title: Association of tumor necrosis factor and human leukocyte antigen DRB1 alleles with Graves' ophthalmopathy.
abstract: Tumor necrosis factor (TNF)-alpha plays a central role in the development of ophthalmopathy in patients with Graves' disease (GD). The aim of this study was to investigate the association of TNF promoter polymorphisms at positions -1031 (T-1031C), -863 (C-863A), -857 (C-857T), -308 (G-308A), and -238 (G-238A) with Graves' ophthalmopathy (GO). We studied the distribution of TNF and human leukocyte antigen (HLA) DRB1 alleles in 228 Polish white patients with GD, 106 of whom had ophthalmopathy (NOSPECS class > or = III) and 248 healthy subjects. TNF -308A and HLA-DRB1*03 alleles were significantly increased in patients with GD compared with healthy subjects. Stratification analysis revealed no independent association of -308A with GD when the DRB1*03 status was considered. Subdividing GD according to eye involvement revealed that the distribution of TNF promoter haplotypes differed significantly in patients with or without ophthalmopathy. The haplotype containing the -238A allele was absent in GO. The association of G-238A with GO was independent of DRB1 alleles. These results indicate that TNF G-308A is associated with susceptibility to GD (however, this association is not independent of HLA-DRB1*03) and that TNF G-238A is associated with the development of ophthalmopathy, suggesting that G-238A or a gene in linkage disequilibrium may be disease modifying in GD.
authors.affiliation: Department of Endocrinology, Medical Research Center in Warsaw, Poland. bernar@amwaw.edu.pl
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bednarczuk
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiromatsu
authors.forename: Naoko
authors.initials: N
authors.lastname: Seki
authors.forename: Rafał
authors.initials: R
authors.lastname: Płoski
authors.forename: Tomoka
authors.initials: T
authors.lastname: Fukutani
authors.forename: Alina
authors.initials: A
authors.lastname: Kuryłowicz
authors.forename: Krystian
authors.initials: K
authors.lastname: Jazdzewski
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Chojnowski
authors.forename: Kyogo
authors.initials: K
authors.lastname: Itoh
authors.forename: Janusz
authors.initials: J
authors.lastname: Nauman
mesh_terms: D000328:Adult; D000483:Alleles; D006111:Graves Disease / Q000235:genetics* / Q000473:pathology; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D011044:Poland; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D044465:White People
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D014409:Tumor Necrosis Factor-alpha