title: Linkage disequilibrium with HLA-DRB1-DQB1 haplotypes explains the association of TNF-308G>A variant with type 1 diabetes in a Brazilian cohort.
abstract: BACKGROUND
  A functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association.
  
  
  METHODS
  659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HLA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects.
  
  
  RESULTS
  Associations with T1D were observed for the A-allele of rs1800629 (OR 1.69, 95% CI 1.33-2.15, p<0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% CI 3.23-8.59, p<0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% CI 1.21-7.21, p=0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14, 95% CI 1.02-4.50, p=0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D.
  
  
  CONCLUSIONS
  Our results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D.
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Brazil.
authors.forename: Thiago A
authors.initials: TA
authors.lastname: Patente
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Brazil.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Monteiro
authors.affiliation: Hospital do Servidor Público Estadual (HSPE), Brazil.
authors.forename: Suzana M
authors.initials: SM
authors.lastname: Vieira
authors.affiliation: Divisão de Endocrinologia, Hospital das Clínicas, FMUSP, Brazil; Laboratório de Investigação Médica (LIM-18), FMUSP, Brazil.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Rossi da Silva
authors.affiliation: Divisão de Endocrinologia, Hospital das Clínicas, FMUSP, Brazil.
authors.forename: Márcia
authors.initials: M
authors.lastname: Nery
authors.affiliation: Divisão de Endocrinologia, Hospital das Clínicas, FMUSP, Brazil.
authors.forename: Márcia
authors.initials: M
authors.lastname: Queiroz
authors.affiliation: Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Brazil.
authors.forename: Mirela J
authors.initials: MJ
authors.lastname: Azevedo
authors.affiliation: Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Brazil.
authors.forename: Luis H
authors.initials: LH
authors.lastname: Canani
authors.affiliation: Divisão de Endocrinologia, Departamento de Clínica Médica, Faculdade de Medicina da Universidade Estadual de Campinas (UNICAMP), Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Parisi
authors.affiliation: Divisão de Endocrinologia, Departamento de Clínica Médica, Faculdade de Medicina da Universidade Estadual de Campinas (UNICAMP), Brazil.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Pavin
authors.affiliation: Laboratório de Investigação Médica (LIM-18), FMUSP, Brazil.
authors.forename: Débora
authors.initials: D
authors.lastname: Mainardi
authors.affiliation: Department of Immunology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Javor
authors.affiliation: INSERM, Research Unit 1138, Équipe 2, Paris, France.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Velho
authors.affiliation: Universidade Santo Amaro (UNISA), Brazil.
authors.forename: Cássio N
authors.initials: CN
authors.lastname: Coimbra
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Brazil; Centro de Terapia Celular e Molecular (NUCEL/NETCEM) da FMUSP, Brazil. Electronic address: malugia@lim25.fm.usp.br.
authors.forename: Maria Lúcia
authors.initials: ML
authors.lastname: Corrêa-Giannella
mesh_terms: D000328:Adult; D001938:Brazil; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D055815:Young Adult
chemical_list: D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: Single nucleotide polymorphism; TNFHLA; Type 1A diabetes