Interaction of HLA-DRB1 alleles with CTLA-4 in the predisposition to Graves' disease: the impact of DRB1*07.
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.
Kula
Dorota
D
Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Branch, Poland.
Bednarczuk
Tomasz
T
Jurecka-Lubieniecka
Beata
B
Polanska
Joanna
J
Hasse-Lazar
Kornelia
K
Jarzab
Michal
M
Steinhof-Radwanska
Katarzyna
K
Hejduk
Beata
B
Zebracka
Jadwiga
J
Kurylowicz
Alina
A
Bar-Andziak
Ewa
E
Stechly
Tomasz
T
Pawlaczek
Agnieszka
A
Gubala
Elzbieta
E
Krawczyk
Aleksandra
A
Szpak-Ulczok
Sylwia
S
Nauman
Janusz
J
Jarzab
Barbara
B
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
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