Campbell Daniel B, Buie Timothy M, Winter Harland, Bauman Margaret, Sutcliffe James S, Perrin James M, Levitt Pat
Vanderbilt University, 8114 MRB3, 465 21st Ave South, Nashville, TN 37232, USA.
Pediatrics. 2009 Mar;123(3):1018-24. doi: 10.1542/peds.2008-0819.
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.
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.
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.
These results suggest that disrupted MET signaling may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction.
除了自闭症谱系障碍的核心行为症状外，许多患者还存在包括胃肠功能障碍在内的复杂医学状况。编码MET受体酪氨酸激酶的基因启动子中的一个功能性变异与自闭症谱系障碍相关，并且在自闭症谱系障碍患者的颞叶皮质中MET蛋白表达降低。MET是一种多效性受体，在大脑发育和胃肠修复中均发挥作用。基于这些功能，我们推测与自闭症谱系障碍相关的MET启动子变异在同时患有自闭症谱系障碍和胃肠疾病的个体亚组中可能更为常见。
研究对象为来自214个自闭症遗传学资源交流家庭的918名个体，这些个体均有完整的病史，包括胃肠疾病报告。确定了与自闭症谱系障碍相关的MET启动子变异rs1858830的基因型。采用基于家系的关联检验和卡方分析来确定MET rs1858830等位基因与自闭症谱系障碍以及胃肠疾病的存在之间的关联。
在整个214个家庭的样本中，MET rs1858830的C等位基因与自闭症谱系障碍和胃肠疾病均相关。按是否存在胃肠疾病进行分层分析发现，在118个至少有1名同时患有自闭症谱系障碍和胃肠疾病的儿童的家庭中，MET C等位基因与自闭症谱系障碍和胃肠疾病均相关。相比之下，在96个没有同时患有自闭症谱系障碍和胃肠疾病的儿童的家庭中，MET多态性与自闭症谱系障碍无关联。对MET rs1858830基因型的卡方分析表明，与非自闭症谱系障碍的同胞、父母及无关对照相比，同时患有自闭症谱系障碍和胃肠疾病的个体中C等位基因的比例过高。
这些结果表明，MET信号通路的破坏可能会增加自闭症谱系障碍（包括家族性胃肠功能障碍）的发病风险。
