MHC2TA single nucleotide polymorphism and genetic risk for autoimmune adrenal insufficiency.
BACKGROUND
The polymorphism of class II HLA genes modulates the genetic risk for several endocrine autoimmune diseases. The constitutive class II expression on antigen-presenting cells is under the control of the MHC class II transactivator, encoded by the MHC2TA gene, which is mapped to chromosome 16p13. The MHC2TA -168 A-->G single nucleotide polymorphism (rs3087456) has been suggested to confer susceptibility to some autoimmune diseases.


METHODS
With the aim of testing whether this MHC2TA single nucleotide polymorphism is independently associated with autoimmune Addison's disease (AAD) and/or modulates the genetic risk conferred by DRB1-DQA1-DQB1 haplotypes, we analyzed DNA samples from 128 AAD patients and 406 healthy control subjects from continental Italy.


RESULTS
Frequency of allele G of MHC2TA was significantly increased among AAD patients (39% alleles), compared with 29% in healthy controls (P = 0.003). Similarly, the frequency of AG+GG genotypes was significantly higher among AAD patients than among healthy control subjects, in both a codominant (P = 0.012) and a G-dominant model (P = 0.018). Multivariate logistic regression analysis showed that MHC2TA AG+GG continued to be positively associated with genetic risk for AAD (P = 0.028, odds ratio = 1.72, 95% confidence interval = 1.06-2.78), after correction for DRB1*03-DQA1*0501-DQB1*0201, DRB1*04 (not 0403)-DQA1*0301-DQB1*0302 and DRB1*0403. Similar results were obtained when the number of G alleles was included in the model (P = 0.004; odds ratio = 1.65, 95% confidence interval = 1.17-2.32).


CONCLUSIONS
Our study provides the first demonstration of the association of the polymorphism of the MHC2TA gene with genetic risk for AAD that appears to be independent from the well-known association with the polymorphism of HLA class II genes.
Ghaderi
Mehran
M
Department of Clinical Pathology and Cytology, Karolinska University Hospital, SE-141 86 Stockholm, Sweden.
Gambelunghe
Giovanni
G
Tortoioli
Cristina
C
Brozzetti
Annalisa
A
Jatta
Ken
K
Gharizadeh
Baback
B
De Bellis
Annamaria
A
Pecori Giraldi
Francesca
F
Terzolo
Massimo
M
Betterle
Corrado
C
Falorni
Alberto
A
D000293:Adolescent; D000309:Adrenal Insufficiency / Q000235:genetics*; D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases / Q000235:genetics*; D002648:Child; D005260:Female; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology
D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators