Genetically Distinct Diseases of
ANCA-Associated Vasculitis
By Blake Bordelon
Bisc 480
ANCA Associated Vasculitis (AAV)
• Antineutrophil cytoplasmic antibodies (ANCA) are
auto-antibodies that attack a persons ...
History of AAV
• Before the 1970’s, individuals with an AAV
died within a matter of months
• The discovery of cyclophospha...
Idiopathic Cause of Auto-Antibodies
• Tadema et al. states that the etiology of AAV
disorders is unknown, but it has been
...
ANCA Associated Vasculitis Cont.

• Determining the specific type of Vasculits and what is causing it is often very
diffic...
2 Major AAV Disorders

• Wegeners Granulomatosis
• Microscopic polyangitis
ANCA Specificity
• According to the University of North Carolina School of
Medicine, “Most patients with ANCA vasculitis h...
Theory of ANCA Pathogenesis
•AAV disorders are believed to
be caused when autoantibodies activate neutrophils

•These acti...
ANCAs Role in AAV
• A study performed by Hoffman et al. first
raised the question of whether there a
different forms life ...
Study Hypothesis
• The association of Genetic variants seem to be
linked with ANCA specificity, and not with
physical attr...
Study Regimen
• A genome wide study of AAV was performed on
1,233 patients from the United Kingdom that
focused on finding...
MHC and Non-MHC Loci in AAV
• Panel A is a “QuantileQuantile” plot that
measured the
association of all SNPs
from the disc...
SNPs associated with AAV
Regrouped

• The entire genome wide analysis was then redone to look for SNPs within a given
locus.
• a SNP in HLA-DQ was ...
Clinical Subtype and ANCA Specificity
• Granulomatosis with
polyangitis (GPA) shows
strong correlation with the
proteinase...
SNP Prevalence in each disease
• -log base 10 P Values of
SNP’s on the MHC locus
that are associated with 3
subgroups of V...
Results
• The polymorphic MHC region on chromosome
6 and the genes coding for α1-antitrypsin
(SERPINA1) on chromosome 14 w...
Conclusions
• A study by Lu et al. confirmed that serine
proteases (like PR3 and MPO) are more
important than superoxide r...
Treatment options
•
•
•
•
•
•

Methotrexate, Azithioprine
Cyclophasphamide (Cytoxin)
Rituximab – Targets B-cells
Prednison...
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Genetically Distinct differences of ANCA-Associated Vasculitis Disorders

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Distinct Genetic Differences of ANCA associated Vasculitis Disorders

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Genetically Distinct differences of ANCA-Associated Vasculitis Disorders

  1. 1. Genetically Distinct Diseases of ANCA-Associated Vasculitis By Blake Bordelon Bisc 480
  2. 2. ANCA Associated Vasculitis (AAV) • Antineutrophil cytoplasmic antibodies (ANCA) are auto-antibodies that attack a persons own cells, specifically a type of white blood cells called neutrophils • When this happens, blood vessels can become inflamed causing a condition called Vasculitis
  3. 3. History of AAV • Before the 1970’s, individuals with an AAV died within a matter of months • The discovery of cyclophosphamide and prednisone pushed the survival rate to 80% in almost 5 years. • Almost 50% of AAV patients who achieve remission, have a relapse within 2 years.
  4. 4. Idiopathic Cause of Auto-Antibodies • Tadema et al. states that the etiology of AAV disorders is unknown, but it has been hypothesized that they could be triggered by a bacterial or viral infection. • Many common disorders are caused by autoantibodies such as rheumatoid arthritis, myasthenia gravis and celiac disease.
  5. 5. ANCA Associated Vasculitis Cont. • Determining the specific type of Vasculits and what is causing it is often very difficult • Doctors must rely on a positive vs. negative ANCA test, but this is not full proof
  6. 6. 2 Major AAV Disorders • Wegeners Granulomatosis • Microscopic polyangitis
  7. 7. ANCA Specificity • According to the University of North Carolina School of Medicine, “Most patients with ANCA vasculitis have autoantibodies specific for perinuclear (P-ANCA) or cytoplasmic (C-ANCA) antibodies. C-ANCA is usually directed against proteinase 3 (PR3) and P-ANCA is usually directed again myeloperoxidase (MPO)”. P-ANCA C-ANCA
  8. 8. Theory of ANCA Pathogenesis •AAV disorders are believed to be caused when autoantibodies activate neutrophils •These activated neutrophils are then primed by cytokines to show MPO and PR3 on their surfaces •They then adhere to the endothelial walls of blood vessels and release oxygen radicals and enzymes that damage the surrounding tissues
  9. 9. ANCAs Role in AAV • A study performed by Hoffman et al. first raised the question of whether there a different forms life within ANCAs. • Is there a Genetic difference between WG and MPA? • Do these genetic differences change the treatment protocol?
  10. 10. Study Hypothesis • The association of Genetic variants seem to be linked with ANCA specificity, and not with physical attributes associated with the diseases.
  11. 11. Study Regimen • A genome wide study of AAV was performed on 1,233 patients from the United Kingdom that focused on finding the genetic differences involved with these diseases. • Patients were put into sub groups that were positive for either the PR3 or MPO ANCA associated with their disease. • Control Factors and statistical evaluations were used to evaluate the accuracy of the study being performed.
  12. 12. MHC and Non-MHC Loci in AAV • Panel A is a “QuantileQuantile” plot that measured the association of all SNPs from the discovery cohert, and replication cohort. • Panel B shows a log base 10 plot of the P values for each SNP that are plotted against its chromosomal location
  13. 13. SNPs associated with AAV
  14. 14. Regrouped • The entire genome wide analysis was then redone to look for SNPs within a given locus. • a SNP in HLA-DQ was found to be associated with the myeloperoxidase ANCA subgroup
  15. 15. Clinical Subtype and ANCA Specificity • Granulomatosis with polyangitis (GPA) shows strong correlation with the proteinase-3 (PR3) ANCA • Microscopic polyangitis (MPA) shows strong correlation with myeloperoxidase (MPO) ANCA Source: New England Journal of Medicine, 2012 <http://www.nejm.org/doi/full/10.1056/NEJMoa1108735#t=article/>
  16. 16. SNP Prevalence in each disease • -log base 10 P Values of SNP’s on the MHC locus that are associated with 3 subgroups of Vasculitic diseases • ANCA-associated Vasculitis (AAV) • PR3 ANCA only • MPO ANCA only Figure 2 Source: New England Journal of Medicine, 2012 <http://www.nejm.org/doi/full/10.1056/NEJMoa1108735#t=article/>
  17. 17. Results • The polymorphic MHC region on chromosome 6 and the genes coding for α1-antitrypsin (SERPINA1) on chromosome 14 were found to be associated with the proteinase 3 ANCA polyangitis patients. • A SNP of the HLA-DQ locus was found to be associated with myeloperoxidase ANCA polyangitis.
  18. 18. Conclusions • A study by Lu et al. confirmed that serine proteases (like PR3 and MPO) are more important than superoxide radicals in mediating cytotoxic damage. • The distinct genetic differences associated with these AAV diseases that target both proteinase 3 and myeloperoxidase ANCAs may allow for new therapy options that make use of the discoveries found in this study.
  19. 19. Treatment options • • • • • • Methotrexate, Azithioprine Cyclophasphamide (Cytoxin) Rituximab – Targets B-cells Prednisone/Prednisolone Plasamapheresis* and Dialysis* Renal Transplant

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