ALS Center, Department of Neuroscience, University of Torino, and Azienda Ospedale Università San Giovanni Battista, Torino, Italy.
Neurobiol Aging. 2013 Jan;34(1):357.e1-5. doi: 10.1016/j.neurobiolaging.2012.07.016. Epub 2012 Aug 22.
The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to amyotrophic lateral sclerosis (ALS), as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1457 Italian control samples. Although rs12608932 was not associated with ALS susceptibility in our series (p = 0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [interquartile range, 2.2-6.4]; CC = 2.5 years [interquartile range, 1.6-4.2]; p = 0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p = 0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an approximate 1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression.
位于 19p13.3 染色体 UNC13A 基因内含子中的常见变体 rs12608932 被认为会影响北欧裔 ALS 患者的易感性和生存。为了进一步研究这种可能性，我们评估了 rs12608932 与 500 名意大利 ALS 患者和 1457 名意大利对照样本的基于人群的队列中易感性和生存的相关性。尽管 rs12608932 在我们的研究中与 ALS 易感性无关（p = 0.124），但它在隐性模型下与生存显著相关（AA/AC 基因型的中位生存时间为 3.5 年[四分位间距，2.2-6.4]；CC 为 2.5 年[四分位间距，1.6-4.2]；p = 0.017）。此外，在调整其他已知影响生存的因素后，rs12608932 基因型在 Cox 多变量分析中仍然是一个独立的预后因素（p = 0.023）。总的来说，rs12608932 的次要等位基因携带者状态与 ALS 患者的生存时间大约减少 1 年密切相关，使其成为表型变异的重要决定因素。UNC13A 作为散发性 ALS 患者预后的修饰因子的鉴定，可能为减缓疾病进展提供了一个新的治疗靶点。
