Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, Beta cell function, ERBB3, Gender, IKZF4, Prediabetes, Prediction, Sex, SNP, Type 1 diabetes, SUSCEPTIBILITY, BETA, AGE, PROGRESSION, DISEASE, Adolescent, Adult, Autoantibodies, Autoantigens, Child, Diabetes Mellitus, Type 1, Disease Progression, Epitopes, Female, Genetic Predisposition to Disease, Humans, Ikaros Transcription Factor, Insulin, Male, Polymorphism, Single Nucleotide, Proportional Hazards Models, Real-Time Polymerase Chain Reaction, Receptor, ErbB-3, Receptor-Like Protein Tyrosine Phosphatases, Class 8, Sex Characteristics, Zinc Transporter 8, Belgian Diabetes Registry, Receptor, erbB-3, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, 1117 Public Health and Health Services, 3202 Clinical sciences, 4206 Public health

Abstract:

AIMS/HYPOTHESIS: We examined whether the non-HLA susceptibility locus ERBB3/IKZF4 influences progression of type 1 diabetes stage specifically according to sex. METHODS: SNPs of ERBB3 (rs2292239 T/G) and IKZF4 (rs1701704 G/T) were screened by allelic discrimination quantitative PCR assay in first-degree relatives of type 1 diabetes patients who had developed at least one circulating autoantibody. The effect of ERBB3/IKZF4 genotypes and sex, on the progression of single autoantibody positivity to multiple autoantibody positivity and from multiple autoantibody positivity to diabetes, was studied by Kaplan-Meier analysis and multivariate Cox regression. RESULTS: In the cohort of autoantibody-positive first-degree relatives, the risk allele frequencies for ERBB3 rs2292239 (T) and IKZF4 rs1701704 (G) were increased. There was a significant male excess at the stage of multiple autoantibody positivity (p = 0.021). In Kaplan-Meier survival analysis, progression from single to multiple antibody positivity was delayed in female participants with genotype ERBB3 GG (p = 0.018, vs ERBB3 TG+TT) or IKZF4 TT (p = 0.023, vs IKZF4 GT+GG), but not in male participants. In multivariate Cox regression models, the interaction effects between female sex and ERBB3 GG (p = 0.012; HR = 0.305 [95% CI 0.120, 0.773]) or between female sex and IKZF4 TT (p = 0.011; HR = 0.329 [95% CI 0.140, 0.777]) emerged as potential determinants of delayed progression to multiple autoantibodies. The progression from multiple autoantibody positivity to type 1 diabetes appeared not to be influenced by ERBB3/IKZF4. CONCLUSIONS/INTERPRETATION: In siblings and offspring of type 1 diabetes patients, polymorphism in region ERBB3/IKZF4 may affect disease progression at the level of epitope spreading in female individuals. Our findings suggest that interaction between sex and ERBB3/IKZF4 may contribute to the post-pubertal male excess in type 1 diabetes.