Dr. Smith transitioned to a discussion of unpublished genetic data on the rare disease eosinophilic granulomatosis with polyangiitis (EGPA), also known as the Churg–Strauss syndrome. The features of EGPA that are present in almost all patients are asthma and eosinophilia, and additional classification criteria include paranasal sinus abnormalities, infiltrates on chest imaging, neuropathy and histological evidence of extravascular eosinophils. Patients with EGPA can get very sick if untreated, with eosinophilic myocarditis as a life-threatening feature and neuropathy as a common source of disability.
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Because many patients with EGPA first present with asthma symptoms, a GWAS of patients with asthma has revealed some clues to the pathophysiology of EGPA.6 Although asthma is genetically heterogeneous, a few common alleles are associated with disease risk. The implicated genes suggest asthma results from a breakdown in the communication of epithelial damage to the adaptive immune system as well as the activation of airway inflammation. Surprisingly (at the time), elevation of total serum IgE levels had only a minor role in the development of asthma. Instead, variants in the ORMDL3/GSDMB locus were strongly associated only with childhood-onset disease. These results, in combination with a more recent GWAS study that interrogated 36 traits across the hematopoietic system, revealed a genetic relatedness between EGPA and asthma, which was consistent with their shared relatedness to eosinophil count.7
Dr. Smith has now documented 11 EGPA SNP associations that support the hypothesis that EGPA is a polygenic disease. Ten of the 11 EGPA loci are associated with eosinophil count, which suggests a unifying hypothesis in which eosinophil count drives the EGPA prodrome.
Genetic variants associated with long-term outcomes, however, are likely to be distinct from those that drive the susceptibility to disease, and therefore future research efforts will focus on genetics’ role on treatment response, which should make it possible to identify new therapies that target GWAS-identified pathways. Continued analysis of EGPA and other AAV subgroups could yield novel potential therapeutic targets, as well as a path toward individualized therapy.8
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
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