Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis.
Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis.
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DOI：
10.1001/jamaneurol.2016.1114
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发表时间：
2016-07-01
期刊：
影响因子：
29
通讯作者：
Powell J
中科院分区：
文献类型：
--
作者：
Fogh I;Lin K;Tiloca C;Rooney J;Gellera C;Diekstra FP;Ratti A;Shatunov A;van Es MA;Proitsi P;Jones A;Sproviero W;Chiò A;McLaughlin RL;Sorarù G;Corrado L;Stahl D;Del Bo R;Cereda C;Castellotti B;Glass JD;Newhouse S;Dobson R;Smith BN;Topp S;van Rheenen W;Meininger V;Melki J;Morrison KE;Shaw PJ;Leigh PN;Andersen PM;Comi GP;Ticozzi N;Mazzini L;D'Alfonso S;Traynor BJ;Van Damme P;Robberecht W;Brown RH;Landers JE;Hardiman O;Lewis CM;van den Berg LH;Shaw CE;Veldink JH;Silani V;Al-Chalabi A;Powell J
肌萎缩性侧索硬化症（ALS）是一种毁灭性的成人神经退行性疾病，预后不良，中位生存期为3年。
鉴定基因变异会影响ALS的生存。
这项全基因组协会研究（GWAS）分析了来自多个欧洲国家和美国的数据集中的生存率，这些数据是由意大利联盟收集的ALS遗传学和国际肌萎缩性硬化性硬化症遗传学的人群。 ALS（3125 [73.4％]已故）通过插补分析扩展到7 174 392变体的基因型数据。从1993年1月1日至2009年12月31日收集了DNA样本，并从2014年3月1日至2015年2月28日进行了分析。
COX比例危害回归在额外的模型下，对年龄的调整，性别和祖先的前4个主要成分，然后使用荟萃分析，用于分析Kaplan的最相关遗传变异的数据。 - 超级分析。
在分析中包括的4256名患者（2589名男性[60.8％]和1667名女性[39.2％]；平均[SD]年龄为59岁，59岁），以下2个新颖的基因座与ALS生存显着相关：在10Q23（在10q23） RS139550538; p = 1.87×10-9）和136的CAMTA1基因（RS2412208，P = 3.53×10-8）。 RS139550538 AA或基因型为1.61（95％CI，1.38–1.89; P = 1.87×10-9），与TT载体相比，生存率降低了8个月。 GG或GT基因型的患者为1.17（95％CI，1.11-1.24； P = 3.53×10-8），与TT相比，生存率降低了4个月载体。
这种GWA在全基因组的显着性水平上稳健地识别出ALS患者的生存水平，因为ALS是一种罕见的疾病，而预防是可行的，因此，修饰生存的治疗是最现实的策略。可能影响ALS的生存可以改善对疾病的生物学的理解，并提出药物干预的生物学靶标生存的风险评分可以用作临床试验的辅助，以说明生存的遗传贡献。
Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. To identify gene variants influencing survival in ALS. This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10−9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10−8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38–1.89; P = 1.87 × 10−9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11–1.24; P = 3.53 × 10−8), corresponding to a 4-month reduction in survival compared with TT carriers. This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.
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DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
12.7
作者：
Al-Sarraj, Safa;King, Andrew;Shaw, Christopher E.
通讯作者：
Shaw, Christopher E.
影响因子：
1.8
作者：
Al-Chalabi, Ammar;Lewis, Cathryn M.
通讯作者：
Lewis, Cathryn M.
DOI：
10.1073/pnas.0914079107
发表时间：
2010-07-06
影响因子：
11.1
作者：
Traynor, Bryan J.;Nalls, Michael;Chio, Adriano
通讯作者：
Chio, Adriano
影响因子：
16.2
作者：
DeJesus-Hernandez M;Mackenzie IR;Boeve BF;Boxer AL;Baker M;Rutherford NJ;Nicholson AM;Finch NA;Flynn H;Adamson J;Kouri N;Wojtas A;Sengdy P;Hsiung GY;Karydas A;Seeley WW;Josephs KA;Coppola G;Geschwind DH;Wszolek ZK;Feldman H;Knopman DS;Petersen RC;Miller BL;Dickson DW;Boylan KB;Graff-Radford NR;Rademakers R
通讯作者：
Rademakers R