BACKGROUND: 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, 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. METHODS: In 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. RESULTS: In 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. CONCLUSIONS: The 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.
BACKGROUND: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, 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. METHODS: In 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. RESULTS: In 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. CONCLUSIONS: The 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.
Authors: A John Iafrate; Lars Feuk; Miguel N Rivera; Marc L Listewnik; Patricia K Donahoe; Ying Qi; Stephen W Scherer; Charles Lee Journal: Nat Genet Date: 2004-08-01 Impact factor: 38.330
Authors: R H S R Roxburgh; S R Seaman; T Masterman; A E Hensiek; S J Sawcer; S Vukusic; I Achiti; C Confavreux; M Coustans; E le Page; G Edan; G V McDonnell; S Hawkins; M Trojano; M Liguori; E Cocco; M G Marrosu; F Tesser; M A Leone; A Weber; F Zipp; B Miterski; J T Epplen; A Oturai; P Soelberg Sørensen; E G Celius; N Téllez Lara; X Montalban; P Villoslada; A M Silva; M Marta; I Leite; B Dubois; J Rubio; H Butzkueven; T Kilpatrick; M P Mycko; K W Selmaj; M E Rio; M Sá; G Salemi; G Savettieri; J Hillert; D A S Compston Journal: Neurology Date: 2005-04-12 Impact factor: 9.910
Authors: Chris H Polman; Stephen C Reingold; Gilles Edan; Massimo Filippi; Hans-Peter Hartung; Ludwig Kappos; Fred D Lublin; Luanne M Metz; Henry F McFarland; Paul W O'Connor; Magnhild Sandberg-Wollheim; Alan J Thompson; Brian G Weinshenker; Jerry S Wolinsky Journal: Ann Neurol Date: 2005-12 Impact factor: 10.422
Authors: Marc A Lazzaro; Osama O Zaidat; Nils Mueller-Kronast; Muhammad A Taqi; Douglas Woo Journal: Front Neurol Date: 2011-07-14 Impact factor: 4.003
Authors: Bianca Weinstock-Guttman; Robert Zivadinov; Gary Cutter; Miriam Tamaño-Blanco; Karen Marr; Darlene Badgett; Ellen Carl; Makki Elfadil; Cheryl Kennedy; Ralph H B Benedict; Murali Ramanathan Journal: PLoS One Date: 2011-02-14 Impact factor: 3.240