago, M., Fernández Pérez, L., Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: A case-control study (2009) Oncol Rep, 22 (6), pp. 1425-1433. , 19885596Van Der Groep, P., Bouter, A., Van Der Zanden, R., Siccama, I., Menko, F.H., Gille, J.J.P., Van Kalken, C., Van Diest, P.J., Distinction between hereditary and sporadic breast cancer on the basis of clinicopathological data (2006) Journal of Clinical Pathology, 59 (6), pp. 611-617. , DOI 10.1136/jcp.2005.032151Van Diest, P.J., No consent should be needed for using leftover body material for scientific purposes (2002) BMJ, 325, pp. 648-651. , 10.1136/bmj.325.7365.648 12269316Kenemans, P., Verstraeten, R.A., Verheijen, R.H.M., Oncogenic pathways in hereditary and sporadic breast cancer (2004) Maturitas, 49 (1), pp. 34-43. , DOI 10.1016/j.maturitas.2004.06.005, PII S0378512204002075Latimer, J.J., Johnson, J.M., Kelly, C.M., Miles, T.D., Beaudry-Rodgers, K.A., Lalanne, N.A., Vogel, V.G., Grant, S.G., Nucleotide excision repair deficiency is intrinsic in sporadic stage i breast cancer (2010) PNAS, 107 (50), pp. 21725-21730. , 10.1073/pnas.0914772107 21118987Henríquez-Hernández, L.A., Pérez, L.F., González, A.H., León, A.C., Díaz-Chico, B.N., Rosales, A.M., TYMS, MTHFR, p53 and MDR1 gene polymorphisms in breast cancer patients treated with adjuvant therapy (2010) Cancer Epidemiol, 34, pp. 490-493. , 10.1016/j.canep.2010.03.004 20371218Jakobsen, A., Nielsen, N.J., Gyldenkerne, N., Lindeberg, J., Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity (2005) J Clin Oncol, 23, pp. 1365-1369. , 10.1200/JCO.2005.06.219 15735113Lecomte, T., Ferraz, J.-M., Zinzindohoue, F., Loriot, M.-A., Tregouet, D.-A., Landi, B., Berger, A., Laurent-Puig, P., Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy (2004) Clinical Cancer Research, 10 (17), pp. 5880-5888. , DOI 10.1158/1078-0432.CCR-04-0169Wang, J., Wang, B., Bi, J., Di, J., The association between two polymorphisms in the TYMS gene and breast cancer risk: A meta-analysis (2011) Breast Cancer Res Treat, 128, pp. 203-209. , 10.1007/s10549-010-1314-0 21188629Zhai, X., Gao, J., Hu, Z., Tang, J., Qin, J., Wang, S., Wang, X., Shen, H., Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: A case-control analysis (2006) BMC Cancer, 6, p. 138. , DOI 10.1186/1471-2407-6-138Feng, I.J., Radivoyevitch, T., SNP-SNP interactions between dNTP supply enzymes and mismatch DNA repair in breast cancer (2009) Proc Ohio Collab Conf Bioinform, 15, pp. 123-128Calascibetta, A., Contino, F., Feo, S., Gulotta, G., Cajozzo, M., Antona, A., Sanguedolce, G., Sanguedolce, R., Analysis of the thymidylate synthase gene structure in colorectal cancer patients and its possible relation with the 5-fluorouracil drug response (2009) J of Nucleic Acids, 2010, pp. 1-4Fariña-Sarasqueta, A., Gosens, M., Moerland, E., Lijnschoten, I.V., Lemmens, V., Slooter, G.D., Rutten, H.J.T., Van Den Brule, A.J.C., TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients (2010) Anal Cell Pathol/Cell Oncol, 33, pp. 1-11Bonadia, L.C., (2004) Estudo de Associação Entre Polimorfismos em Genes Que Codificam Enzimas Participantes Do Metabolismo Do Folato e A Formação de Embriões Com Aberrações Cromossômicas, , Campinas: Dissertação [Mestrado em Ciências Médicas]. Departamento de Genética Médica, Universidade Estadual de Campinas(2011) SPSS 17.0 for Windows (Computer Program). Statistical Package for Social Science (SPSS). Release Version 17.0.1. Chicago (IL): SPSS. Incorporation, , http://www.spss.comBarrett, J.C., Fry, B., Maller, J., Daly, M.J., Haploview: Analysis and visualization of LD and haplotype maps (2005) Bioinformatics, 21 (2), pp. 263-265. , DOI 10.1093/bioinformatics/bth457Dunning, A.M., Healey, C.S., Pharoah, P.D.P., Teare, M.D., Ponder, B.A.J., Easton, D.F., A systematic review of genetic polymorphisms and breast cancer risk (1999) Cancer Epidemiology Biomarkers and Prevention, 8 (10), pp. 843-854Kawakita, D., Matsuo, K., Sato, F., Oze, I., Hosono, S., Ito, H., Watanabe, M., Tanaka, H., Association between dietary folate intake and clinical outcome in head and neck squamous cell carcinoma (2012) Ann Oncol, 23 (1), pp. 186-192. , 10.1093/annonc/mdr057 21460376Ghosh, S., Winter, J.M., Patel, K., Kern, S.E., Reexamining a proposal thymidylate synthase 5'-untranslated region as a regulator of translation efficiency (2011) Cancer Biol Ther, 12 (8), pp. 750-755. , 10.4161/cbt.12.8.16867 21811101Brown, K.S., Kluijtmans, L.A.J., Young, I.S., McNulty, H., Mitchell, L.E., Yarnell, J.W.G., Woodside, J.V., Whitehead, A.S., The thymidylate synthase tandem repeat polymorphism is not associated with homocysteine concentrations in healthy young subjects (2004) Human Genetics, 114 (2), pp. 182-185. , DOI 10.1007/s00439-003-1039-9Düzgün, N., Duman, T., Morris, Y., Tutkak, H., Köse, K., Ertuǧrul, E., Aydintuǧ, O.T., Thymidylate synthase genotype and serum concentrations of homocysteine and folate in Behçet's disease (2008) Clin Rheumatol, 27, pp. 1221-1225. , 10.1007/s10067-008-0889-x 18458991Uchida, K., Hayashi, K., Kawakami, K., Schneider, S., Yochim, J.M., Kuramochi, H., Takasaki, K., Danenberg, P.V., Loss of Heterozygosity at the Thymidylate Synthase (TS) Locus on Chromosome 18 Affects Tumor Response and Survival in Individuals Heterozygous for A 28-bp Polymorphism in the TS Gene (2004) Clinical Cancer Research, 10 (2), pp. 433-439. , DOI 10.1158/1078-0432.CCR-0200-03Brody, J.R., Hucl, T., Gallmeier, E., Winter, J.M., Kern, S.E., Murphy, K.M., Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: A model for patient classification to aid fluoropyrimidine therapy (2006) Cancer Research, 66 (19), pp. 9369-9373. , DOI 10.1158/0008-5472.CAN-06-2165Hur, H., Kang, J., Kim, N.K., Min, B.S., Lee, K.Y., Shin, S.J., Keum, K.C., Lee, M.Y., Thymidylate synthase gene polymorphism affects the response to preoperative 5-fluorouracil chemoradiation therapy in patients with rectal cancer (2011) J Radiat Oncol Biol Phys, 81 (3), pp. 669-676. , 10.1016/j.ijrobp.2010.06.049Tan, B.R., Thomas, F., Myerson, R.J., Zehnbauer, B., Trinkaus, K., Malyapa, R.S., Mutch, M.G., McLeod, H.L., Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma (2011) J Clin Oncol, 45, pp. 1-10Tanaka, F., Wada, H., Fukui, Y., Fukushima, M., Thymidylate synthase (TS) gene expression in primary lung cancer patients: A large-scale study in Japanese population (2011) Ann Oncol, 22 (8), pp. 1791-1797. , 10.1093/annonc/mdq730 21321092Weekes, C.D., Nallapareddy, S., Rudek, M.A., Norris-Kirby, A., Laheru, D., Jimeno, A., Donehower, R.C., Messersmith, W.A., Thymidylate synthase (TYMS) enhancer region genotype-directed phase II trial of oral capecitabine for 2nd line treatment of advanced pancreatic cancer (2011) Invest New Drugs, 29, pp. 1057-1065. , 10.1007/s10637-010-9413-7 20306339Wynes, M.W., Dziadziuszko, R., Singh, S., Ranger-Moore, J., Szostakiewicz, B., Dziadziuszko, K., Jassem, J., Hirsch, F.R., Thymidylate synthase (TS) gene copy number in NSCLC (2010) J Clin Oncol, 28 (15), pp. 21063-21067Skibola, C.F., Forrest, M.S., Coppedé, F., Agana, L., Hubbard, A., Smith, M.T., Bracci, P.M., Holly, E.A., Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma (2004) Blood, 104 (7), pp. 2055-2062Liersch, T., Langer, C., Ghadimi, B.M., Kulle, B., Aust, D.E., Baretton, G.B., Schwabe, W., Jakob, C., Lymph node status and TS gene expression are prognostic markers in stage II/III rectal cancer after neoadjuvant fluorouracil-based chemoradiotherapy (2006) Journal of Clinical Oncology, 24 (25), pp. 4062-4068. , DOI 10.1200/JCO.2005.04.2739Kawakami, K., Omura, K., Kanehira, E., Watanabe, Y., Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers (1999) Anticancer Research, 19 (4 B), pp. 3249-3252Trinh, B.N., Ong, C.-N., Coetzee, G.A., Yu, M.C., Laird, P.W., Thymidylate synthase: A novel genetic determinant of plasma homocysteine and folate levels (2002) Human Genetics, 111 (3), pp. 299-302. , DOI 10.1007/s00439-002-0779-2Xi, Y., Nakajima, G., Schmitz, J.C., Chu, E., Ju, J., Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer (2006) BMC Genom, 7, pp. 68-83. , 10.1186/1471-2164-7-68Calascibetta, A., Contino, F., Feo, S., Gulotta, G., Cajozzo, M., Antona, A., Sanguedolce, G., Sanguedolce, R., Analysis of the thymidylate synthase gene structure in colorectal cancer patients and its possible relation with the 5-fluorouracil drug response (2010) J of Nucl Acids, 2010, pp. 1-4Mauritz, R., Giovannetti, E., Beumer, I.J., Smid, K., Van Groeningen, C.J., Pinedo, H.M., Peters, G.J., Polymorphisms in the enhancer region of the thymidylate synthase gene are associated with thymidylate synthase levels in normal tissues but not in malignant tissues of patients with colorectal cancer (2009) Clin Colorectal Cancer, 8 (3), pp. 146-154. , 10.3816/CCC.2009.n.024 19632929Gusella, M., Padrini, R., G>C SNP of thymidylate synthase with respect to colorectal cancer (2007) Pharmacogenomics, 8 (8), pp. 985-996. , http://www.futuremedicine.com/doi/pdf/10.2217/14622416.8.8.985, DOI 10.2217/14622416.8.8.985Martinez-Balibrea, E., Abad, A., Martínez-Cardús, A., Ginés, A., Valladares, M., Navarro, M., Aranda, E., Moreno, V., UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy (2010) BJ of Cancer, 103, pp. 581-589. , 10.1038/sj.bjc.6605776(2006) Parâmetros Técnicos Para Programação de Ações de Detecção Precoce Do Câncer de Mama. Recomendações Para Gestores Estaduais e Municipais, , http://www.inca.gov.br/inca/Arquivos/publicacoes/Parametrostexto.pdf, Ministério da Saúde. Instituto Nacional de Câncer Ministério da Saúde RJ Rio de Janeiro [Acess: 2011 dez. 13