title: Association of polymorphisms within the promoter region of the tumor necrosis factor-alpha with clinical outcomes of rheumatic fever.
abstract: Rheumatic fever (RF)/rheumatic heart disease (RHD) is an inflammatory disease with a complex etiology in which Group A streptococci within a genetically susceptible host untreated for strep-throat may deviate the innate and adaptive arms of the immune system towards recognition of autoantigens. The TNFA gene has been associated with a number of autoimmune diseases, including RF. We investigated whether the G-308A and G-238A polymorphisms of the TNFA gene are associated with clinical outcomes of RF in a cohort of 318 patients and 281 healthy controls (HC). Both polymorphisms showed borderline associations with RF (TNFA -308G/A, OR=1.4 [1-2.2], P=0.026; TNFA -238G/A, OR=1.9 [1-3.3], P=0.015). The presence of either one of the minor alleles (-308A and -238A) was more common among patients with RF/RHD than controls (P=0.0006). Stratification of patients according to clinical phenotype also showed significant associations between presence of either one of the minor alleles and RHD (Pc=0.0006) when compared with controls. This association was stronger with the development of aortic valve lesions. In contrast, there was no association between genotype and Sydenham's chorea or RF patients with mild carditis. In conclusion, we show that the TNFA is a susceptibility locus for RF. The ability to predict which RF patients will develop valve lesion may have therapeutic, economic and social implications.
authors.affiliation: Heart Institute (InCor), School of Medicine, University of Sao Paulo, Brazil. ramasawm@usp.br
authors.forename: Rajendranath
authors.initials: R
authors.lastname: Ramasawmy
authors.forename: Kellen C
authors.initials: KC
authors.lastname: Faé
authors.forename: Guilherme
authors.initials: G
authors.lastname: Spina
authors.forename: Gabriel D
authors.initials: GD
authors.lastname: Victora
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Tanaka
authors.forename: Selma A
authors.initials: SA
authors.lastname: Palácios
authors.forename: Ana G
authors.initials: AG
authors.lastname: Hounie
authors.forename: Euripides C
authors.initials: EC
authors.lastname: Miguel
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Oshiro
authors.forename: Anna C
authors.initials: AC
authors.lastname: Goldberg
authors.forename: Jorge
authors.initials: J
authors.lastname: Kalil
authors.forename: Luiza
authors.initials: L
authors.lastname: Guilherme
mesh_terms: D000293:Adolescent; D000328:Adult; D001018:Aortic Diseases / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D002648:Child; D002819:Chorea / Q000235:genetics / Q000276:immunology; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009205:Myocarditis / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D040641:Quantitative Trait Loci / Q000235:genetics* / Q000276:immunology; D012214:Rheumatic Heart Disease / Q000150:complications / Q000235:genetics* / Q000276:immunology; D013290:Streptococcal Infections / Q000235:genetics; D013297:Streptococcus pyogenes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology
chemical_list: D014409:Tumor Necrosis Factor-alpha