TORNA ALL’ELENCO

Common polymorphisms of the CX3CR1 gene are modifiers of ALS outcomes: A population-based study in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

2016
AOU Città della Salute di Torino

Tipo pubblicazione

Conference Abstract

Autori/Collaboratori (8)Vedi tutti...

Calvo A

Canosa A

Moglia C


et alii...

Abstract

Background: The pathogenesis of ALS is likely related to a complex interplay between several mechanisms, such as mitochondrial dysfunction, cytoplasmic accumulation of misfolded proteins, and altered axonal transport. Neuroinflammation has come to the fore as being important, particularly in the propagation of the disease. The CX3CR1 gene (chemokine (C-X3-C motif) receptor 1, also known as Fractalkine receptor (OMIM: 601470), in the brain is only expressed by microglia where it is a key mediator of the neuron-microglia interactions that are upregulated in many inflammatory conditions. Aim: To assess whether the two common polymorphisms of the CX3CR1 gene (rs3732379 and rs3732378) alter the risk of developing ALS and/or modify phenotype in a large population-based series of ALS patients. Methods: The study includes 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 ageand gender-matched controls from the same geographical area. Cases and controls were genotyped using Illumina Infinium II HumanHap<50 SNP chips (Illumina, San Diego, CA), which assayed 555,352 common SNPs across the genome. Genotype data for rs3732379 (build hg19, chr3:39307256C>T) and rs3732378 (chr3:39307162G>A) were extracted from the larger dataset. Results: Neither V249I nor T280M variants were associated with increased risk of ALS under any of the tested statistical models. Age at onset and site of onset of ALS were not influenced by either the V249I or T280M variants under any of the considered statistical models. The V249I genotype was related to a 6 months shorter survival in patients with a 249v/v genotype (387 cases, median survival time 2.6 years, IQR 1.7-4.4) compared to those with a 249I/I and 249V/I genotype (368 cases, median survival time 3.1 years, IQR 1.7-5.3, p=0.02) under the dominant model. The T280M genotype additive model showed a significant difference between the three genotypes (p=0.04, test for trend). In Cox multivariable analysis, the interaction be

DOI : 10.1080/21678421.2016.1232052/0022

Keywords

chemokine receptor CX3CR1; endogenous compound; brain; controlled study; diagnosis; female; gender; gene frequency; gene mutation; genetic susceptibility; genome; genotype; human; major clinical study; male; median survival time; mediator; microglia; nervous system inflammation; onset age; phenotype; population based case control study; population model; single nucleotide polymorphism; statistical model;