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

Vandewalle, Julie; Auwera, Bart J. Van der; Amin, Henna; Quartier, Erik; Desouter, Aster; Tenoutasse, Sylvie; Gillard, Pieter; Block, Christophe De; Keymeulen, Bart; Gorus, Frans; Casteele, Mark Van de

doi:10.1007/s00125-021-05546-9

Cited by 6 publications

(8 citation statements)

References 15 publications

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“…However, the exact mechanism of how these differences would affect the risk of T1D remains unclear. Interestingly, a recent paper from the Belgian Diabetes Registry described that ERBB3/IKZF4 risk alleles increased the progression from single to multiple AABs, but this was seen only in female relatives ( 41 ). Alleged multiple independent effects emphasize the possibility of the importance of the IKZF4 gene, which encodes the Eos molecule, which in turn in mouse models seems to be important for T-reg cell functions and suppression of autoimmunity ( 42 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects

et al. 2022

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The non-HLA loci conferring susceptibility to type 1 diabetes determine approximately half of the genetic disease risk, and several of them have been shown to affect immune-cell or pancreatic β-cell functions. A number of these loci have shown associations with the appearance of autoantibodies or with progression from seroconversion to clinical type 1 diabetes. In the current study, we have re-analyzed 21 of our loci with prior association evidence using an expanded DIPP follow-up cohort of 976 autoantibody positive cases and 1,910 matched controls. Survival analysis using Cox regression was applied for time periods from birth to seroconversion and from seroconversion to type 1 diabetes. The appearance of autoantibodies was also analyzed in endotypes, which are defined by the first appearing autoantibody, either IAA or GADA. Analyzing the time period from birth to seroconversion, we were able to replicate our previous association findings at PTPN22, INS, and NRP1. Novel findings included associations with ERBB3, UBASH3A, PTPN2, and FUT2. In the time period from seroconversion to clinical type 1 diabetes, prior associations with PTPN2, CD226, and PTPN22 were replicated, and a novel association with STAT4 was observed. Analyzing the appearance of autoantibodies in endotypes, the PTPN22 association was specific for IAA-first. In the progression phase, STAT4 was specific for IAA-first and ERBB3 to GADA-first. In conclusion, our results further the knowledge of the function of non-HLA risk polymorphisms in detailing endotype specificity and timing of disease development.

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Section: Discussionmentioning

confidence: 99%

Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects

et al. 2022

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“…Next, a combined Cox model was constructed for the immune activation stage, starting from a base model including 3 main variables: age at first autoAb positivity, HLA-DQ2/DQ8 and HLA-A*24. Identified interaction effects and the previously reported protective interaction effect between female sex and ERBB3 GG [10] were added to this model in a conditional forward approach. The goodness of fit of the models was tested using the Akaike information criterion (AIC), which represents an estimate of information not explained by the model and includes a penalty for the number of variables [23].…”

Section: Statistical Analysesmentioning

confidence: 99%

“…How these non-HLA loci modulate disease progression, is not yet fully understood. However, there are indications that at least some non-HLA polymorphisms may have a relatively large impact in specific subgroups and disease stages in time-to-event analysis [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, once the stage of multiple autoAb positivityconsidered to represent asymptomatic type 1 diabetes [16,17] -is reached, the progression rate towards clinical onset is mainly influenced by HLA class I-inferred risk and the presence of autoAbs directed against IA-2 (IA-2A) and/or zinc transporter 8 (ZnT8A) [13]. Our group previously reported statistical models built by Cox regression to predict progression through both these stages [10,12].…”

Section: Introductionmentioning

confidence: 99%

“…This may help to better understand mechanisms underlying disease progression, and to identify those subjects who are at the highest risk of entering the next disease stage and likely to benefit most from participation in novel stage-specific prevention trials. We therefore selected 8 SNPs in non-HLA loci (INS, SH2B3, PTPN2, PTPN22, CTLA4, CLEC16A and IL2RA) to be tested on a cohort of Belgian autoAb + FDRs under 40 years of age [10]. This selection was based on the relatively high odds ratios for type 1 diabetes in several GWAS [3].…”

Section: Introductionmentioning

confidence: 99%

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CTLA4,SH2B3, andCLEC16Adiversely affect the progression of early islet autoimmunity in relatives of Type 1 diabetes patients

Vandewalle

Desouter

Auwera

et al. 2023

Clinical and Experimental Immunology

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The HLA region is the major genetic risk determinant of type 1 diabetes. How non-HLA loci contribute to the genetic risk is incompletely understood, but there are indications that at least some impact progression of asymptomatic autoimmunity. We examined whether SNPs in 7 susceptibility loci (INS, SH2B3, PTPN2, PTPN22, CTLA4, CLEC16A and IL2RA) could improve prediction of the progression from single to multiple autoantibody positivity, and from there on to diagnosis. SNPs were genotyped in persistently autoantibody positive relatives by allelic discrimination qPCR and disease progression was studied by multivariate Cox regression analysis. In our cohort, only the CTLA4 GA genotype (rs3087243, p=0.002) and the CLEC16A AA genotype (rs12708716, p=0.021) were associated with accelerated progression from single to multiple autoantibody positivity, but their effects were restricted to presence of HLA-DQ2/DQ8, and IAA as first autoantibody, respectively. The interaction of CTLA4 and HLA-DQ2/DQ8 overruled the effect of DQ2/DQ8 alone. The HLA-DQ2/DQ8-mediated risk of progression to multiple autoantibodies nearly entirely depended on heterozygosity for CTLA4. The SH2B3 TT genotype (rs3184504) was protective for HLA-DQ8 positive subjects (p=0.003). At the stage of multiple autoantibodies, only the CTLA4 GA genotype was a minor independent risk factor for progression towards clinical diabetes (p=0.034). Our study shows that non-HLA polymorphisms impact progression of islet autoimmunity in a subgroup-, stage- and SNP-specific way, suggesting distinct mechanisms. If confirmed, these findings may help refine risk assessment, follow-up, and prevention trials in risk groups.

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Epitope Spreading in Autoimmune Diseases

Venkatesha,

Durai,

Moudgil

2024

Infection and Autoimmunity

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

Cited by 6 publications

References 15 publications

Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects

Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects

CTLA4,SH2B3, andCLEC16Adiversely affect the progression of early islet autoimmunity in relatives of Type 1 diabetes patients

Epitope Spreading in Autoimmune Diseases

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