Genetic Evidence Implicating Multiple Genes in the MET Receptor Tyrosine Kinase Pathway in Autism Spectrum Disorder
Genetic Evidence Implicating Multiple Genes in the MET Receptor Tyrosine Kinase Pathway in Autism Spectrum Disorder
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DOI：
10.1002/aur.27
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发表时间：
2008-06-01
期刊：
影响因子：
4.7
通讯作者：
Levitt, Pat
中科院分区：
文献类型：
--
作者：
Campbell, Daniel B.;Li, Chun;Levitt, Pat
编码MET受体酪氨酸激酶的基因的功能性启动子变体改变SP1和SUB1转录因子结合，并与自闭症谱系障碍（ASD）相关。最近对ASD患者死后大脑皮层的分析显示MET蛋白和三种编码调节MET信号传导的蛋白质的转录物表达改变，所述蛋白质为肝细胞生长因子（HGF）、尿激酶纤溶酶原激活物受体（PLAUR）和纤溶酶原激活物抑制剂-1（SERPINE 1）。为了解决MET信号通路中多个基因带来的潜在风险，我们筛选了所有外显子和5'启动子区域，以寻找编码调节MET表达和活性的蛋白质的五个基因中的变体。在664个家族（2，712个个体，包括1，228名ASD患者）和312个无关对照中对鉴定的变体进行了基因分型。重复我们的初步研究结果，基于家庭的关联检验（FBAT）分析表明，MET启动子变异rs 1858830 C等位基因与ASD在101个新的家庭（P = 0.033）。MET信号通路中的另外两个基因也可能带来风险。SERPINE 1基因的单倍型表现出显着的关联。此外，通过FBAT（P = 0.006）和病例对照分析（P = 0.007），PLAUR启动子变体rs344781 T等位基因与ASD相关。与CC基因型相比，TT基因型和CT基因型的PLAUR启动子rs344781相对风险分别为1.93（95%置信区间[CI]：1.12-3.31）和2.42（95% CI：1.38-4.25）。基因-基因互作分析表明MET和PLAUR之间存在显著的互作。这些数据进一步支持了我们的假设，即影响MET信号通路多个组分的遗传易感性有助于ASD风险。
A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor-1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5' promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family-based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P = 0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P = 0.006) and case-control analyses (P = 0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% confidence interval [CI]: 1.12-3.31) for genotype TT and 2.42 (95% CI: 1.38-4.25) for genotype CT compared to genotype CC. Gene-gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.