The repeat length of C9orf72 is associated with the survival of amyotrophic lateral sclerosis patients without C9orf72 pathological expansions.
The repeat length of C9orf72 is associated with the survival of amyotrophic lateral sclerosis patients without C9orf72 pathological expansions.
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C9orf72的重复长度与无C9orf72病理扩张的肌萎缩侧索硬化症患者的生存相关
DOI：
10.3389/fneur.2022.939775
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发表时间：
2022
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
探讨9号染色体开放阅读框72（C9 orf 72）基因和共济失调蛋白-2（ATXN 2）基因的重复长度在无C9 orf 72重复扩增的肌萎缩侧索硬化症（ALS）患者中是否赋予ALS的风险或ALS的生存劣势。我们筛选了一个以医院为基础的中国散发性ALS患者队列，这些患者没有C9 orf 72重复扩增，神经系统健康对照为C9 orf 72 GGGGCC和AXTN 2 CAG重复长度，使用几个阈值比较可能有害长度等位基因的频率。此外，ALS的临床特征进行了比较ALS亚组患者使用不同的长度阈值的最大C9 orf 72和ATXN 2重复等位基因，如性别，发病年龄，诊断延迟，和生存。总体而言，879例散发性ALS患者和535名对照被包括在内，C9 orf 72和ATXN 2的重复长度都被检测到。我们发现使用一系列C9 orf 72重复长度阈值从2到5的患者中存在显著的生存差异，其中最显著的差异是在截止值2处（重复2对>2：中位生存期67对55个月，对数秩p = 0.032）。此外，考克斯回归分析显示，发病年龄[风险比（HR）1.04，95% CI 1.03-1.05，p < 0.001]，诊断延迟（0.95，0.94-0.96，p < 0.001），并且携带C9 orf 72重复长度为2（0.72，0.59-0.89，p = 0.002）的患者的存活率没有C9 orf 72重复扩增。此外，当患者携带最大C9 orf 72重复等位基因超过2时，延髓发病与较差的生存率相关（1.81，1.32-2.48，p < 0.001）。然而，当应用ATXN 2的一系列连续截止值或按C9 orf 72重复2分层时，未发现生存差异。在没有C9 orf 72重复扩增的ALS患者中，最大C9 orf 72重复等位基因的长度为2与有利的生存相关。我们的研究结果从临床环境中暗示了可能的截止定义有害的C9 orf 72重复，这应该是有助于了解遗传学在ALS和临床遗传咨询。
To explore whether the repeat lengths of the chromosome 9 open reading frame 72 (C9orf72) gene and the ataxin-2 (ATXN2) gene in amyotrophic lateral sclerosis (ALS) patients without C9orf72 repeat expansions confer a risk of ALS or survival disadvantages in ALS. We screened a hospital-based cohort of Chinese patients with sporadic ALS without C9orf72 repeat expansions and neurologically healthy controls for C9orf72 GGGGCC and AXTN2 CAG repeat length to compare the frequency of possible detrimental length alleles using several thresholds. Furthermore, the clinical features of ALS were compared between patients with ALS subgroups using different length thresholds of maximum C9orf72 and ATXN2 repeat alleles, such as sex, age of onset, diagnostic delay, and survival. Overall, 879 sporadic patients with ALS and 535 controls were included and the repeat lengths of the C9orf72 and ATXN2 were both detected. We found significant survival differences in patients using a series of C9orf72 repeat length thresholds from 2 to 5, among which the most significant difference was at the cutoff value of 2 (repeats 2 vs. >2: median survival 67 vs. 55 months, log-rank p = 0.032). Furthermore, Cox regression analysis revealed the role of age of onset [hazard ratio (HR) 1.04, 95% CI 1.03–1.05, p < 0.001], diagnostic delay (0.95, 0.94–0.96, p < 0.001), and carrying C9orf72 repeat length of 2 (0.72, 0.59–0.89, p = 0.002) in the survival of patients without C9orf72 repeat expansions. In addition, bulbar onset was associated with poorer survival when the patients carried the maximum C9orf72 repeat allele over 2 (1.81, 1.32–2.48, p < 0.001). However, no survival difference was found when applying a series of continuous cutoff values of ATXN2 or stratified by C9orf72 repeats of 2. The length of 2 in the maximum C9orf72 repeat allele was identified to be associated with favorable survival in ALS patients without C9orf72 repeat expansions. Our findings from the clinical setting implicated the possible cutoff definition of detrimental C9orf72 repeats, which should be helpful in the understanding of genetics in ALS and in clinical genetic counseling.
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影响因子：
48
作者：
Goutman, Stephen A.;Hardiman, Orla;Al-Chalabi, Ammar;Chio, Adriano;Savelieff, Masha G.;Kiernan, Matthew C.;Feldman, Eva L.
通讯作者：
Feldman, Eva L.
影响因子：
4.2
作者：
van Blitterswijk M;Mullen B;Heckman MG;Baker MC;DeJesus-Hernandez M;Brown PH;Murray ME;Hsiung GY;Stewart H;Karydas AM;Finger E;Kertesz A;Bigio EH;Weintraub S;Mesulam M;Hatanpaa KJ;White CL 3rd;Neumann M;Strong MJ;Beach TG;Wszolek ZK;Lippa C;Caselli R;Petrucelli L;Josephs KA;Parisi JE;Knopman DS;Petersen RC;Mackenzie IR;Seeley WW;Grinberg LT;Miller BL;Boylan KB;Graff-Radford NR;Boeve BF;Dickson DW;Rademakers R
通讯作者：
Rademakers R
DOI：
10.1016/s1474-4422(12)70043-1
发表时间：
2012-04
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Majounie E;Renton AE;Mok K;Dopper EG;Waite A;Rollinson S;Chiò A;Restagno G;Nicolaou N;Simon-Sanchez J;van Swieten JC;Abramzon Y;Johnson JO;Sendtner M;Pamphlett R;Orrell RW;Mead S;Sidle KC;Houlden H;Rohrer JD;Morrison KE;Pall H;Talbot K;Ansorge O;Chromosome 9-ALS/FTD Consortium;French research network on FTLD/FTLD/ALS;ITALSGEN Consortium;Hernandez DG;Arepalli S;Sabatelli M;Mora G;Corbo M;Giannini F;Calvo A;Englund E;Borghero G;Floris GL;Remes AM;Laaksovirta H;McCluskey L;Trojanowski JQ;Van Deerlin VM;Schellenberg GD;Nalls MA;Drory VE;Lu CS;Yeh TH;Ishiura H;Takahashi Y;Tsuji S;Le Ber I;Brice A;Drepper C;Williams N;Kirby J;Shaw P;Hardy J;Tienari PJ;Heutink P;Morris HR;Pickering-Brown S;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
9.9
作者：
Chio, Adriano;Calvo, Andrea;Bottacchi, Edo
通讯作者：
Bottacchi, Edo
影响因子：
4.2
作者：
Tsai, Ching-Paio;Soong, Bing-Wen;Lee, Yi-Chung
通讯作者：
Lee, Yi-Chung