caa a22 4500 475772288 CHVBK 20180406123620.0 cr unu---uuuuu 170329e20000401xx s 000 0 eng 10.1007/s001250051336 doi (NATIONALLICENCE)springer-10.1007/s001250051336 Association of MHC Class I chain-related A (MIC-A) gene polymorphism with Type I diabetes [Elektronische Daten] [G. Gambelunghe, M. Ghaderi, A. Cosentino, Ad. Falorni, P. Brunetti, Al. Falorni, C. B. Sanjeevi] Aims/hypothesis. A distinct family of MHC genes has been identified in the class III region and denominated MHC Class I chain-related genes (MIC). The MIC-A gene is located between the TNFA and the HLA-B genes. The aim of our study was to test the association of the polymorphism of the MIC-A gene with Type I (insulin-dependent) diabetes mellitus and evaluate the interaction between MIC-A and TNFA, HLA-B, HLA-DR and HLA-DQ gene polymorphism.¶Methods. Type I diabetic (n = 95) and healthy (n = 98) Italian subjects were typed for exon 5 of MIC-A and for HLA-DRB1, HLA-DQA1, HLA-DQB1 and TNFA alleles. All subjects were also typed for the presence of HLA-B8 or HLA-B15.¶Results. The frequency of MIC-A5 was increased in diabetic subjects (53 % vs 15 %) (OR = 6.1) (corrected p, p c < 0.0005). Among HLA class II haplotypes, both HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) ("at-risk class II haplotypes”) were positively associated with diabetes (OR = 6.7 and 6.0, respectively) (p c < 0.003). Also HLA-B8 was more frequent among Type I diabetic subjects than among healthy control subjects (OR = 2.8, p = 0.01). None of the TNFA alleles were statistically significantly associated with Type I diabetes. The MIC-A5 exon was negatively associated with age at clinical onset of diabetes (p = 0.012). Thus, 68 % diabetic subjects younger than 25 years and 29 % older than 25 years were carrying this allele. Both MIC-A5 and the at-risk class II haplotypes were independently associated with Type I diabetes and the combined association of the two markers had the highest relative risk (OR = 172). In subjects younger than 25 years, the OR of MIC-A5 was as high as 21.7 and was more than twofold that of at-risk class II haplotypes (OR = 9.5). The MIC-A5 exon was not in linkage disequilibrium with any of the HLA-class I, class II or TNFA alleles studied.¶Conclusions/interpretation. The MIC-A gene polymorphism is associated with genetic risk for Type I diabetes and the combination of MIC-A5 and at-risk class II haplotypes is now to be seen as the strongest genetic marker for this disease. [Diabetologia (2000) 43: 507-514] Springer-Verlag Berlin Heidelberg, 2000 Keywords Autoimmunity, genetic risk, HLA, insulin-dependent diabetes, major histocompatibility complex, TNFA gene nationallicence Gambelunghe G. Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden, SE aut Ghaderi M. Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden, SE aut Cosentino A. Department of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Italy, IT aut Falorni Ad Department of Gynaecology, Obstetrics and Paediatric Sciences, University of Perugia, Italy, IT aut Brunetti P. Department of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Italy, IT aut Falorni Al Department of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Italy, IT aut Sanjeevi C. B. Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden, SE aut https://doi.org/10.1007/s001250051336 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s001250051336 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gambelunghe G. Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden, SE aut NATIONALLICENCE 700 1- Ghaderi M. Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden, SE aut NATIONALLICENCE 700 1- Cosentino A. Department of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Italy, IT aut NATIONALLICENCE 700 1- Falorni Ad Department of Gynaecology, Obstetrics and Paediatric Sciences, University of Perugia, Italy, IT aut NATIONALLICENCE 700 1- Brunetti P. Department of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Italy, IT aut NATIONALLICENCE 700 1- Falorni Al Department of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Italy, IT aut NATIONALLICENCE 700 1- Sanjeevi C. B. Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden, SE aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer