Association of Intermediate HTT CAG Repeats with Increased Risk and Disease Severity in Amyotrophic Lateral Sclerosis
Maurizio Grassano1, Antonio Canosa1, Lucia Corrado2, Sandra D'Alfonso2, Umberto Manera1, Rosario Vasta1, Emanuele Koumantakis1, Giorgia Brodini1, Francesca Palumbo1, Cristina Moglia1, Ruth Chia3, Letizia Mazzini2, Andrea Calvo1, Sonja Scholz3, Bryan Traynor3, Adriano Chio1
1Dept. of Neuroscience, University of Turin, 2Department of Health Sciences, University of Eastern Piedmont, 3National Institute on Aging, NIH
Objective:
This study investigates the frequency of intermediate HTT CAG expansions in ALS patients relative to healthy controls, thereby determining their contribution to ALS pathogenesis. Their effect on ALS phenotype and disease progression was also evaluated.
Background:
The pathological role of expanded CAG trinucleotide repeats (≥ 40) in the Huntingtin gene (HTT) has recently been established in amyotrophic lateral sclerosis (ALS). However, the impact of intermediate-sized HTT CAG expansions (i.e., 27–35 repeats) remains unclear.
Design/Methods:
We analyzed whole-genome sequencing data from a population-based case-control cohort and conducted a comprehensive meta-analysis of existing research to substantiate the association between intermediate HTT expansions and ALS susceptibility. We included 1,324 ALS patients and 757 healthy controls from the Piemonte and Valle d'Aosta Register for ALS (PARALS) in Northern Italy. The meta-analysis further integrated data from three published studies, incorporating data from 1,909 ALS cases and 4,420 control subjects. We further performed a phenotypic analysis comparing ALS patients with and without intermediate HTT expansions. Phenotypic comparisons included the age at disease onset, cognitive impairment, ALSFRS-R decline rate, and survival from symptom onset.
Results:
In the PARALS cohort, 6.80% of ALS cases and 4.62% of controls carried between 27 and 35 CAG repeats in the HTT gene, suggesting a modestly elevated ALS risk among carriers of intermediate-repeat expansions (OR = 1.50, 95% CI = 1.01–2.28, P = 0.0501). The meta-analysis reinforced this association (OR = 1.82, 95% CI = 1.48–2.23, P = 2.03 x 10-8). ALS patients with intermediate HTT expansions also demonstrated faster disease progression (ΔALSFRS-R difference = +0.20 points per month, 95% CI = 0.02–0.41, P = 0.0316) and reduced survival (HR = 1.42, 95% CI = 1.13–1.79, P = 0.0018).
Conclusions:
This research presents compelling evidence implicating intermediate HTT expansions in ALS pathogenesis. These findings enhance our understanding of ALS and point toward potential therapeutic interventions.