TY -的T1 -协会Copresence肌萎缩性脊髓侧索硬化症和预后相关的致病变种JF -神经学乔-神经病学SP - e83 LP - e93做- 10.1212 / WNL。半岛投注体育官网0000000000207367六世- 101 - 1 AU -阿德里亚诺亚蔡盟克里斯蒂娜Moglia AU -安东尼奥Canosa盟Umberto Manera AU -莫里吉奥Grassano AU -罗萨里奥Vasta盟弗朗西斯卡帕伦博AU -萨尔瓦多Gallone AU -莫拉Brunetti盟马可barberi AU -法德马奇盟克利夫顿Dalgard盟——露丝Chia盟——Gabriele莫拉AU -芭芭拉Iazzolino AU -劳拉Peotta AU -布莱恩j . Traynor AU -卢西亚拉盟桑德拉·D 'Alfonso AU -莱蒂齐亚马志尼盟安德里亚·卡尔沃Y1 - 2023/07/04 UR - //www.ebmtp.com/content/101/1/e83.abstract N2 -背景和目标尽管最新进展,目前尚不清楚的各种基因/遗传变异相关的肌萎缩性脊髓侧索硬化症(ALS)交互修改患者的表型。半岛投注体育官网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 & lt;0.001)和UNC13AC / C(2.3年,差1.3 - -3.9; p < 0.001) significantly reduced survival. In Cox multivariable analysis, CAMTA1 also emerged to be independently related to survival (hazard ratio 1.13, 95% CI 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 ER -