Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Diabetes Clinic, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.
Diabetologia. 2021 Nov;64(11):2511-2516. doi: 10.1007/s00125-021-05546-9. Epub 2021 Aug 26.
AIMS/HYPOTHESIS: We examined whether the non-HLA susceptibility locus ERBB3/IKZF4 influences progression of type 1 diabetes stage specifically according to sex.
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.
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.
目的/假设：我们研究了非 HLA 易感性基因座 ERBB3/IKZF4 是否会根据性别影响 1 型糖尿病的进展阶段。
通过等位基因区分定量 PCR 检测方法，在已出现至少一种循环自身抗体的 1 型糖尿病患者的一级亲属中筛选 ERBB3(rs2292239T/G)和 IKZF4(rs1701704G/T)的 SNP。通过 Kaplan-Meier 分析和多变量 Cox 回归研究 ERBB3/IKZF4 基因型和性别对单自身抗体阳性向多自身抗体阳性以及从多自身抗体阳性向糖尿病的进展的影响。
在自身抗体阳性的一级亲属队列中，ERBB3rs2292239(T)和 IKZF4rs1701704(G)的风险等位基因频率增加。在多自身抗体阳性阶段，男性明显过剩(p=0.021)。在 Kaplan-Meier 生存分析中，与 ERBB3TG+TT 相比，基因型 ERBB3GG 的女性参与者(p=0.018)或 IKZF4TT(p=0.023)从单抗体阳性向多抗体阳性的进展延迟，但男性参与者无此现象。在多变量 Cox 回归模型中，女性性别与 ERBB3GG(p=0.012;HR=0.305[95%CI0.120,0.773])或女性性别与 IKZF4TT(p=0.011;HR=0.329[95%CI0.140,0.777])之间的交互作用是潜在的决定因素，这些因素可导致多自身抗体向多自身抗体的进展延迟。多自身抗体阳性向 1 型糖尿病的进展似乎不受 ERBB3/IKZF4 的影响。
结论/解释：在 1 型糖尿病患者的兄弟姐妹和后代中，ERBB3/IKZF4 区域的多态性可能会影响女性个体中表位扩展的疾病进展。我们的研究结果表明，性别与 ERBB3/IKZF4 之间的相互作用可能导致 1 型糖尿病青春期后男性过剩。
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