Genetic Modifiers Have an Additive Effect on ALS Prognosis: a Population-Based Study

Objective: To determine if the co-presence of genetic polymorphisms related to ALS has additive effects on the course of the disease in a population-based cohort of Italian patients. Background: Besides the disease-causing genes, several other genes have been reported to act as modifiers of ALS phenotype, especially patients’ survival. However, the interactions of these genes at clinical level have never been explored. Design/Methods: The study population includes 1245 ALS patients identified through the Piemonte Register for ALS, diagnosed between 2007 and 2016 and not carrying SOD1, TARDBP and FUS mutations. Controls were 766 age, sex, and geographically matched Italian subjects. We considered UNC13A (rs12608932), CAMTA1 (rs2412208), SLC112A (rs407135) and ZNF512B (ZNF512B) polymorphisms, as well as ATXN2 polyQ intermediate repeats (≥31) and C9ORF72 GGGGCC intronic expansion (≥30). Results: The variants in C9orf72 (p=0.016), ATXN2 (p<0.001) and UNC13A (p<0.001) were significantly related to survival in univariate analysis, while the other considered variants did not influence ALS outcome. However, in the Cox multivariable analysis, also CAMTA1 emerged to be independently related to survival (p=0.048). When assessing the interaction by pairs of genes, we found that the presence of both detrimental alleles/expansion was correlated with significantly shorter survival compared to subjects non-carrying both detrimental alleles/expansions. Each association of pairs of detrimental alleles was characterized by specific clinical phenotypes. Conclusions: We demonstrated that gene polymorphisms acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental common polymorphism or repeat expansion, highlighting the clinical impact of our findings. In addition, the identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity and should be considered in designing and interpreting clinical trials. Disclosure: Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cytokinetics. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Cristina Moglia has nothing to disclose. Antonio Canosa has nothing to disclose. Dr. Manera has nothing to disclose. Mr. Grassano has nothing to disclose. Dr. Vasta has nothing to disclose. Francesca Palumbo has nothing to disclose. Maura Brunetti has nothing to disclose. Fabiola De Marchi has nothing to disclose. Ruth Chia has nothing to disclose. Dr. Mora has nothing to disclose. Barbara Iazzolino has nothing to disclose. Laura Peotta has nothing to disclose. The institution of Dr. Traynor has received research support from ALS Association. The institution of Dr. Traynor has received research support from Merck. The institution of Dr. Traynor has received research support from Myasthenia Gravis Foundation. The institution of Dr. Traynor has received research support from Cerevel Therapeutics. Dr. Traynor has received intellectual property interests from a discovery or technology relating to health care. Lucia Corrado has nothing to disclose. Sandra D’Alfonso has nothing to disclose. Letizia Mazzini has nothing to disclose. Dr. Calvo has nothing to disclose.