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HLA Genotyping Supports a Nonautoimmune Etiology in Patients Diagnosed With Diabetes Under the Age of 6 Months

¹ Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
² Department of Clinical Science at North Bristol, University of Bristol, Bristol, U.K

Address correspondence and reprint requests to Dr. K.M. Gillespie, Medical School Unit, Southmead Hospital, Bristol BS10 5NB, U.K. E-mail: k.m.gillespie{at}bristol.ac.uk

Abbreviations: PNDM, permanent neonatal diabetes

Children with permanent diabetes are usually assumed to have type 1 diabetes. It has recently been shown that there are genetic subgroups of diabetes that are often diagnosed during the neonatal period but may present later. A recent Italian study proposed that type 1 diabetes is rare before 6 months of age. We aimed to examine genetic susceptibility to type 1 diabetes in patients diagnosed with diabetes before the age of 2 years. We analyzed HLA class II genotypes, markers of autoimmune diabetes, in 187 children with permanent diabetes diagnosed at <2 years of age. Of the 79 subjects diagnosed at <6 months of age, 41% (95% CI 0.30–0.51) had type 1 diabetes–associated high-risk genotypes, a proportion similar to that in healthy population control subjects (44%, P = 0.56). This group included 32 patients with mutations in the KCNJ11 gene, which encodes Kir6.2 (44% high-risk HLA class II genotypes), and 47 in whom the etiology of diabetes was unknown (38% high-risk HLA class II genotypes). Of 108 patients diagnosed between 6 and 24 months of age, 93% (0.86–0.99) had high-risk HLA class II genotypes compared with 44% of the population control subjects (P < 0.0001). We conclude that infants diagnosed with diabetes before 6 months of age are unlikely to have autoimmune type 1 diabetes and are most likely to have a monogenic etiology.

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