title: Polymorphisms in the TNFA and IL6 genes represent risk factors for autoimmune thyroid disease.
abstract: BACKGROUND
  Autoimmune thyroid disease (AITD) comprises diseases including Hashimoto's thyroiditis and Graves' disease, both characterized by reactivity to autoantigens causing, respectively, inflammatory destruction and autoimmune stimulation of the thyroid-stimulating hormone receptor. AITD is the most common thyroid disease and the leading form of autoimmune disease in women. Cytokines are key regulators of the immune and inflammatory responses; therefore, genetic variants at cytokine-encoding genes are potential risk factors for AITD.
  
  
  METHODS
  Polymorphisms in the IL6-174 G/C (rs1800795), TNFA-308 G/A (rs1800629), IL1B-511 C/T (rs16944), and IFNGR1-56 T/C (rs2234711) genes were assessed in a case-control study comprising 420 Hashimoto's thyroiditis patients, 111 Graves' disease patients and 735 unrelated controls from Portugal. Genetic variants were discriminated by real-time PCR using TaqMan SNP genotyping assays.
  
  
  RESULTS
  A significant association was found between the allele A in TNFA-308 G/A and Hashimoto's thyroiditis, both in the dominant (OR = 1.82, CI = 1.37-2.43, p-value = 4.4×10(-5)) and log-additive (OR = 1.64, CI = 1.28-2.10, p-value = 8.2×10(-5)) models. The allele C in IL6-174 G/C is also associated with Hashimoto's thyroiditis, however, only retained significance after multiple testing correction in the log-additive model (OR = 1.28, CI = 1.06-1.54, p-value = 8.9×10(-3)). The group with Graves' disease also registered a higher frequency of the allele A in TNFA-308 G/A compared with controls both in the dominant (OR = 1.85, CI = 1.19-2.87, p-value = 7.0×10(-3)) and log-additive (OR = 1.69, CI = 1.17-2.44, p-value = 6.6×10(-3)) models. The risk for Hashimoto's thyroiditis and Graves' disease increases with the number of risk alleles (OR for two risk alleles is, respectively, 2.27 and 2.59).
  
  
  CONCLUSIONS
  This study reports significant associations of genetic variants in TNFA and IL6 with the risk for AITD, highlighting the relevance of polymorphisms in inflammation-related genes in the etiopathogenesis of AITD.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: Cecília
authors.initials: C
authors.lastname: Durães
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Moreira
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Alvelos
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: Adélia
authors.initials: A
authors.lastname: Mendes
authors.affiliation: Faculty of Medicine of the University of Porto, Porto, Portugal; Faculty of Medicine of the University of Coimbra, Coimbra, Portugal.
authors.forename: Liliana R
authors.initials: LR
authors.lastname: Santos
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Machado
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Department of Endocrinology, Diabetes and Metabolism, University and Hospital Center of Coimbra, Coimbra, Portugal; Unit of Endocrinology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Melo
authors.affiliation: Department of Endocrinology, Hospital of S. João, Porto, Portugal.
authors.forename: César
authors.initials: C
authors.lastname: Esteves
authors.affiliation: Faculty of Medicine of the University of Porto, Porto, Portugal; Department of Endocrinology, Hospital of S. João, Porto, Portugal.
authors.forename: Celestino
authors.initials: C
authors.lastname: Neves
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine of the University of Porto, Porto, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sobrinho-Simões
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine of the University of Porto, Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006111:Graves Disease / Q000235:genetics*; D050031:Hashimoto Disease / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha