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Open AccessArticle

Genetic Association and Altered Gene Expression of CYBB in Multiple Sclerosis Patients

Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy
Institute for Molecular Medicine Finland, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, 00290 Helsinki, Finland
Author to whom correspondence should be addressed.
Biomedicines 2018, 6(4), 117;
Received: 21 November 2018 / Revised: 13 December 2018 / Accepted: 15 December 2018 / Published: 18 December 2018
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
PDF [999 KB, uploaded 18 December 2018]


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. View Full-Text
Keywords: multiple sclerosis; association study; reactive oxygen species; NADPH oxidase; CYBB multiple sclerosis; association study; reactive oxygen species; NADPH oxidase; CYBB

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Cardamone, G.; Paraboschi, E.M.; Soldà, G.; Duga, S.; Saarela, J.; Asselta, R. Genetic Association and Altered Gene Expression of CYBB in Multiple Sclerosis Patients. Biomedicines 2018, 6, 117.

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