Custom CGH array profiling of copy number variations (CNVs) on chromosome 6p21.32 (HLA locus) in patients with venous malformations associated with multiple sclerosis

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.

Chronic Cerebrospinal Vascular Insufficiency Is Not Associated with HLA DRB1*1501 Status in Multiple Sclerosis Patients

“…These authors reported that CCSVI was associated of copy number variations in the HLA region for a small group of 15 MS patients [13]. In other diseases with venous pathophysiologies, a role for gender, and environmental and genetic factors is suggested.…”

Polymorphisms in the genes coding for iron binding and transporting proteins are associated with disability, severity, and early progression in multiple sclerosis

“…It has been hypothesized that CCSVI might favourite erythrocytes diapedesis, and subsequent iron deposition [12,13,38,46]. Even though this is an intriguing and interesting hypothesis and a genetic dependence of CCSVI has recently been described by our group [47], other authors do not directly link CCSVI with increased iron and MS [48-50]. …”

Small internal jugular veins with restricted outflow are associated with severe multiple sclerosis: a sonographer-blinded, case–control ultrasound study

“…The most important finding was that small IJV represents an independent factor associated with MS severity. It has been suggested that venous malformations may have a genetic etiology, and both environmental and genetic factors could play a role in venous pathophysiology [29,30]. Asymmetries and inborn anatomical differences have been observed in the truncular venous system [31,32], particularly during catheterization/interventional procedures in different groups of patients [11,33-36].…”