title: Interaction of HLA-DRB1 alleles with CTLA-4 in the predisposition to Graves' disease: the impact of DRB1*07.
abstract: OBJECTIVE
  To study interactions between the two most widely confirmed Graves' disease (GD) loci: HLA-DRB1 and CTLA-4. HLA-DRB1*03 (risk allele) and DRB1*07 (protective allele) were analyzed in this aspect, the linked TNF G(-308)A polymorphism was also considered.
  
  
  METHODS
  A case-control study of 429 patients with GD compared to 308 healthy subjects. The impact of genes and their interactions were analyzed by stepwise logistic regression.
  
  
  RESULTS
  The independent effects of DRB1*03 and DRB1*07 were confirmed in our study both by stratification studies and logistic regression. CTLA-4 did not appear to be associated with GD when the interactions with other genes were considered. By logistic regression we observed a significant interaction between DRB1*07 and CTLA-4 and revealed that CTLA-4 49G attenuated the DRB1*07-related protection, the effect noticed also in three-way stratification studies. We confirmed that the TNF G(-308)A polymorphism is only a marker of the DRB1 status.
  
  
  CONCLUSIONS
  Our results stress the importance of complex gene interactions in the multigene predisposition to GD. The interactions between two predisposing loci, DRB1 and CTLA-4, are exerted rather by DRB1*07 than DRB1*03 allele: CTLA-4 acts via switching off the protective DRB1*07 influence, whereas the effect of DRB1*03 is independent.
authors.affiliation: Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Branch, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kula
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bednarczuk
authors.forename: Beata
authors.initials: B
authors.lastname: Jurecka-Lubieniecka
authors.forename: Joanna
authors.initials: J
authors.lastname: Polanska
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hasse-Lazar
authors.forename: Michal
authors.initials: M
authors.lastname: Jarzab
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Steinhof-Radwanska
authors.forename: Beata
authors.initials: B
authors.lastname: Hejduk
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Zebracka
authors.forename: Alina
authors.initials: A
authors.lastname: Kurylowicz
authors.forename: Ewa
authors.initials: E
authors.lastname: Bar-Andziak
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stechly
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Pawlaczek
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Gubala
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Krawczyk
authors.forename: Sylwia
authors.initials: S
authors.lastname: Szpak-Ulczok
authors.forename: Janusz
authors.initials: J
authors.lastname: Nauman
authors.forename: Barbara
authors.initials: B
authors.lastname: Jarzab
mesh_terms: D000328:Adult; D000483:Alleles; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D005260:Female; D020022:Genetic Predisposition to Disease; D006111:Graves Disease / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012306:Risk
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C456920:HLA-DRB1*07 antigen