This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pugliese, A. Articles by Eisenbarth, G. S. Search for Related Content PubMed PubMed Citation Articles by Pugliese, A. Articles by Eisenbarth, G. S.

Sequence Analysis of the Diabetes-Protective Human Leukocyte Antigen-DQB1¹0602 Allele in Unaffected, Islet Cell Antibody-Positive First Degree Relatives and in Rare Patients with Type 1 Diabetes^,1

Diabetes Research Institute (A.P., M.Z., C.R.) and the Department of Neurology (C.T.M.), University of Miami School of Medicine, Miami, Florida 33136; the First Department of Internal Medicine, Nagasaki University School of Medicine (E.K.), Nagasaki, Japan; the Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center (E.K., L.Y., S.B., G.S.E.), Denver, Colorado 80262; the Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine (M.S.), New Haven, Connecticut 06510; the Division of Immunogenetics, Children’s Hospital of Pittsburgh, University of Pittsburgh (M.P., R.P.F., M.T.), Pittsburgh, Pennsylvania 15213; the Human Genetics Department, Roche Molecular Systems (M.A., J.A.N.), Alameda, California 94501; and the Children’s Hospital Oakland Research Institute (J.A.N., H.A.E.), Oakland, California 94609

Address all correspondence and requests for reprints to: Alberto Pugliese, M.D., Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue, Miami, Florida 33136. E-mail: apuglies{at}mednet.med.miami.edu

The human leukocyte antigen (HLA)-DQA1*0102/DQB1*0602/DRB1*1501 (DR2) haplotype confers strong protection from type 1 diabetes. Growing evidence suggests that such protection may be mostly encoded by the DQB1*0602 allele, and we reported that even first degree relatives with islet cell antibodies (ICA) have an extremely low diabetes risk if they carry DQB1*0602. Recently, novel variants of the DQB1*0602 and *0603 alleles were reported in four patients with type 1 diabetes originally typed as DQB1*0602 with conventional techniques. One inference from this observation is that DQB1*0602 may confer absolute protection and may never occur in type 1 diabetes. By this hypothesis, all patients typed as DQB1*0602 positive with conventional techniques should carry one of the above diabetes-permissive variants instead of the protective DQB1*0602. Such variants could also occur in ICA/DQB1*0602-positive relatives, with the implication that their diabetes risk could be significantly higher than previously estimated. We therefore sequenced the DQB1*0602 and DQA1*0102 alleles in all ICA/DQB1*0602-positive relatives (n = 8) previously described and in six rare patients with type 1 diabetes and DQB1*0602. We found that all relatives and patients carry the known DQB1*0602 and DQA1*0102 sequences, and none of them has the mtDNA A3243G mutation associated with late-onset diabetes in ICA-positive individuals. These findings suggest that diabetes-permissive DQB1*0602/3 variants may be very rare. Thus, although the protective effect associated with DQB1*0602 is extremely powerful, it is not absolute. Nonetheless, the development of diabetes in individuals with DQB1*0602 remains extremely unlikely, even in the presence of ICA, as confirmed by our further evaluation of ICA/DQB1*0602-positive relatives, none of whom has yet developed diabetes.

This article has been cited by other articles:

				M. J. Redondo, S. Babu, A. Zeidler, T. Orban, L. Yu, C. Greenbaum, J. P. Palmer, D. Cuthbertson, G. S. Eisenbarth, J. P. Krischer, et al. Specific Human Leukocyte Antigen DQ Influence on Expression of Antiislet Autoantibodies and Progression to Type 1 Diabetes J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1705 - 1713. [Abstract] [Full Text] [PDF]

				F. A. Al-Jenaidi, S. F. Wakim-Ghorayeb, A. Al-Abbasi, M. R. Arekat, N. Irani-Hakime, P. Najm, K. Al-Ola, A. A. Motala, and W. Y. Almawi Contribution of Selective HLA-DRB1/DQB1 Alleles and Haplotypes to the Genetic Susceptibility of Type 1 Diabetes among Lebanese and Bahraini Arabs J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5104 - 5109. [Abstract] [Full Text] [PDF]

				E. L. Edghill, A. L. Gloyn, K. M. Gillespie, A. P. Lambert, N. T. Raymond, P. G. Swift, S. Ellard, E. A.M. Gale, and A. T. Hattersley Activating Mutations in the KCNJ11 Gene Encoding the ATP-Sensitive K+ Channel Subunit Kir6.2 Are Rare in Clinically Defined Type 1 Diabetes Diagnosed Before 2 Years Diabetes, November 1, 2004; 53(11): 2998 - 3001. [Abstract] [Full Text] [PDF]

				E. M. Al-Harbi, A.-J. Abbassi, H. Tamim, F. al-Jenaidi, M. Kooheji, M. Kamal, S. al-Mahroos, F. al-Nasir, A. A. Motala, and W. Y. Almawi Specific HLA-DRB and -DQB Alleles and Haplotypes Confer Disease Susceptibility or Resistance in Bahraini Type 1 Diabetes Patients Clin. Vaccine Immunol., March 1, 2004; 11(2): 292 - 296. [Abstract] [Full Text] [PDF]

				M A Kelly, M L Rayner, C H Mijovic, and A H Barnett Molecular aspects of type 1 diabetes Mol. Pathol., February 1, 2003; 56(1): 1 - 10. [Abstract] [Full Text] [PDF]

				J. P. Krischer, D. D. Cuthbertson, L. Yu, T. Orban, N. Maclaren, R. Jackson, W. E. Winter, D. A. Schatz, J. P. Palmer, and G. S. Eisenbarth Screening Strategies for the Identification of Multiple Antibody-Positive Relatives of Individuals with Type 1 Diabetes J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 103 - 108. [Abstract] [Full Text] [PDF]

				G. Stenstrom, B. Berger, H. Borg, P. Fernlund, J. S. Dorman, and G. Sundkvist HLA-DQ Genotypes in Classic Type 1 Diabetes and in Latent Autoimmune Diabetes of the Adult Am. J. Epidemiol., November 1, 2002; 156(9): 787 - 796. [Abstract] [Full Text] [PDF]

				L. Yu, D. D. Cuthbertson, N. Maclaren, R. Jackson, J. P. Palmer, T. Orban, G. S. Eisenbarth, and J. P. Krischer Expression of GAD65 and Islet Cell Antibody (ICA512) Autoantibodies Among Cytoplasmic ICA+ Relatives Is Associated With Eligibility for the Diabetes Prevention Trial-Type 1 Diabetes, August 1, 2001; 50(8): 1735 - 1740. [Abstract] [Full Text] [PDF]

				C. J. Greenbaum, D. A. Schatz, D. Cuthbertson, A. Zeidler, G. S. Eisenbarth, and J. P. Krischer Islet Cell Antibody-Positive Relatives with Human Leukocyte Antigen DQA10102, DQB10602: Identification by the Diabetes Prevention Trial-Type 1 J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1255 - 1260. [Abstract] [Full Text]