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When enough significant anomalies have accrued against a current paradigm, the scientific discipline is thrown into a state of crisis, according to Kuhn. During this crisis, new ideas, perhaps ones previously discarded, are tried. Eventually a new paradigm is formed, which gains its own new followers, and an intellectual "battle" takes place between the followers of the new paradigm and the hold-outs of the old paradigm.

Reporting this week in Nature1, the researchers, led by Sergio Baranzini at the University of California, San Francisco, and Stephen Kingsmore of the National Center for Genome Resources in Santa Fe, New Mexico, next looked for a difference in epigenetics — chemical modifications to DNA that affect gene expression but not genetic sequence — in the twins' immune cells and in cells of two other sets of similarly affected twins. But no differences were found in the expression levels of key genes, either.

Although they did not sequence the genomes of the other two sets of twins, they did compare 1 million specific 'spelling variations' (known as single nucleotide polymorphisms, or SNPs) in the sequences of twins with and without MS, confirming that their genomes were the same.

Because the study examined the genome so comprehensively, "it is an incredibly important negative", says David Hafler, a neurologist at Yale University in New Haven, Connecticut. The results indicate that there is no clear genetic reason to explain why one twin developed MS while the other did not.

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 (6,899,999bp; 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.

Author: Alessandra FerliniMatteo BovolentaMarcella NeriFrancesca GualandiAlessandra BalboniAnton YuryevFabrizio SalviDonato GemmatiAlberto LiboniPaolo Zamboni
Credits/Source: BMC Medical Genetics 2010, 11:64

cheerleader wrote:NEW PUBLICATION: Strong correlation between venous malformation, CCSVI and MS-
http://www.biomedcentral.com/content/pd ... -11-64.pdf

I heard Dr. Ferlini speak in Bologna, and to be honest...nothing confuses me more than genetics medicalese. It's unbelievably difficult to follow---but here's new research showing how stenosing vascular malformations and multiple sclerosis are STRONGLY related, as shown by shared "copy number variations" in DNA samples. This is more proof that the genetic connection of venous malformations is connected to MS.

Here's the research...good luck!!

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 (6,899,999bp; 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.

Author: Alessandra FerliniMatteo BovolentaMarcella NeriFrancesca GualandiAlessandra BalboniAnton YuryevFabrizio SalviDonato GemmatiAlberto LiboniPaolo Zamboni
Credits/Source: BMC Medical Genetics 2010, 11:64

cheer

The results indicate that there is no clear genetic reason to explain why one twin developed MS while the other did not.