Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families
Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families
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DOI：
10.2337/db18-0882
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发表时间：
2019-04-01
期刊：
影响因子：
7.7
通讯作者：
Ziegler, Anette-G.
中科院分区：
文献类型：
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作者：
Hippich, Markus;Beyerlein, Andreas;Ziegler, Anette-G.
有1型糖尿病一级家族史的儿童（FDR儿童）发生自身免疫和随后发生1型糖尿病的风险是普通人群儿童（GP儿童）的10倍。我们分析了纵向TEDDY出生队列中具有高风险HLA基因型的儿童（n = 4，573），以确定有多少差异风险可归因于受影响家庭的遗传富集。与GP儿童相比，在FDR儿童中发现了多个1型糖尿病相关基因和一个新的风险基因BTNL 2的易感基因型富集。在对基因富集进行校正后，FDR和GP儿童的风险趋于一致，但对于多种胰岛自身抗体（风险比[HR] 2.26 [95%CI 1.6-3.02]）和糖尿病（HR 2.92 [95%CI 2.05-4.16]），风险并不相同。收敛性因遗传易感性的程度而异。在最高遗传易感性组中，多种胰岛自身抗体（14.3%vs.12.7%）和糖尿病（4.8%vs.4.1%）的风险相似，在最低遗传易感性组中，儿童的风险差异高达5.8倍，GP儿童的风险逐渐降低，而FDR儿童的风险则没有降低。这些研究结果表明，在受影响的家庭中富集的其他因素优先增加自身免疫和1型糖尿病的风险，在较低的遗传易感性阶层。
The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes-associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6-3.02]) and for diabetes (HR 2.92 [95% CI 2.05-4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.