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. 2021 Nov;64(11):2511-2516.
doi: 10.1007/s00125-021-05546-9. Epub 2021 Aug 26.

Genetic variation at ERBB3/IKZF4 and sexual dimorphism in epitope spreading in single autoantibody-positive relatives

Julie Vandewalle  1 , Bart J Van der Auwera  1 , Henna Amin  1 , Erik Quartier  1 , Aster K Desouter  1   2 , Sylvie Tenoutasse  3 , Pieter Gillard  1   2   4 , Christophe De Block  5 , Bart Keymeulen  1   2 , Frans K Gorus  1   2 , Mark Van de Casteele  6 ; Belgian Diabetes Registry
Affiliations

Genetic variation at ERBB3/IKZF4 and sexual dimorphism in epitope spreading in single autoantibody-positive relatives

Julie Vandewalle et al. Diabetologia. 2021 Nov.

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.

Keywords: Beta cell function; ERBB3; Gender; IKZF4; Prediabetes; Prediction; SNP; Sex; Type 1 diabetes.

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Figures

Fig. 1
Fig. 1
Sex-specific effect of ERBB3 and IKZF4 on the development of multiple autoAbs. Kaplan–Meier survival plots for conversion from single to multiple autoAb positivity according to presence (red line) or absence (blue line) of at least one risk allele for ERBB3-rs2292239 (a, c) or IKZF4-rs1701704 (b, d) in either female (a, b) or male (c, d) FDRs. For each arm the genotype and number (events/cases) are indicated above the graph. The numbers of individuals at risk are indicated below the x-axis. Significant effects (p<0.05) were observed for ERBB3 and IKZF4 in female participants, but not in male participants
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References

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