From the "Rita Levi Montalcini" Department of Neuroscience (A. Chiò, C.M., A. Canosa, U.M., M.G., R.V., F.P., S.G., M. Brunetti, G.M., B.I., L.P., A. Calvo), University of Turin; Neurology 1 (A. Chiò, C.M., A. Canosa, U.M., S.G., M. Barberis, A. Calvo), AOU Città della Salute e della Scienza Hospital of Turin; Institute of Cognitive Sciences and Technologies (A. Chiò, A. Canosa), CNR, Rome; ALS Center (F.D.M., L.M.), Department of Neurology, Maggiore della Carità Hospital, University of Piemonte Orientale, Novara, Italy; Department of Anatomy, Physiology & Genetics (C.D.), and The American Genome Center (C.D.), Uniformed Services University of the Health Sciences; Neuromuscular Diseases Research Section (R.C., B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, Bethesda; Department of Neurology (B.J.T.), Johns Hopkins University Medical Center, Baltimore, MD; and Department of Health Sciences (L.C., S.D.A., L.M.), University of Eastern Piedmont, Novara, Italy.
Neurology. 2023 Jul 4;101(1):e83-e93. doi: 10.1212/WNL.0000000000207367. Epub 2023 May 18.
Despite recent advances, it is not clear whether the various genes/genetic variants related to amyotrophic lateral sclerosis (ALS) interact in modifying patients' phenotype. The aim of this study was to determine whether the copresence of genetic variants related to ALS has interactive effects on the course of the disease.
The study population includes 1,245 patients with ALS identified through the Piemonte Register for ALS between 2007 and 2016 and not carrying superoxide dismutase type 1, TAR DNA binding protein, and fused in sarcoma pathogenic variants. Controls were 766 Italian participants age-matched, sex-matched, and geographically matched to cases. We considered Unc-13 homolog A () (rs12608932), calmodulin binding transcription activator 1 () (rs2412208), solute carrier family 11 member 2 () (rs407135), and zinc finger protein 512B () (rs2275294) variants, as well as ataxin-2 () polyQ intermediate repeats (≥31) and chromosome 9 open reading frame 72 () GGGGCC intronic expansions (≥30).
The median survival time of the whole cohort was 2.67 years (interquartile range [IQR] 1.67-5.25). In univariate analysis, only (2.51 years, IQR 1.74-3.82; = 0.016), (1.82 years, IQR 1.08-2.33; < 0.001), and (2.3 years, IQR 1.3-3.9; < 0.001) significantly reduced survival. In Cox multivariable analysis, also emerged to be independently related to survival (hazard ratio 1.13, 95% CI 1.001-1.30, = 0.048). The copresence of 2 detrimental alleles/expansions was correlated with shorter survival. In particular, the median survival of patients with and alleles was 1.67 years (1.16-3.08) compared with 2.75 years (1.67-5.26) of the patients not carrying these variants ( < 0.001); the survival of patients with alleles and intermediate polyQ repeats was 1.75 years (0.84-2.18) ( < 0.001); the survival of patients with polyQ repeats and allele was 1.33 years (0.84-1.75) ( < 0.001); the survival of patients with and allele was 1.66 years (1.41-2.16). Each pair of detrimental alleles/expansions was associated to specific clinical phenotypes.
We showed that gene variants acting as modifiers of ALS survival or phenotype can act on their own or in unison. Overall, 54% of patients carried at least 1 detrimental common variant or repeat expansion, emphasizing the clinical impact of our findings. In addition, the identification of the interactive effects of modifier genes represents a crucial clue for explaining ALS clinical heterogeneity and should be considered when designing and interpreting clinical trials results.
尽管最近取得了一些进展，但仍不清楚与肌萎缩侧索硬化症（ALS）相关的各种基因/遗传变异是否会相互作用，从而改变患者的表型。本研究的目的是确定与 ALS 相关的遗传变异的共存是否会对疾病的进程产生交互影响。
研究人群包括通过 2007 年至 2016 年间皮埃蒙特 ALS 登记处确定的 1245 名未携带超氧化物歧化酶 1、TAR DNA 结合蛋白和融合肉瘤致病变异的 ALS 患者，以及 766 名意大利年龄匹配、性别匹配和地域匹配的对照者。我们考虑了 Unc-13 同源物 A ()（rs12608932）、钙调蛋白结合转录激活因子 1 ()（rs2412208）、溶质载体家族 11 成员 2 ()（rs407135）和锌指蛋白 512B ()（rs2275294）变异，以及共济失调-2 () 多聚 Q 中间重复（≥31）和染色体 9 开放阅读框 72 () GGGGCC 内含子扩展（≥30）。
整个队列的中位生存时间为 2.67 年（四分位距 [IQR] 1.67-5.25）。在单变量分析中，仅 （2.51 年，IQR 1.74-3.82； = 0.016）、 （1.82 年，IQR 1.08-2.33； < 0.001）和 （2.3 年，IQR 1.3-3.9； < 0.001）显著降低了生存。在 Cox 多变量分析中， 也被证明与生存相关（风险比 1.13，95%置信区间 1.001-1.30， = 0.048）。2 种有害等位基因/扩展的共存与较短的生存时间相关。特别是，携带 和 等位基因的患者的中位生存时间为 1.67 年（1.16-3.08），而未携带这些变异的患者为 2.75 年（1.67-5.26）（ < 0.001）；携带 等位基因和 中间多聚 Q 重复的患者的生存时间为 1.75 年（0.84-2.18）（ < 0.001）；携带 多聚 Q 重复和 等位基因的患者的生存时间为 1.33 年（0.84-1.75）（ < 0.001）；携带 和 等位基因的患者的生存时间为 1.66 年（1.41-2.16）。每对有害等位基因/扩展都与特定的临床表型相关。
我们表明，作为 ALS 生存或表型修饰因子的基因变异可以单独或协同作用。总体而言，54%的患者携带至少 1 种有害的常见变异或重复扩展，这强调了我们研究结果的临床意义。此外，修饰基因的交互作用的鉴定为解释 ALS 临床异质性提供了关键线索，在设计和解释临床试验结果时应考虑这一点。
