Genetically Distinct Diseases of ANCA-Associated Vasculitis

By Blake BordelonBisc 480

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

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.

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 auto-antibodies such as rheumatoid arthritis, myasthenia gravis and celiac disease.

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

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 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

Theory of ANCA Pathogenesis• AAV disorders are believed to

be caused when auto-antibodies 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

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?

Study Hypothesis

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

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.

MHC and Non-MHC Loci in AAV

• Panel A is a “Quantile-Quantile” 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

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 found to be associated with the myeloperoxidase ANCA

subgroup

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/>

SNP Prevalence in each disease

Source: New England Journal of Medicine, 2012 <http://www.nejm.org/doi/full/10.1056/NEJMoa1108735#t=article/>

• -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

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.

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.

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