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. 2014 May 7;9(5):e96528.
doi: 10.1371/journal.pone.0096528. eCollection 2014.

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

Alan Lopez-Lopez  1 , Josep Gamez  2 , Emilio Syriani  3 , Miguel Morales  4 , Maria Salvado  2 , Manuel J Rodríguez  1 , Nicole Mahy  1 , Jose M Vidal-Taboada  1
Affiliations

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

Alan Lopez-Lopez et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts: According to diagnostic potential of the research ALL, JG, ES, MM, MJR, NM and JVT have applied for a PCT application to develop a clinical diagnostic kit. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. All other authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Kaplan–Meier survival curves for CX3CR1-V249I genotypes according to a dominant genetic model in the sALS group (A) and the sALS group with only spinal topography (B).
The green line is for V/I+I/I genotypes, and the blue line is for the VV genotype.
See this image and copyright information in PMC

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