Non-HLA Risk Loci ERBB3/IKZF4 and ERBB2/IKZF3/GSDMB/ORMDL3 Interact to Influence Progression of Autoimmunity in...

The genetic loci, ERBB2/IKZF3/GSDMB/ORMDL3 on chromosome 17q, and ERBB3/IKZF4 on chromosome 12q represent confirmed non-HLA risk factors for the development of autoimmunity and progression to type 1 diabetes (T1D). It is unknown whether both regions can interact to influence the progression of T1D. Given the known molecular cooperation between ERBB2 and ERBB3 receptors in regulating cell function, we explored the hypothesis of a potential T1D risk-interaction of these regions.

Quantitative PCR TaqMan genotyping was used to screen five novel SNPs in addition to the previously studied rs2941522 within the ERBB2/IKZF3/GSDMB/ORMDL3 region in 462 first-degree relatives of T1D patients who were positive for at least one circulating islet autoantibody. We used Kaplan-Meier survival and multivariable Cox regression analysis to investigate the effect of the SNP genotypes and their potential interaction with rs2292239 of ERBB3/IKZF4 on progression from single to multiple autoantibody-positivity, and from thereon to type 1 diabetes onset. Allele and genotype patterns were analysed by Pearson correlation and chi-square test.

The six SNPs within ERBB2/IKZF3/GSDMB/ORMDL3 all influenced the progression from single to multiple autoantibody-positivity through interaction with ERBB3 rs2292239 in Cox regression (p = 0.006-0.013). The genotype of three SNPs located near ERBB2 within ERBB2/IKZF3/GSDMB/ORMDL3 correlated significantly (p = 0.003) with the ERBB3 rs2292239 genotype in our study population. None of the observed interaction effects played a role in the progression from multiple autoantibody-positivity to T1D.

Two distant non-HLA loci containing ERBB3 and ERBB2 interact to influence the progression of autoimmunity in T1D, which involves genotype correlations within the risk population.