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*Diabetes
*Diabetes Type 1
The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 574-582
Copyright © 2001 by The Endocrine Society

Original Studies

Possible Human Leukocyte Antigen-Mediated Genetic Interaction between Type 1 and Type 2 Diabetes1

Haiyan Li, Eero Lindholm, Peter Almgren, Åsa Gustafsson, Carol Forsblom, Leif Groop and Tiinamaija Tuomi

Diabetes and Endocrine Research Laboratory (H.L., E.L., P.A., Å.G., L.G., T.T.), Department of Endocrinology, Lund University, S-20502 Malmö, Sweden; and Department of Internal Medicine (C.F., T.T.), Helsinki University Central Hospital, FIN-00029 Helsinki, Finland

Address all correspondence and requests for reprints to: Dr. Tiinamaija Tuomi, Wallenberg Laboratory, Department of Endocrinology, Lund University, S-20502 Malmö, Sweden.

We assessed the prevalence of families with both type 1 and type 2 diabetes in Finland; and we studied, in patients with type 2 diabetes, the association between a family history of type 1 diabetes, glutamic acid decarboxylase (GAD) antibodies (GADab), and type 1 diabetes-associated human leukocyte antigen (HLA) DQB1-genotypes. Further, in mixed type 1/type 2 diabetes families, we investigated whether sharing an HLA haplotype with a family member with type 1 diabetes influenced the manifestation of type 2 diabetes. Among 695 families ascertained through the presence of more than 1 patient with type 2 diabetes, 100 (14%) also had members with type 1 diabetes. Type 2 diabetic patients from the mixed families had, more often, GADab (18% vs. 8%, P < 0.0001) and DQB1*0302/X genotype (25% vs. 12%, P = 0.005) than patients from families with only type 2 diabetes; but they had a lower frequency of DQB1*02/0302 genotype, compared with adult-onset type 1 patients (4% vs. 27%, P < 0.0001). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared with patients without such haplotypes (P = 0.016). This finding was independent of the presence of GADab.

We conclude that type 1 and type 2 diabetes cluster in the same families. A shared genetic background with a patient with type 1 diabetes predisposes type 2 diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. The findings support a possible genetic interaction between type 1 and type 2 diabetes mediated by the HLA locus.




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