Genetic Susceptibility to ANCA-Associated Vasculitis: State of the Art

Abstract

ANCA-associated vasculitis (AAV) is a group of disorders that is caused by inflammation affecting small blood vessels. Both arteries and veins are affected. AAV includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) renamed from Wegener’s granulomatosis, and eosinophilic granulomatosis with polyangiitis (EGPA), renamed from Churg–Strauss syndrome. AAV is primarily due to leukocyte migration and resultant damage. Despite decades of research, the mechanisms behind AAV disease etiology are still not fully understood, although it is clear that genetic and environmental factors are involved. To improve the understanding of the disease, the genetic component has been extensively studied by candidate association studies and two genome-wide association studies. The majority of the identified genetic AAV risk factors are common variants. These have uncovered information that still needs further investigation to clarify its importance. In this review, we summarize and discuss the results of the genetic studies in AAV. We also present the novel approaches to identifying the causal variants in complex susceptibility loci and disease mechanisms. Finally, we discuss the limitations of current methods and the challenges that we still have to face in order to incorporate genomic and epigenomic data into clinical practice.

Eosinophils from Physiology to Disease: A Comprehensive Review

“…However, while NETs are crucial for the induction and maintenance of inflammation in AAV [ 288 ] and correlate with eosinophil count in EGPA [ 289 ], the potential role of EETs in EGPA is unknown. In addition, little is known about possible genetic factors accounting for enhanced eosinophil activity in EGPA [ 290 ], since most candidate-gene studies have focused on the HLA system and on alterations of the adaptive immune response [ 291 ]. The results from a GWAS are awaited.…”

Eosinophils in Autoimmune Diseases

“…EGPA is an idiopathic type of small vessel vasculitis and is also part of the hypereosinophilic syndromes ( 194 ). It is associated with HLA and IL-10 polymorphisms ( 195 ). About 40% of EGPA patients have perinuclear ANCA antibodies against myeloperoxidase (MPO), resulting in the classification of EGPA as an ANCA-associated vasculitis ( 192 , 193 ).…”

Distinct HLA and non‐HLA associations in different subtypes of ANCA‐associated vasculitides in North India

“…(IL)10, HLA-DR and -DQ. 6 However, HLA and disease association is not completely understood. There are two major hypotheses, used to explain the same.…”

“…Susceptibility to AAV is caused by interplay of genetic and environmental factors 5 . Genome‐wide association studies (GWAS) have pinpointed risk loci including human leukocyte antigen (HLA)‐DP, DQ (class II alleles), proteinase 3 and Serpin Family A Member 1, while candidate genes involved in pre‐GWAS include protein tyrosine phosphatase, non‐receptor type 22 (PTPN22), cytotoxic T‐Lymphocyte‐associated protein 4 (CTLA‐4), interleukin (IL)10, HLA‐DR and ‐DQ 6 . However, HLA and disease association is not completely understood.…”