Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical sciences, Tehran, Iran.
Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Metab Brain Dis. 2017 Oct;32(5):1595-1601. doi: 10.1007/s11011-017-0049-6. Epub 2017 Jun 12.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with various epidemiologic, genetic, epigenetic, and environmental factors being associated with it. The observed sex bias in ASD towards male has prompted investigators to propose sex-dependent mechanisms for ASD. Retinoic acid-related orphan receptor-alpha (RORA) is a new autism candidate gene that has been shown to be differentially regulated by male and female hormones. Previous studies have shown deregulation of its expression in the prefrontal cortex and the cerebellum of ASD patients. In the present study we aimed at identification of the possible associations between two functional polymorphisms in the RORA gene (rs11639084 and rs4774388) and the risk of ASD in 518 Iranian ASD patients and 472 age, gender, and ethnic-matched healthy controls by means of tetra primer-amplification refractory mutation system-PCR. The allele and genotype frequencies of rs11639084 were not significantly different between patients and controls. However, the allele frequencies of rs4774388 showed significant overrepresentation of T allele in patients compared with controls (P = 0.04, OR (95% CI) =1.21 (1.01-1.46)). The rs4774388-TT genotype was significantly higher in patients compared with controls and was associated with ASD risk in dominant inheritance model (P = 0.04, OR (95% CI) =0.77 (0.59-0.99)). Haplotype analysis showed significant association of two estimated blocks of rs11639084/ rs4774388 with ASD risk. Consequently, the present data provide further evidence for RORA participation in the pathogenesis of ASD.
自闭症谱系障碍（ASD）是一种神经发育障碍，其与多种流行病学、遗传、表观遗传和环境因素有关。ASD 观察到的性别偏向男性促使研究人员提出了与 ASD 相关的性别依赖机制。维甲酸相关孤儿受体-α（RORA）是一个新的自闭症候选基因，其表达被男性和女性激素差异调节。先前的研究表明，其在 ASD 患者的前额叶皮层和小脑中的表达失调。在本研究中，我们旨在通过四引物扩增受阻突变系统-PCR 方法，鉴定 RORA 基因（rs11639084 和 rs4774388）中的两个功能多态性与 518 名伊朗 ASD 患者和 472 名年龄、性别和种族匹配的健康对照者患 ASD 的风险之间的可能关联。rs11639084 的等位基因和基因型频率在患者和对照组之间无显著差异。然而，rs4774388 的等位基因频率显示患者中 T 等位基因的过度表达与对照组相比具有显著意义（P=0.04，OR（95%CI）=1.21（1.01-1.46））。与对照组相比，rs4774388-TT 基因型在患者中显著升高，并与显性遗传模型中的 ASD 风险相关（P=0.04，OR（95%CI）=0.77（0.59-0.99））。单体型分析显示，rs11639084/rs4774388 的两个估计块与 ASD 风险显著相关。因此，本研究数据为 RORA 参与 ASD 发病机制提供了进一步的证据。
