It's important to understand the connection between the genetics of the immune system and the genetics of venous malformations---or the posited cause of CCSVI. The study by Dr. Ferlini is linked on this page, and she showed the multitude of copy number variations that the immune system in pwMS and the vascular malformations of CCSVI share. Here is is again:
http://www.fondazionehilarescere.org/pdf/ferlini-etal-2010-final.pdf
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 Vascular Malformations (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.
Dr. Compston believes that he can silence MS vascular research by claiming that there is no interplay between the vascular system and the immune system, and that the genes he has located in MS are purely immune modulating genes, but he is wrong. Dead wrong. As anyone who reads this page knows, the endothelium is responsible for the interaction of the immune system and the vascular system, and functions as such by providing the lining of our blood vessels and lymphatic system. Here is more specific information on just one of genes responsible for venous malformations--such as atresia, webs, inverted valves and hypoplasia. These specific malformations are what the doctors are finding in CCSVI--
This gene, FAP48, is also noted as an immune modulating gene. FAP48 is found to contribute to venous malformations, and it is also found to modify t-cell immune response. Many genes, as Dr. Ferlini's study shows, have this kind of interaction.
Venous malformation is a common type of vascular anomaly. Two genes have been identified for venous malformations, TIE2 for mucocutaneous venous malformations (MIM #600195) and glomulin for glomuvenous malformations (MIM #138000). A linkage study of a three generation family with multiple cutaneous and mucosal venous malformations mapped the genetic locus to chromosome 9p21.45. The disease-causing gene was later identified as TIE2 that codes for the endothelial cell-specific receptor tyrosine kinase TIE2, which is a receptor for angiogenic factors angiopoietin-1 (Ang-1) and angiopoietin-2.
Glomuvenous malformations or glomangiomas are venous malformations with smooth muscle-like glomus cells (GVM, MIM #138000). Boon et al.46 identified the first locus for GVM on chromosome 1p22-p21. The specific gene was later identified as the glomulin 47 (FAP48) gene coding for an FK506-binding protein (FKBP)-associated protein of 48 kD. The function of glomulin is unknown.
http://www.sld.cu/galerias/pdf/sitios/genetica/malfromaciones_vasculares.pdf
Now--let's look at a gene which is implicated in venous malformations....Glomulin 47, or FAP48-FKBP. This gene is not only involved in venous malformations, it is also associated with the activation of t-cells. Here's some research:
In the present study, we provide evidence for an implication of FAP48 in the activation of T lymphocytes and for its antiproliferative properties. The involvement of target molecules in the signaling pathway of FAP48 is discussed.
To sum up, we provide evidence that the FKBP endogenous ligand FAP48 exerts different biological effects in T cells. In unstimulated T cells, free FAP48 regulates cellular proliferation possibly by down-regulating ASS with a resulting lack of arginine for protein synthesis and by up-regulating the tumor-suppressor molecule Mxi1. In activated T cells, the FAP48–FKBP complexes up-regulate IL2 synthesis. Additional studies are required to identify which FKBP when complexed with FAP48 is involved in the increase of IL2 secretion and to assess the possible role of ASS and Mxi1 as mediators of the biological effects of FAP48. The results presented here suggest that FAP48 could be implicated in the control of the immune response and exert an antigrowth function.
http://www.pnas.org/content/100/5/2444.full.pdf
What does this all mean? It means that genetics is a very complex subject. It means that it may be too complex for the Globe and Carly Weeks. It means that Dr. Compston's research into genetics only related to the immune system in MS is limited in scope. It means that the research into the vascular paradigm of MS is far from over. It's only just beginning.
Joan
