Abstract
BackgroundMultiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance.MethodsIn order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999 bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate.ResultsIn total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r = 0.6590, p = 0.0104; linear regression analysis r = 0.6577, p = 0.0106).The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype.ConclusionsThe CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.
Highlights
Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, it is known to be associated with the HLA region on 6p21.32
The copy number variations (CNVs) contained in the HLA locus region in patients with the novel phenotype of chronic cerebrospinal venous insufficiency (CCSVI)/venous malformations (VM) and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients
We recently described the CCSVI/VM phenotype associated with MS, which might participate in iron accumulation in the brain, a feature known to be present in several neurodegenerative diseases, including MS [34,35,36]
Summary
Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, it is known to be associated with the HLA region on 6p21.32. Even when controls are accurately randomised, undetectable errors may occur, especially linked to the geographical origins of the population and known differences in SNPs density, depending on the various human chromosomes or even genomic regions involved. These errors may inflate the apparently significant differences between patients and controls (genomic inflation) generating false positives or negatives and impeding true recognition of the associated loci [11]. It is evident that CNVs account for more nucleotide variations between individuals, and, the functional significance of these variations might be more immediate, especially if they are located within genes, regulatory regions or known imprinted regions, since the possible consequence of genome imbalance(s) may be more interpretable
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