Translational Immunology, Research Programs Unit, University of Helsinki, Helsinki, Finland.
Department of Neurology, Helsinki University Hospital, P.O. Box 63, 00014, Helsinki, Finland.
Acta Neuropathol Commun. 2020 Nov 9;8(1):187. doi: 10.1186/s40478-020-01059-5.
The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson's disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7-45, 17-45, 21-45, 24-45 and 24-30). The carriership of an intermediate-length allele did not associate with ALS (Fisher's test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18-65, 66-84 and 85-105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02-14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79-61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.
C9orf72 基因内含子 1 的六核苷酸重复扩展导致肌萎缩侧索硬化症（ALS）和额颞叶痴呆。除了致病性扩展的影响外，中等长度等位基因在 ALS、皮质基底节变性和帕金森病中也具有作用。由于具有 20 个以上重复的中等长度等位基因的罕见性及其频率的地理变异性，需要进行大型研究来阐明其影响，这些研究需要考虑人口分层。为此，我们使用重复引物 PCR 和确认性 PCR 检测法，对来自芬兰的 705 名 ALS 患者和 3958 名对照者的 C9orf72 重复等位基因长度进行了检测。在排除扩展携带者（25.5%的 ALS 患者和 0.2%的对照者）后，我们使用几种中等长度等位基因阈值（7-45、17-45、21-45、24-45 和 24-30）比较了 525 例 ALS 病例和 3950 例对照者的中等长度等位基因携带者频率。当我们将对照组分为三组（18-65、66-84 和 85-105 岁）时，无论是否考虑生存时间（p≥0.33），携带中等长度等位基因与 ALS 均无关联（Fisher 检验，所有 p 值≥0.15）。当两个等位基因均存在较长的等位基因时（p=0.002，OR 5.32，95%CI 2.02-14.05）或较长的等位基因时（p=0.00016，OR 15.21，95%CI 3.79-61.0），携带两个中等长度等位基因与 ALS 相关。我们的研究结果表明，当两个等位基因均存在中等长度等位基因时，其是 ALS 的危险因素，而仅携带一个中等长度等位基因与 ALS 或生存无关。
