CX3CR1 is a modifying gene of survival and progression in amyotrophic lateral sclerosis.

Alan Lopez-Lopez,Jose M Vidal-Taboada,Manuel J Rodríguez,Nicole Mahy,Josep Gamez,Miguel Morales,Emilio Syriani,Maria Salvado,Cedric Raoul

doi:10.1371/journal.pone.0096528

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.

Highlights

Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease or maladie de Charcot, is the most common adult onset neurodegenerative motor neuron disease [1,2]
All the DNA samples were genotyped for the functional variants V249I and T280M of the CX3CR1 gene
Both genetic variants were within the Hardy-Weinberg equilibrium in the different groups (wALS, sporadic ALS (sALS), fALS and controls, HWE for V249I = 0.579; for T280M = 0.399; Table S1)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease or maladie de Charcot, is the most common adult onset neurodegenerative motor neuron disease [1,2]. Epidemiological studies suggest that major genetic defects make fewer than 10% of ALS patients susceptible to the disease. For the majority of the population, ALS is considered a multifactorial disease with multiple interactive pathogenic mechanisms [3,4,5,6]. This variability of pathogenic mechanisms may be the reason why ALS is a heterogeneous disorder from the clinical perspective, in terms of the age at onset, progression, initial topography and survival

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