Genetic Breakthrough into ANCA-Associated Vasculitis

The first genome-wide association study of antineutrophil cytoplasm antibody (ANCA)–associated vasculitis (AAV) has identified key genetic distinctions between the two major clinical syndromes of the disease. Although the syndromes—granulomatosis with polyangiitis and microscopic polyangiitis—can be differentiated in extreme versions, many patients “fall into the middle in sort of a gray zone where physicians classify them inconsistently,” said Kenneth Smith, MD, PhD, of the University of Cambridge. The confirmation that the syndromes have different genetic underpinnings could lead to improved diagnoses and better clinical trial designs for possible treatments.

Previous genome-wide association studies have successfully identified single nucleotide polymorphisms associated with several disease states, including diabetes, Parkinson disease, and Crohn disease. Presenting on behalf of the European Vasculitis Genetics Consortium, Smith showed the results of the first genome-wide association study in AAV that validated the genetic differences between granulomatosis with polyangiitis and microscopic polyangiitis, both of which cause kidney failure. The analysis included a discovery cohort of 1233 patients with AAV and 5884 controls from the United Kingdom and a replication cohort of 1454 patients with AAV and 1666 controls from Europe.

Researchers found that the disease exhibited familial clustering (similar to rheumatoid arthritis), and also observed genetic distinctions with antigenetic specificity—anti–proteinase 3 AAV and anti–myeloperoxidase AAV. The identification of the two distinct autoimmune syndromes and associated risk alleles has implications for the etiology of AAV and for future research that could lead to disease-specific pathways and therapeutic targets.