Hagopian William, Lee Hye-Seung, Liu Edwin, Rewers Marian, She Jin-Xiong, Ziegler Anette-G, Lernmark Åke, Toppari Jorma, Rich Stephen S, Krischer Jeffrey P, Erlich Henry, Akolkar Beena, Agardh Daniel
Diabetes Programs Division, Pacific Northwest Research Institute, Seattle, Washington;
Department of Pediatrics, Health Informatics Institute, University of South Florida, Tampa, Florida.
Pediatrics. 2017 Nov;140(5). doi: 10.1542/peds.2017-1305. Epub 2017 Oct 10.
Few birth cohorts have prospectively followed development of type 1 diabetes (T1D) and celiac disease (CD) autoimmunities to determine timing, extent of co-occurrence, and associated genetic and demographic factors.
In this prospective birth cohort study, 8676 children at high genetic risk of both diseases were enrolled and 5891 analyzed in median follow-up of 66 months. Along with demographic factors and HLA-DR-DQ, genotypes for HLA-DPB1 and 5 non-HLA loci conferring risk of both T1D and CD were analyzed.
Development of persistent islet autoantibodies (IAs) and tissue transglutaminase autoantibodies (tTGAs), as well as each clinical disease, was evaluated quarterly from 3 to 48 months of age and semiannually thereafter. IAs alone appeared in 367, tTGAs alone in 808, and both in 90 children. Co-occurrence significantly exceeded the expected rate. IAs usually, but not always, appeared earlier than tTGAs. IAs preceding tTGAs was associated with increasing risk of tTGAs (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.15-1.91). After adjusting for country, sex, family history, and all other genetic loci, significantly greater co-occurrence was observed in children with a T1D family history (HR: 2.80), HLA-DR3/4 (HR: 1.94) and single-nucleotide polymorphism rs3184504 at SH2B3 (HR: 1.53). However, observed co-occurrence was not fully accounted for by all analyzed factors.
In early childhood, T1D autoimmunity usually precedes CD autoimmunity. Preceding IAs significantly increases the risk of subsequent tTGAs. Co-occurrence is greater than explained by demographic factors and extensive genetic risk loci, indicating that shared environmental or pathophysiological mechanisms may contribute to the increased risk.
很少有出生队列对1型糖尿病（T1D）和乳糜泻（CD）自身免疫性疾病的发展进行前瞻性跟踪，以确定其同时发生的时间、程度以及相关的遗传和人口统计学因素。
在这项前瞻性出生队列研究中，招募了8676名患这两种疾病遗传风险高的儿童，对其中5891名儿童进行了中位数为66个月的随访分析。除了人口统计学因素和HLA-DR-DQ外，还分析了HLA-DPB1以及5个赋予T1D和CD风险的非HLA基因座的基因型。
从3至48月龄每季度评估持续性胰岛自身抗体（IAs）和组织转谷氨酰胺酶自身抗体（tTGAs）的发生情况以及每种临床疾病的发生情况，此后每半年评估一次。仅出现IAs的有367名儿童，仅出现tTGAs的有808名儿童，两种自身抗体都出现的有90名儿童。同时发生的情况显著超过预期发生率。IAs通常（但并非总是）比tTGAs出现得早。IAs先于tTGAs出现与tTGAs风险增加相关（风险比[HR]：1.48；95%置信区间[CI]：1.15-1.91）。在对国家、性别、家族史和所有其他基因座进行校正后，在有T1D家族史（HR：2.80）、HLA-DR3/4（HR：1.94）以及SH2B3基因座的单核苷酸多态性rs3184504（HR：1.53）的儿童中观察到显著更高的同时发生率。然而，所有分析因素并未完全解释观察到的同时发生情况。
在儿童早期，T1D自身免疫性疾病通常先于CD自身免疫性疾病出现。先前出现的IAs会显著增加随后出现tTGAs的风险。同时发生率高于人口统计学因素和广泛的遗传风险基因座所解释的情况，这表明共同的环境或病理生理机制可能导致风险增加。
