Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Neurology and Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Eur J Neurol. 2019 Aug;26(8):1130-1136. doi: 10.1111/ene.13954. Epub 2019 Apr 15.
The expanded repeat length in ATXN1 negatively correlates with age at onset (AAO) of spinocerebellar ataxia type 1 (SCA1) but can explain only part of it, indicating that other factors affect AAO. Some studies have explored the influence of non-causative CAG repeats on the AAO of SCA patients. However, studies on Chinese SCA1 patients regarding candidate modifier factors involved in the variability in AAO are rare.
In all, 152 Chinese SCA1 patients who were genotyped for ATXN1 and nine other (CAG) -containing genes were enrolled. Regression analysis was performed to determine the effect of the expanded allele of ATXN1 (linear and quadratic effects) on AAO. Then, different models were used to explore the modulatory effect of nine other (CAG) -containing genes.
Our results verified the negative effect of the expanded allele in ATXN1 by regression analysis. Some (CAG) -containing genes including TBP, ATN1 and HTT modified AAO with variance ranging from 0.8% to 3.8% and tended to decrease or delay AAO. However, no modifier effects of ATXN2, ATXN3, CACNA1A, ATXN7, KCNN3, RAI1 and normal ATXN1 alleles in trans were detected.
By using interaction analyses, TBP, ATN1 and HTT were determined to have modifying effects. Our study revealed that differences in modulation may be due to ethnic and geographic diversity across different populations. Furthermore, the variability of AAO was not completely explained by the genetic modifiers examined here, suggesting that other genetic or environmental factors are involved in these diseases.
ATXN1 中的扩展重复长度与脊髓小脑共济失调 1 型（SCA1）的发病年龄（AAO）呈负相关，但只能解释其中的一部分，表明其他因素会影响 AAO。一些研究已经探索了非致病 CAG 重复对 SCA 患者 AAO 的影响。然而，关于涉及 AAO 变异性的候选修饰因子的中国 SCA1 患者的研究很少。
共纳入 152 名经 ATXN1 和其他 9 个（CAG）-含基因进行基因分型的中国 SCA1 患者。进行回归分析以确定 ATXN1 扩展等位基因（线性和二次效应）对 AAO 的影响。然后，使用不同的模型来探索其他 9 个（CAG）-含基因的调节作用。
我们的结果通过回归分析验证了 ATXN1 扩展等位基因的负效应。一些包含（CAG）的基因，包括 TBP、ATN1 和 HTT，修饰了 AAO，方差范围为 0.8%至 3.8%，并趋于降低或延迟 AAO。然而，未检测到 ATXN2、ATXN3、CACNA1A、ATXN7、KCNN3、RAI1 和正常 ATXN1 等位基因的反式修饰作用。
通过使用相互作用分析，确定 TBP、ATN1 和 HTT 具有修饰作用。我们的研究表明，不同的调节差异可能是由于不同人群的种族和地理多样性所致。此外，这里检查的遗传修饰剂并不能完全解释 AAO 的变异性，这表明其他遗传或环境因素也参与了这些疾病。
