Genetic susceptibility to type 1 diabetes in childhood - estimation of HLA class II associated disease risk and class II effect in various phases of islet autoimmunity

: Ilonen J, Kiviniemi M, Lempainen J, Simell O, Toppari J, Veijola R, Knip M

Publisher: WILEY-BLACKWELL

: 2016

: Pediatric Diabetes

: Pediatr Diabetes

: PEDIATRIC DIABETES

: PEDIATR DIABETES

: 17

: S22

: 8

: 16

: 9

: 1399-543X

: 1399-5448

DOI: https://doi.org/10.1111/pedi.12327

: https://www.ncbi.nlm.nih.gov/pubmed/27411431

Objective: The HLA-DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside human leukocyte antigen (HLA) region that have been identified. We aimed at developing a simple risk estimation based on HLA class II genotyping, which was also tested by analyzing HLA class II effect on the autoantibody seroconversion and further progression to diabetes.Subjects and methods: A total of 2991 trio families with a diabetic child from the Finnish Pediatric Diabetes Register were genotyped and the risk contributed by each DR-DQ haplotype calculated through transmission analysis. The genotype risk was estimated based on the summary effect of haplotypes. Genotype grouping was further tested in a subcohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) StudyResults: The summary effect of haplotypes was generally seen in genotypes, while the expected synergistic effect of DR3-DQ2 and DR4-DQ8 (DRB1*04:03 excluded) combination was also clear in the T1D risk association analysis. This highest risk DR/DQ genotype was found in 21.6% of patients and 2.0% of controls, odds ratio (OR) = 13.2 (10.1-17.2), whereas the lowest risk genotype contained only 0.8% of patients and 28.0% of controls, OR = 0.02 (0.01-0.03). In the subcohort from the DIPP study the risk grades correlated clearly with seroconversion for islet autoantibodies and T1D development. In contrast, DR/DQ risk groups did not associate with the progression rate from advanced autoimmunity to clinical diabetes.Conclusions: Class II HLA genotype groups improve the estimation of T1D risk. Class II effect is limited to the early phase of the disease process characterized by seroconversion for islet autoantibodies.