Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients.
This study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR = 4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group. The 51.9% frequency of HLA DRB1*1501 positivity (HLA+) in MS was higher compared (OR = 2.33, p<0.001) to 31.6% to controls. The HLA+ frequency in the non-progressive (51.6%) and progressive MS groups (52.3%) was similar. The frequency of HLA+ CCSVI+ was 40.7% in progressive MS, 27.5% in non-progressive MS and 8.4% in controls. The presence of CCSVI was independent of HLA DRB1*1501 status in MS patients.
The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS.
Other than the report of Ferlini et al. , who conducted preliminary analysis of copy number variations associated with CCSVI in a group of 15 MS patients, no information is available on the role of genetic factors in CCSVI. These authors reported that CCSVI was associated of copy number variations in the HLA region for a small group of 15 MS patients . In other diseases with venous pathophysiologies, a role for gender, and environmental and genetic factors is suggested. Female gender, older age, and pregnancy are risk factors for chronic venous diseases  and women have greater frequency of variant hepatic veins . Women have also been reported to have a smaller internal jugular vein size than men (1.48 for men vs. 1.27 in women) . Venous malformations may have genetic contributions and a “double-hit” mechanism has been invoked to explain incomplete penetrance and variability , . The R849W substitution in the angiopoietin receptor Tie2 , an endothelial receptor tyrosine kinase, has been linked to familial venous malformations and results in variable thickness or lack of smooth-muscle cells in the veins of patient lesions. Interestingly Tie2 activates Stat1, which is also critical in interferon signaling. We did not observe, age, gender or disease duration differences in the occurrence of CCSVI (results not shown) in MS. However, a more detailed analysis of candidate gender-dimorphic factors, e.g., vein diameters and autoimmune factors, is warranted as these could strongly interact with changes in cerebral venous outflow.
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.
scorpion wrote:I am not sure why you consider this study to be misleading. The researchers tested a large number of people and concluded from the data that CCSVI is NOT associated with HLA DRB 1501 status. Study after study continues to call into question Zamboni's original CCSVI hypothesis and certainly brings into doubt his original findings which no study has even gottn close to validating. Instead of skepticim these studies seem to continually elicite "damage control" which is unfortunate for all of us trying to make sense of this chaos. If anyone can break down, in layman terms, what this study actually proves without throwing in their own "spin" it would be greatly appreciated. Patientx?? Any objective science buffs out there???
A region at or near the HLA-DRB1 locus in the MHC influences the risk of MS. HLA-DRB1 has over 400 different alleles. The dominant haplotype of Northern Europe, marked by the presence of DRB1*1501, increases risk of MS by 3-fold. The environment also plays a key role in MS. The most striking illustration of this is the geographical distribution of the disease in populations matched for ethnicity.
fiddler wrote:Scorpion, the numbers provided in the paper contradict its title. The correlation of HLA DRB 1501 status with CCSVI is almost 5 times as high as for normals (40.7% versus 8.4%). Therefore the title is COMPLETELY misleading and cheerleader is right. If you are going to be a skeptic, great, but then at least do your homework. You get an "F" for this one, as should the authors and/or the journal editor.
The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution.
scorpion wrote:The study above is another study that did not find the results one would expect if Zamboni's original hypothesis is correct and prior to that there were three or four studies calling into question his hypothesis.
cheerleader wrote:scorpion wrote:The study above is another study that did not find the results one would expect if Zamboni's original hypothesis is correct and prior to that there were three or four studies calling into question his hypothesis.
Your statement is not true.
This study has nothing to do with his hypothesis, which is that CCSVI is found in pwMS.
The allele HLA-DRB 1501 is a gene related to northern Europeans genetic make-up.
It is an MS susceptibility gene. It does not cause MS. It only increases susceptibility. Why should it be directly related to CCSVI?
People who live in Sardinia have MS, but do not have the specific allele HLA-DRB 1501. Does that mean people in Sardinia do not have MS? No, it means this gene is only ONE factor in susceptability.
47% of the pwMS screened in Buffalo did not have this allele. Does that mean they do not have MS? No.
The study doesn't prove anything about CCSVI. It is not a negative study against the viability of CCSVI. It is only more smoke.