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Analysis of extended human leukocyte antigen haplotype association with Addison's disease in three populations

¹ Immunogenetics Laboratory, University of Turku, Medicity, Tykistökatu 6 A 4th, 20520 Turku, Finland² Immunogenomics Laboratory,, CellScreen Applied Biomedical Research Center, Semmelweis University, Budapest, Hungary³ Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory,, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK⁴ Immunology Group,, Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia⁵ Department of Endocrinology,, Moscow Medical Academy, Moscow, Russia⁶ Institute of Medical Technology,, University of Tampere, Tampere, Finland⁷ Molecular Pathology Group,, Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia and ⁸ Department of Clinical Microbiology,, University of Kuopio, Kuopio, Finland

(Correspondence should be addressed to Z Gombos; Email: zsogom{at}utu.fi)

Objective: Addison's disease is an organ-specific autoimmune disorder with a polygenic background. The aim of the study was to identify non-class II human leukocyte antigen (HLA) susceptibility genes for Addison's disease.

Design and methods: Addison's disease patients from three European populations were analysed for selected HLA–DR–DQ alleles and for 11 microsatellite markers covering 4 Mb over the HLA region. Subjects were 69 patients with Addison's disease from Estonia (24), Finland (14) and Russia (31). Consecutively recruited healthy newborns from the same geographical regions were used as controls (269 Estonian, 1000 Finnish and 413 Russian). Association measures for HLA–DRB1, DQB1, DQA1 and 11 microsatellites between D6S273 and D6S2223 were taken. A low-resolution full-house typing was used for HLA class II genes, while microsatellite markers were studied using fluorescence-based DNA fragment sizing technology.

Results: We confirmed that the HLA–DR3–DQ2 and the DQB1*0302–DRB1*0404 haplotypes confer disease susceptibility. In Russian patients, we also found an increase of DRB1*0403 allele, combined with DQB1*0305 allele in three out of six cases (P<0.0001). Analysis of 11 microsatellite markers including STR MICA confirmed the strong linkage in DR3–DQ2 haplotypes but DRB1*0404–DQB1*0302 haplotypes were diverse. MICA5.1 allele was found in 22 out of 24 Estonian patients, but results from Finnish and Russian patients did not support its independent role in disease susceptibility.

Conclusion: HLA–DRB1*0403 was identified as a novel susceptibility allele for Addison's disease. Additionally, we found no evidence of a non-class II HLA disease susceptibility locus; however, the HLA–DR3–DQ2 haplotype appeared more conserved in patient groups with high DR–DQ2 frequencies.