A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes
A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes
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DOI：
10.1016/j.ebiom.2019.09.020
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发表时间：
2019-10-01
期刊：
影响因子：
11.1
通讯作者：
Monckton, Darren G.
中科院分区：
文献类型：
--
作者：
Ciosi, Marc;Maxwell, Alastair;Monckton, Darren G.
背景：亨廷顿病（HD）是由编码毒性多聚谷氨酰胺链的不稳定CAG/CAA重复扩增引起的。在这里，我们测试了HD结果受HIT CAG/CAA谷氨酰胺编码重复序列和DNA修复基因的体细胞扩增和多态性影响的假设。使用高通量超深亚微米微阵列技术测定TRACK-HD和Enroll-HD队列中遗传40至50个CAG重复的参与者的血液DNA中谷氨酰胺编码重复序列和体细胞CAG扩增的比例。测序候选基因多态性采用竞争等位基因特异性PCR（KASP）进行基因分型。结果：使用来自203名TRACK-HD和531名Enroll-HD参与者的数据，我们发现血液DNA体细胞CAG重复扩增分数较高的个体具有更差的HD结局：躯体扩张评分增加1个单位与运动发作的考克斯风险比为3.05相关（95%CI =1.94 - 4.80，p = 1.3 x 10 - 6）。我们还表明，个体特异性体细胞扩增评分与FANI（pFDR = 4.8 x 10（-6））、MLH 3（pFDR= 8.0 x 10（-4））、MLHI（pFDR = 0.004）和MSH 3（pFDR = 0.009）中的变体相关。我们还表明，HD的结果是最好的预测纯CAG的数量，而不是总encoded-glutamines.Interpretation：这些数据建立纯CAG长度，而不是encoded-glutamines. Interpretation，作为下游病理生理学的关键遗传决定因素。这些发现对HD诊断有意义，并支持体细胞扩张作为临床结果的遗传修饰剂的机制联系，疾病的驱动因素，以及HD和相关重复扩张疾病的潜在治疗靶点。(C)2019作者由爱思唯尔公司出版
Background: Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HIT CAG/CAA glutamine-encoding repeat, and DNA repair genes.Methods: The sequence of the glutamine-encoding repeat and the proportion of somatic CAG expansions in blood DNA from participants inheriting 40 to 50 CAG repeats within the TRACK-HD and Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene polymorphisms were genotyped using kompetitive allele-specific PCR (KASP). Genotypic associations were assessed using time-to-event and regression analyses.Findings: Using data from 203 TRACK-HD and 531 Enroll-HD participants, we show that individuals with higher blood DNA somatic CAG repeat expansion scores have worse HD outcomes: a one-unit increase in somatic expansion score was associated with a Cox hazard ratio for motor onset of 3.05 (95% CI =1.94 to 4.80, p = 1.3 x 10(-6)). We also show that individual-specific somatic expansion scores are associated with variants in FANI (pFDR = 4.8 x 10(-6)), MLH3 (pFDR= 8.0 x 10(-4)), MLHI (pFDR = 0.004) and MSH3 (pFDR = 0.009). We also show that HD outcomes are best predicted by the number of pure CAGs rather than total encoded-glutamines.Interpretation: These data establish pure CAG length, rather than encoded-glutamine, as the key inherited determinant of downstream pathophysiology. These findings have implications for HD diagnostics, and support somatic expansion as a mechanistic link for genetic modifiers of clinical outcomes, a driver of disease, and potential therapeutic target in HD and related repeat expansion disorders. (C) 2019 The Authors. Published by Elsevier B.V.