% 0期刊文章%阿德里亚诺亚蔡%一个安东尼奥Canosa克里斯蒂娜Moglia % %一个Umberto Manera % Maurizio Grassano %罗萨里奥Vasta %一个萨尔瓦多Gallone弗朗西斯卡帕伦博% %一个Maura Brunetti %马可barberi %法比奥·德·马奇%一露丝Chia克利夫顿Dalgard % % Gabriele Mora %一个芭芭拉Iazzolino %劳拉Peotta %布莱恩j . Traynor %卢西亚拉%桑德拉·D 'Alfonso %莱蒂齐亚马志尼%安德里亚·卡尔沃% T协会Copresence肌萎缩性脊髓侧索硬化症和预后相关的致病变种% D R 10.1212 / WNL 2023%。0000000000207367 % J半岛投注体育官网神经病学% P e83-e93 % V 101% N 1% X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症(ALS)交互修改患者的表型。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)。在单变量分析中,只有C9orf72(2.51年,差1.74 - -3.82;p = 0.016), ATXN2(1.82年,差1.08 - -2.33;p < 0.001), UNC13AC / C(2.3年,差1.3 - -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%可信区间1.001 - -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 (1.16–3.08) compared with 2.75 years (1.67–5.26) 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 (0.84–2.18) (p < 0.001); the survival of patients with ATXN2≥31 polyQ repeats and UNC13AC/C allele was 1.33 years (0.84–1.75) (p < 0.001); the survival of patients with C9ORF72≥30 and UNC13AC/C allele was 1.66 years (1.41–2.16). 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 %U //www.ebmtp.com/content/neurology/101/1/e83.full.pdf