ArticleDiabetologia2021
Genetic variation at ERBB3/IKZF4 and sexual dimorphism in epitope spreading in single autoantibody-positive relatives.
Article in Diabetologia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 9 citations in OpenAlex.
- The stage- and subgroup-specific impact of non-HLA polymorphisms on preclinical type 1 diabetes progression.Heliyon · 2025Article
- CTLA4, SH2B3, and CLEC16A diversely affect the progression of early islet autoimmunity in relatives of Type 1 diabetes patients.Clinical and experimental immunology · 2023Article
- Review
- Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects.Frontiers in immunology · 2022Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisWe examined whether the non-HLA susceptibility locus ERBB3/IKZF4 influences progression of type 1 diabetes stage specifically according to sex.
methodsSNPs 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.
resultsIn 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/
interpretationIn 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.
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