title: The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease.
abstract: BACKGROUND
  Despite great progress, the genetic basis of Graves' disease (GD) remains poorly understood. Recently, a population-based genomewide association study (GWAS) identified five novel loci (ATXN2/SH2B3, MAGI3, BACH2, TPO and KALRN) as significantly associated with the presence of thyroid peroxidase autoantibodies (TPOAbs), whereas several other loci showed suggestive association.
  
  
  METHODS
  In this study, we investigated 16 single nucleotide polymorphisms (SNPs) associated with TPOAbs for the association with susceptibility to and phenotype of GD in a cohort of 647 patients with GD and 769 controls from a Polish Caucasian population.
  
  
  RESULTS
  SNPs within/near HCP5 (rs3094228, P = 1·6 × 10(-12) , OR = 1·88), MAGI3 (rs1230666, P = 1·9 × 10(-5) , OR = 1·51) and ATXN2/SH2B3 (rs653178, P = 0·0015, OR = 1·28) loci were significantly associated with susceptibility to GD. Allele frequencies differed significantly in subgroups of patients with GD stratified by age of GD onset for HCP5 (P = 0·0014, OR = 1·50) and showed a suggestive difference for MAGI3 (P = 0·0035, OR = 1·50) SNPs. Although rs11675434 located near TPO showed no association with GD susceptibility, it was significantly associated with the presence of clinically evident Graves' ophthalmopathy (GO, P = 5·2 × 10(-5) , OR = 1·64), and this effect was independent from smoking status, age of GD onset and gender.
  
  
  CONCLUSIONS
  This is the first study showing an association of the ATXN2/SH2B3 locus with susceptibility to GD. Furthermore, we observed a novel significant association within the HLA region at a SNP located near HCP5 and confirmed the association of the MAGI3 locus with GD susceptibility. HCP5 and MAGI3 SNPs were further correlated with age of GD onset. Finally, we identified TPO as a new susceptibility locus for GO.
authors.affiliation: Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Kuś
authors.affiliation: Department of Medical Genetics, Centre for Biostructure, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Konrad
authors.initials: K
authors.lastname: Szymański
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
authors.affiliation: Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Miśkiewicz
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.|Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.|Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pistis
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Naitza
authors.affiliation: Department of Medical Genetics, Centre for Biostructure, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Płoski
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Medici
authors.affiliation: Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bednarczuk
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000235:genetics*; D001324:Autoantigens / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006111:Graves Disease / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007453:Iodide Peroxidase / Q000276:immunology*; D033862:Iron-Binding Proteins / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D033862:Iron-Binding Proteins; C056658:TPO protein, human; D007453:Iodide Peroxidase