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De novo vs. inherited copy number variations in multiple sclerosis susceptibility

Cellular & Molecular Immunology volume 15, pages 812–814 (2018)Cite this article

The Human Genome Project has identified, along with single nucleotide polymorphisms (SNPs), a range of other DNA sequence variations, including insertions and deletions of nucleotides and translocations of various segments of a chromosome.1 These variations have, collectively, been named copy number variants (CNVs).1 They represent a major source of genomic variation, with nearly 1500 variable regions covering approximately 12% of the human genome.2 A CNV could act directly by affecting gene dosage and gene expression through complex mechanisms. It is thought, therefore, that CNVs in gene-dosage sensitive genes may have considerable influence on disease susceptibility.2 Among genes overlapped by CNVs, significant enrichments in certain gene ontology categories have been identified, including those related to immune responses and interaction with the environment.3 CNVs have already been associated with several monogenic, syndromic and complex diseases.

Candidate gene association studies in multiple sclerosis (MS) have identified multiple common allelic variants. Given the important role of vitamin D in MS, polymorphisms in the vitamin D receptor (VDR) gene have been extensively studied in relation to MS susceptibility. A meta-analysis by Tizaoui et al.4 showed that SNPs in the VDR gene were significantly associated with MS risk. The genetic effects were modest, implicating other genetic variations such as CNVs, which may have larger effects than SNPs. Interestingly, the meta-analysis reported the interaction of VDR polymorphisms with exogenous factors. In fact, as a receptor for vitamin D, VDR expression is, directly and indirectly, dependent on environmental factors. Vitamin D deficiency may increase the incidence of CNVs. Genes involved in vitamin D pathways may be particularly prone to genetic variations. Gene ontology analyses have revealed that CNVs are frequent in genes implicated in immune responses and responses to external biotic stimuli.5 Although investigations of SNPs could provide important information in MS genetics, the results remain partial. In the future, more interest should be given to CNVs in genes related to vitamin D pathways.

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  1. Department of Basic Sciences, Medicine Faculty of Tunis, Tunis El Manar University, 15 Rue Djebel Lakdar, 1007, Tunis, Tunisia

    Kalthoum Tizaoui

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Correspondence to Kalthoum Tizaoui.

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Tizaoui, K. De novo vs. inherited copy number variations in multiple sclerosis susceptibility. Cell Mol Immunol 15, 812–814 (2018). https://doi.org/10.1038/cmi.2017.166

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