title: CX3CR1 is a modifying gene of survival and progression in amyotrophic lateral sclerosis.
abstract: The objective of this study was to investigate the association of functional variants of the human CX3CR1 gene (Fractalkine receptor) with the risk of Amyotrophic Lateral Sclerosis (ALS), the survival and the progression rate of the disease symptoms in a Spanish ALS cohort. 187 ALS patients (142 sporadic [sALS] and 45 familial) and 378 controls were recruited. We investigated CX3CR1 V249I (rs3732379) and T280M (rs3732378) genotypes and their haplotypes as predictors of survival, the progression rate of the symptoms (as measured by ALSFRS-R and FVC decline) and the risk of suffering ALS disease. The results indicated that sALS patients with CX3CR1 249I/I or 249V/I genotypes presented a shorter survival time (42.27 ± 4.90) than patients with 249V/V genotype (67.65 ± 7.42; diff -25.49 months 95%CI [-42.79,-8.18]; p = 0.004; adj-p = 0.018). The survival time was shorter in sALS patients with spinal topography and CX3CR1 249I alleles (diff =  -29.78 months; 95%CI [-49.42,-10.14]; p = 0.003). The same effects were also observed in the spinal sALS patients with 249I-280M haplotype (diff =  -27.02 months; 95%CI [-49.57, -4.48]; p = 0.019). In the sALS group, the CX3CR1 249I variant was associated with a faster progression of the disease symptoms (OR = 2.58; 95IC% [1.32, 5.07]; p = 0.006; adj-p = 0.027). There was no evidence for association of these two CX3CR1 variants with ALS disease risk. The association evidenced herein is clinically relevant and indicates that CX3CR1 could be a disease-modifying gene in sALS. The progression rate of the disease's symptoms and the survival time is affected in patients with one or two copies of the CX3CR1 249I allele. The CX3CR1 is the most potent ALS survival genetic factor reported to date. These results reinforce the role of the immune system in ALS pathogenesis.
authors.affiliation: Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine - IDIBAPS, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain.
authors.forename: Alan
authors.initials: A
authors.lastname: Lopez-Lopez
authors.affiliation: ALS Unit, Neurology Department, Hospital Universitari Vall d'Hebron - VHIR. Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Gamez
authors.affiliation: ALS Unit, Neurology Department, Hospital Universitari Vall d'Hebron - VHIR. Autonomous University of Barcelona, Barcelona, Spain; Synaptic Structural Plasticity Lab, CIBIR, Logroño, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Syriani
authors.affiliation: Synaptic Structural Plasticity Lab, CIBIR, Logroño, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Morales
authors.affiliation: ALS Unit, Neurology Department, Hospital Universitari Vall d'Hebron - VHIR. Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Salvado
authors.affiliation: Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine - IDIBAPS, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain.
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Rodríguez
authors.affiliation: Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine - IDIBAPS, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain.
authors.forename: Nicole
authors.initials: N
authors.lastname: Mahy
authors.affiliation: Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine - IDIBAPS, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Vidal-Taboada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality; D000073883:CX3C Chemokine Receptor 1; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019707:Receptors, Chemokine / Q000235:genetics*; D013030:Spain; D015996:Survival Rate
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D019707:Receptors, Chemokine