Abstract
Objective:To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was 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 = 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.
Highlights
This study incorporated genetic data into past amyotrophic lateral sclerosis (ALS) trials to determine treatment effects in a genetic post hoc analysis
We explore the possibility that patients with genetic subgroups of ALS may have responded to treatment in previously conducted negative trials evaluating lithium carbonate, but that a proportionally larger cohort of nonresponders diluted the treatment effect in the overall analysis
Data were available for 518 participants in 3 randomized clinical trials evaluating the efficacy of lithium carbonate; study characteristics are given in table 1
Summary
Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. This may further reduce the statistical power by multiple testing, but more importantly, will inflate the false-positive risk To overcome these issues, we performed an individual participant data (IPD) meta-analysis of randomized controlled trials with lithium carbonate in ALS; multiple trials with this compound have been performed and, a large sample size could be obtained. Repeat expansions in C9orf[72] are the most common genetic cause of ALS and are found in approximately 5%–10% of patients with ALS of European descent (familial and sporadic cases combined).[7,8] Genome-wide association studies (GWAS) have repeatedly detected an association for a single nucleotide polymorphism (SNP: rs12608932) located in the UNC13A gene.[9,10,11] The effect of this SNP on disease risk is modest, with an odds ratio ,1.30, but appears to convey a large effect on survival. Multiple studies have shown that the mean survival in patients homozygous for the C allele of rs12608932 is 6 to 12 months shorter, implying that this SNP, or variants in linkage disequilibrium with it, is a strong phenotypic modifier and of biological relevance.[12,13,14,15] Approximately 16% of patients with ALS are homozygous for the C allele of rs12608932.9–11
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