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Absolute Risk of Childhood-Onset Type 1 Diabetes Defined by Human Leukocyte Antigen Class II Genotype: A Population-Based Study in the United Kingdom

Division of Medicine (A.P.L., K.M.G., E.A.M.G., P.J.B.), University of Bristol, Bristol BS10 5NB, United Kingdom; Department of Integrative Biology (G.T.), University of California, Berkeley, California 94720-3140; and Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory (H.J.C., J.A.T.), Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, United Kingdom

Address all correspondence and requests for reprints to: Prof. Polly Bingley, Diabetes and Metabolism, Medical School Unit, Southmead Hospital, Bristol BS10 5NB, United Kingdom. E-mail: Polly.Bingley{at}bristol.ac.uk.

The autoimmune disease process leading to childhood-onset type 1 diabetes appears to start in infancy, and decisions on treatment to prevent initiation of autoimmunity will need to be based on genetic susceptibility alone. We set out to quantify the absolute risk associated with human leukocyte antigen (HLA) DRB1-DQA1-DQB1 class II genotypes and to develop strategies for recruitment into primary prevention trials. HLA class II haplotype- and genotype-specific risks were derived from 753 United Kingdom families from the Bart’s-Oxford population-based study of type 1 diabetes and combined with incidence data from the region to calculate the absolute risk of development of diabetes. A hierarchy of susceptibility was established for both HLA class II haplotypes and genotypes, and the sensitivity and specificity of each genotype was established relative to age at disease onset. Highest risk was conferred by the genotype DRB1*03-DQA1*0501-DQB1*0201/DRB1*0401-DQA1*0301-DQB1*0302 (5% absolute risk of diabetes by age 15 yr), although sensitivity was only 22.6%. Combining the six highest risk genotypes conferred similar risk but increased sensitivity to 36.6% and was most sensitive for diagnosis of diabetes before age 5 yr (48.4%), whereas inclusion of 11 genotypes achieved the same sensitivity for diagnosis for ages 10–14 yr. Analysis of genotype-specific risk should form the basis for design of future primary prevention trials in the general population.

This work was supported by the Wellcome Trust, by Diabetes UK, and by the Juvenile Diabetes Research Foundation. G.T. is funded by the National Institutes of Health (Grant NIH GM35326).

Abbreviations: AFBAC, Affected family-based control; AUC, area under the curve; BOX, Bart’s-Oxford; HLA, human leukocyte antigen; PC, ratio of haplotype and genotype frequencies in patients and controls; ROC, receiver-operator characteristic.

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