This document summarizes a study that investigated genetic differences between two types of ANCA-associated vasculitis (AAV): granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The study analyzed over 1,200 AAV patients and found that GPA has a strong correlation with proteinase-3 (PR3) ANCA while MPA correlates with myeloperoxidase (MPO) ANCA. The study identified genetic variants in the MHC region of chromosome 6 and the SERPINA1 gene that are associated with PR3-positive AAV. It also found a SNP in the HLA-DQ locus linked to MPO-positive AAV. These genetic differences between

1. Genetically Distinct Diseases of
ANCA-Associated Vasculitis
By Blake Bordelon
Bisc 480

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. 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. 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. 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. 2 Major AAV Disorders
• Wegeners Granulomatosis
• Microscopic polyangitis

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. 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. 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. Study Hypothesis
• The association of Genetic variants seem to be
linked with ANCA specificity, and not with
physical attributes associated with the
diseases.

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. 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. SNPs associated with AAV

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. 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. 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. 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. 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. Treatment options
•
•
•
•
•
•
Methotrexate, Azithioprine
Cyclophasphamide (Cytoxin)
Rituximab – Targets B-cells
Prednisone/Prednisolone
Plasamapheresis* and Dialysis*
Renal Transplant