Distinct Genetic Risk Based on Association of MET in Families With Co-occurring Autism and Gastrointestinal Conditions
Distinct Genetic Risk Based on Association of MET in Families With Co-occurring Autism and Gastrointestinal Conditions
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DOI：
10.1542/peds.2008-0819
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发表时间：
2009-03-01
期刊：
影响因子：
8
通讯作者：
Levitt, Pat
中科院分区：
文献类型：
--
作者：
Campbell, Daniel B.;Buie, Timothy M.;Levitt, Pat
OBJECTIVE.除了自闭症谱系障碍的核心行为症状外，许多患者还存在复杂的医疗状况，包括胃肠道功能障碍。编码MET受体酪氨酸激酶的基因的启动子中的功能变体与自闭症谱系障碍相关，并且MET蛋白表达在患有自闭症谱系障碍的受试者的颞叶皮层中降低。MET是一种多效性受体，在脑发育和胃肠道修复中发挥作用。在这些功能的基础上，我们假设自闭症谱系障碍相关MET启动子变体的关联可能在患有共发自闭症谱系障碍和胃肠道疾病的个体的子集中富集。研究对象为来自214个自闭症遗传资源交换家庭的918名个体，他们有完整的病史，包括胃肠道疾病报告。确定了自闭症谱系障碍相关MET启动子变体rs 1858830的基因型。采用基于家族的关联检验和卡方检验来确定MET rs 1858830等位基因与自闭症谱系障碍和胃肠道疾病的关联。在整个214个家庭样本中，MET rs 1858830 C等位基因与自闭症谱系障碍和胃肠道疾病相关。分层的胃肠道疾病的存在下，发现MET C等位基因与自闭症谱系障碍和胃肠道疾病在118个家庭，其中至少有一个孩子同时患有自闭症谱系障碍和胃肠道疾病。相比之下，在96个缺乏自闭症谱系障碍和胃肠道疾病并存儿童的家庭中，MET多态性与自闭症谱系障碍没有关联。对MET rs 1858830基因型的chi（2）分析表明，与非自闭症谱系障碍的兄弟姐妹、父母和无关对照相比，患有自闭症谱系障碍和胃肠道疾病的个体中C等位基因的过度表达。这些结果表明，破坏MET信号可能有助于增加自闭症谱系障碍的风险，包括家族性胃肠道功能障碍。儿科2009;123：1018-1024
OBJECTIVE. In addition to the core behavioral symptoms of autism spectrum disorder, many patients present with complex medical conditions including gastrointestinal dysfunction. A functional variant in the promoter of the gene encoding the MET receptor tyrosine kinase is associated with autism spectrum disorder, and MET protein expression is decreased in the temporal cortex of subjects with autism spectrum disorder. MET is a pleiotropic receptor that functions in both brain development and gastrointestinal repair. On the basis of these functions, we hypothesized that association of the autism spectrum disorder-associated MET promoter variant may be enriched in a subset of individuals with co-occurring autism spectrum disorder and gastrointestinal conditions.PATIENTS AND METHODS. Subjects were 918 individuals from 214 Autism Genetics Resource Exchange families with a complete medical history including gastrointestinal condition report. Genotypes at the autism spectrum disorder-associated MET promoter variant rs1858830 were determined. Family-based association test and chi(2) analyses were used to determine the association of MET rs1858830 alleles with autism spectrum disorder and the presence of gastrointestinal conditions.RESULTS. In the entire 214-family sample, the MET rs1858830 C allele was associated with both autism spectrum disorder and gastrointestinal conditions. Stratification by the presence of gastrointestinal conditions revealed that the MET C allele was associated with both autism spectrum disorder and gastrointestinal conditions in 118 families containing at least 1 child with co-occurring autism spectrum disorder and gastrointestinal conditions. In contrast, there was no association of the MET polymorphism with autism spectrum disorder in the 96 families lacking a child with co-occurring autism spectrum disorder and gastrointestinal conditions. chi(2) analyses of MET rs1858830 genotypes indicated over-representation of the C allele in individuals with co-occurring autism spectrum disorder and gastrointestinal conditions compared with non-autism spectrum disorder siblings, parents, and unrelated controls.CONCLUSION. These results suggest that disrupted MET signaling may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction. Pediatrics 2009;123:1018-1024