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MHC2TA Single Nucleotide Polymorphism and Genetic Risk for Autoimmune Adrenal Insufficiency

Department of Clinical Pathology and Cytology (M.G.), Karolinska University Hospital, SE-141 86 Stockholm, Sweden; Department of Internal Medicine (G.G., C.T., A.B., A.F.), Section of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, 06126 Perugia, Italy; Division of Biomedicine (K.J.), Department of Clinical Medicine, University of Örebro, SE-701 82 Örebro, Sweden; Stanford Genome Technology Center (B.G.), Stanford University, Palo Alto, California 94305; Department of Clinical and Experimental Medicine and Surgery (A.D.B.) F. Magrassi, A. Lanzara, Second University of Naples, 10-81100 Naples, Italy; Chair of Endocrinology (F.P.G.), University of Milan, Ospedale San Luca, Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico, 7–20122 Milan, Italy; Medicina Interna I (M.T.), Department of Clinical and Biological Sciences, University of Torino, ASO San Luigi, 185-10149 Orbassano, Italy; and Department of Medical and Surgical Sciences (C.B.), University of Padova, 2-35122 Padova, Italy

Address all correspondence and requests for reprints to: Alberto Falorni, M.D., Ph.D., Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, Via E. Dal Pozzo, 06126 Perugia, Italy. E-mail: falorni{at}dimisem.med.unipg.it.

Context: 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 AG single nucleotide polymorphism (rs3087456) has been suggested to confer susceptibility to some autoimmune diseases.

Design: 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.

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