Possible human leukocyte antigen-mediated genetic interaction between type1 and type 2 diabetes

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 associat ion between a family history of type 1 diabetes, glutamic acid decarboxylas e (GAD) antibodies (GADab), and type 1 diabetes-associated human leukocyte antigen (HLA) DQB1-genotypes. Further, in mixed type 1/type 2 diabetes fami lies, we investigated whether sharing an HLA haplotype with a family member with type 1 diabetes influenced the manifestation of type 2 diabetes. Amon g 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 d iabetic 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 patien ts 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 gluc ose load was impaired in patients who had HLA class II risk haplotypes, eit her DR3(17)DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared wi th patients without such haplotypes (P = 0.016). This finding was independe nt 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.