Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

被引：78

作者：

van Eijk, Ruben P. A. ^{[1
]}

Jones, Ashley R. ^{[3
,4
]}

Sproviero, William ^{[3
,4
]}

Shatunov, Aleksey ^{[3
,4
]}

Shaw, Pamela J. ^{[5
]}

Leigh, P. Nigel ^{[6
]}

Young, Carolyn A. ^{[7
]}

Shaw, Christopher E. ^{[3
,4
]}

Mora, Gabriele ^{[8
]}

Mandrioli, Jessica ^{[9
]}

Borghero, Giuseppe ^{[10
]}

Volanti, Paolo ^{[11
]}

Diekstra, Frank P. ^{[1
]}

van Rheenen, Wouter ^{[1
]}

Verstraete, Esther ^{[12
]}

Eijkemans, Marinus J. C. ^{[2
]}

Veldink, Jan H. ^{[1
]}

Chio, Adriano ^{[13
,14
]}

Al-Chalabi, Ammar ^{[3
,4
]}

van den Berg, Leonard H. ^{[1
]}

van Es, Michael A. ^{[1
]}

机构：

[1] Univ Med Ctr Utrecht, Dept Neurol, Brain Ctr Rudolf Magnus, Utrecht, Netherlands

[2] Univ Med Ctr Utrecht, Dept Biostat & Res Support, Utrecht, Netherlands

[3] Kings Coll London, Maurice Wohl Clin Neurosci Inst, London, England

[4] Kings Coll London, United Kingdom Dementia Res Inst Ctr, Dept Basic & Clin Neurosci, London, England

[5] Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, Sheffield, S Yorkshire, England

[6] Brighton & Sussex Med Sch, Trafford Ctr Biomed Res, Dept Clin Neurosci, Brighton, E Sussex, England

[7] Walton Ctr NHS Trust, Liverpool, Merseyside, England

[8] Ist Clin Sci Maugeri IRCSS, Milan, Italy

[9] St Agostino Estense Hosp, Dept Neurosci, Modena, Italy

[10] Azienda Univ Osped Cagliari, Dept Neurol, Cagliari, Italy

[11] Ist Clin Sci Maugeri IRCSS, Mistretta, Italy

[12] Rijnstate Ziekenhuis, Arnhem, Netherlands

[13] Univ Torino, Rita Levi Montalcini Dept Neurosci, ALS Ctr, Turin, Italy

[14] Azienda Osped Citta Salute & Sci, Turin, Italy

来源：

NEUROLOGY | 2017年 / 89卷 / 18期

基金：

英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; REPEAT EXPANSIONS; RISK-FACTOR; LITHIUM; UNC13A; SURVIVAL; C9ORF72; LOCI; GENE; SOD1;

D O I：

10.1212/WNL.0000000000004606

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatmentwith lithium carbonate, but that the treatment effectwas lost in a large cohort of nonresponders. Methods: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype. Results: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p 5 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3). Conclusions: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.

引用

页码：1915 / 1922

页数：8

共 35 条

[31] Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis [J].

van Rheenen, Wouter ;

Shatunov, Aleksey ;

Dekker, Annelot M. ;

McLaughlin, Russell L. ;

Diekstra, Frank P. ;

Pulit, Sara L. ;

van der Spek, Rick A. A. ;

Vosa, Urmo ;

de Jong, Simone ;

Robinson, Matthew R. ;

Yang, Jian ;

Fogh, Isabella ;

van Doormaal, Perry T. C. ;

Tazelaar, Gijs H. P. ;

Koppers, Max ;

Blokhuis, Anna M. ;

Sproviero, William ;

Jones, Ashley R. ;

Kenna, Kevin P. ;

van Eijk, Kristel R. ;

Harschnitz, Oliver ;

Schellevis, Raymond D. ;

Brands, William J. ;

Medic, Jelena ;

Menelaou, Androniki ;

Vajda, Alice ;

Ticozzi, Nicola ;

Lin, Kuang ;

Rogelj, Boris ;

Vrabec, Katarina ;

Ravnik-Glavac, Metka ;

Koritnik, Blazi ;

Zidar, Janez ;

Leonardis, Lea ;

Groselj, Leja Dolenc ;

Millecamps, Stephanie ;

Salachas, Francois ;

Meininger, Vincent ;

de Carvalho, Mamede ;

Pinto, Susana ;

Mora, Jesus S. ;

Rojas-Garcia, Ricardo ;

Polak, Meraida ;

Chandran, Siddharthan ;

Colville, Shuna ;

Swingler, Robert ;

Morrison, Karen E. ;

Shaw, Pamela J. ;

Hardy, John ;

Orrell, Richard W. .

NATURE GENETICS, 2016, 48 (09) :1043-+

[32] Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases [J].

van Rheenen, Wouter ;

van Blitterswijk, Marka ;

Huisman, Mark H. B. ;

Vlam, Lotte ;

van Doormaal, Perry T. C. ;

Seelen, Meinie ;

Medic, Jelena ;

Dooijes, Dennis ;

de Visser, Marianne ;

van der Kooi, Anneke J. ;

Raaphorst, Joost ;

Schelhaas, Helenius J. ;

van der Pol, W. Ludo ;

Veldink, Jan H. ;

van den Berg, Leonard H. .

NEUROLOGY, 2012, 79 (09) :878-882

[33] Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial [J].

Verstraete, Esther ;

Veldink, Jan H. ;

Huisman, Mark H. B. ;

Draak, Tim ;

Uijtendaal, Esther V. ;

van der Kooi, Anneke J. ;

Schelhaas, H. Jurgen ;

de Visser, Marianne ;

van der Tweel, Ingeborg ;

van den Berg, Leonard H. .

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2012, 83 (05) :557-564

[34] Statistics in medicine - Reporting of subgroup analyses in clinical trials [J].

Wang, Rui ;

Lagakos, Stephen W. ;

Ware, James H. ;

Hunter, David J. ;

Drazen, Jeffrey M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2007, 357 (21) :2189-2194

[35] Adjusting for partially missing baseline measurements in randomized trials [J].

White, IR ;

Thompson, SG .

STATISTICS IN MEDICINE, 2005, 24 (07) :993-1007

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