Abstract
Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation, demyelination, and axonal damage. Increased levels of reactive oxygen species (ROS), produced by macrophages and leading to oxidative stress, have been implicated as mediators of demyelination and axonal injury in both MS and experimental autoimmune encephalomyelitis, the murine model of the disease. On the other hand, reduced ROS levels can increase susceptibility to autoimmunity. In this work, we screened for association with MS 11 single nucleotide polymorphisms (SNPs) and two microsatellite markers in the five genes (NCF1, NCF2, NCF4, CYBA, and CYBB) of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) system, the enzymatic pathway producing ROS in the brain and neural tissues, in 347 Finnish patients with MS and 714 unaffected family members. This analysis showed suggestive association signals for NCF1 and CYBB (lowest p = 0.038 and p = 0.013, respectively). Functional relevance for disease predisposition was further supported for the CYBB gene, by microarray analysis in CD4+/− mononuclear cells of 21 individuals from five Finnish multiplex MS families, as well as by real-time RT-PCRs performed on RNA extracted from peripheral blood mononuclear cells of an Italian replication cohort of 21 MS cases and 21 controls. Our results showed a sex-specific differential expression of CYBB, suggesting that this gene, and more in general the NOX2 system, deserve to be further investigated for their possible role in MS.
Highlights
Multiple sclerosis (MS) (Online Mendelian Inheritance in Men, OMIM #126200) is a chronic disease of the central nervous system (CNS) characterized by multifocal inflammation, plaques of myelin degeneration, axonal damage, and by a high degree of individual variability in the severity and progression of symptoms [1,2,3]
NCF1 and CYBB Are Associated with MS in the Finnish Population
For investigating the potential role of oxidative stress (OS) genes in the pathogenesis of MS, we performed an association analysis on a Finnish cohort of 63 MS families (547 individuals) with two microsatellite markers and 11 single nucleotide polymorphisms (SNPs) mapping in or located close to the five genes coding for the main components of the NOX2 complex
Summary
Multiple sclerosis (MS) (Online Mendelian Inheritance in Men, OMIM #126200) is a chronic disease of the central nervous system (CNS) characterized by multifocal inflammation, plaques of myelin degeneration, axonal damage, and by a high degree of individual variability in the severity and progression of symptoms [1,2,3]. 100,000 person/year; the highest prevalence and incidence rates have been reported in Finland [4]. The NOX2 system is a complex that, in resting cells, is compartmentalized between cytosol and plasma membrane: the core enzyme is composed of three cytoplasmic polypeptides (p47phox, p67phox, and p40phox, encoded by NCF1, NCF2, and NCF4 genes, respectively), and a membrane-bound flavo-hemo-cytochrome, b558, constituted by two components, the p22phox and gp91phox subunits (encoded by CYBA and CYBB, respectively) [29,30]. Given the proposed role of OS in MS, its contribution to the pathogenesis of the disease was here investigated by genetic association and expression analyses of the five genes coding for the main components of the NOX2 complex
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