@article{气{\ ' o} e83作者={阿德里亚诺气{\ ' o}和克里斯蒂娜Moglia和安东尼奥Canosa Umberto Manera和Maurizio Grassano罗萨里奥Vasta弗朗西斯卡帕伦博和萨尔瓦多Gallone莫拉Brunetti马可barberi和法比奥·德·马奇克利夫顿Dalgard和露丝Chia Gabriele莫拉和芭芭拉Iazzolino和劳拉Peotta和布莱恩j . Traynor和露西亚拉和桑德拉·D {\ textquoteright}阿方索和莱蒂齐亚马志尼和安德里亚·卡尔沃}title ={协会Copresence肌萎缩性脊髓侧索硬化症和预后相关的致病变种},体积={101}={1},页面= {e83——e93} = {2023}, doi = {10.1212 / WNL。出版商0000000000207367}= {Wolters Kluwer健康,公司代表美国神经病学学会},文摘={背景和目标尽管最新进展,目前尚不清楚的各种基因/基因变异与肌萎缩性脊髓侧索硬化半岛投注体育官网症(ALS)交互修改患者{\ textquoteright}表型。本研究的目的是确定是否copresence ALS基因变异相关的互动对病程的影响。方法研究人群包括1245名ALS患者识别通过皮埃蒙特注册ALS 2007年和2016年之间,没有携带1型超氧化物歧化酶,焦油DNA结合蛋白,融合在肉瘤致病性变异。控制766年意大利参与者年龄、sex-matched和地理位置匹配的情况。我们认为Unc-13同族体(UNC13A) (rs12608932)、钙调蛋白结合转录激活1 (CAMTA1) (rs2412208)溶质载体家庭11成员2 (SLC11A2) (rs407135)和锌指蛋白512 b (ZNF512B) (rs2275294)变异,以及ataxin-2 (ATXN2) polyQ中间重复(> = 31)和染色体9 72年开放阅读框(C9orf72) GGGGCC intronic扩张(> = 30)。结果整个队列的平均生存时间是2.67年(四分位范围(差)1.67 5.25 {\ textendash})。在单变量分析中,只有C9orf72(2.51年,差1.74 {\ textendash} 3.82;p = 0.016), ATXN2(1.82年,差1.08 {\ textendash} 2.33;p \ < 0.001), UNC13AC / C(2.3年,差1.3 {\ textendash} 3.9;p \ < 0.001)显著降低生存。在考克斯多变量分析中,CAMTA1也出现了相关的独立生存(风险比1.13,95 \ % CI 1.001 {\ textendash} 1.30, p = 0.048)。 The copresence of 2 detrimental alleles/expansions was correlated with shorter survival. In particular, the median survival of patients with CAMTA1G/G+G/T and UNC13AC/C alleles was 1.67 years (1.16{\textendash}3.08) compared with 2.75 years (1.67{\textendash}5.26) of the patients not carrying these variants (p \< 0.001); the survival of patients with CAMTA1G/G+G/T alleles and ATXN2>=31 intermediate polyQ repeats was 1.75 years (0.84{\textendash}2.18) (p \< 0.001); the survival of patients with ATXN2>=31 polyQ repeats and UNC13AC/C allele was 1.33 years (0.84{\textendash}1.75) (p \< 0.001); the survival of patients with C9ORF72>=30 and UNC13AC/C allele was 1.66 years (1.41{\textendash}2.16). Each pair of detrimental alleles/expansions was associated to specific clinical phenotypes.Discussion 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.ALS=amyotrophic lateral sclerosis; ALSFRS-R=Revised ALS Functional Rating Scale; ATXN2=ataxin-2; C9orf72=chromosome 9 open reading frame 72; CAMTA1=calmodulin binding transcription activator 1; FTD=frontotemporal dementia; FUS=fused in sarcoma; GP=general practitioner; HR=hazard ratio; IQR=interquartile range; SLC11A2=solute carrier family 11 member 2; SOD1=superoxide dismutase type 1; TARDBP=TAR DNA binding protein; TDP-43=TAR DNA binding protein-43; UNC13A=Unc-13 homolog A; WGS=whole genome sequencing; ZNF512B=zinc finger protein 512B}, issn = {0028-3878}, URL = {//www.ebmtp.com/content/101/1/e83}, eprint = {//www.ebmtp.com/content/101/1/e83.full.pdf}, journal = {Neurology} }