Approved research

A Genome-Wide Association Study in ANCA-Associated Vasculitis

Lay summary

Vasculitis is a rare disease where the immune system -which normally fights infection- mistakenly attacks the blood vessels and surrounding tissues, leading to dysfunction of potentially any organ and system in the body. ANCA-associated vasculitis (AAV) is a type of vasculitis characterized by the abnormal production of antibodies against inflammatory blood cells called neutrophils. These antibodies, known as ANCAs (Anti-Neutrophil Cytoplasmic Antibodies), are directed against one of two neutrophil components, myloperoxidase (MPO) and proteinase-3 (PR3), and activate neutrophils upon binding, leading to inflammation of small and medium-sized vessels. Disease manifestations can be very different from one patient to the other, ranging from life-threatening (especially when the kidneys, the lungs or the heart are involved) to a relatively benign presentation. Drugs that suppress the immune response are the mainstay of treatment and are usually effective, but can have severe side effects. What causes the disease, and why it can be so different from one patient to the other, is not well understood. We previously conducted the first large-scale genetic association study in more than 1200 patients with AAV, and identified genetic variants that differentially predispose to the 2 main subsets of the disease, namely PR3-positive and MPO-positive AAV. This project aims to further look into the genetic architecture of AAV by studying a new cohort of over 3000 patients, recruited from all over Europe thanks to the European Vasculitis Genetics Consortium (EVGC). The genetic makeup of AAV patients will be compared with healthy controls from the UK BioBank, and the results will be combined with those of our previous study. By substantially increasing the number of patients and healthy controls to study, we will have significantly higher chances to discover new genetic variants that affect predisposition to AAV. Moreover, we will look into whether different genetic profiles can explain clinically relevant differences between patients (for instance, whether the vasculitis affect the kidneys, or the lungs). A better understanding of the genetic architecture of AAV can provide novel insights into biological processes that play a key role in the disease. This line of research can identify promising drug targets, aiding the development of new medicines with an improved safety profile. Moreover, the discovery of genetic markers that modulate disease course may help doctors to better tailor treatment to patients' needs, improving disease outcomes and quality of life.