Wegener's Granulomatosis is one of the anti-neutrophil cytoplasmic antibody (ANCA) positive systemic vasculitides which is characterized by inflammatory lesions with granuloma formation in the upper and lower airways, by pauci-immune glomerulonephritis and by anti-proteinase 3 autoantibodies (PR#-ANCA). Although WG is idiopathic, there has been substantial interest in environmental factors as either etiologic or accelerating risk factors. Because of epidemiological studies implicating nasal carriage and therapeutic studies implicating efficacy of anti-staphylococcal agents at least for upper airway disease, Staphylococcus aureus has attracted substantial attention as one such environmental factor. Although consensus about etiology remains elusive, the nature of the host response has emerged as an important determinant for disease phenotype and severity. There are may examples of human disease, provoked by environmental exposures, which have important genetic factors contributing to both susceptibility and severity. HIV presents one such example. Thus the identification of important genetic factors in a disease such as WG is not only feasible but also potentially very fruitful in providing insights into pathogenesis and potential therapeutic targets. Building on the clinical trial of Etanercept in WG (Wegener's Granulomatosis Etanercept Trial, WGET), we propose to develop a renewable genetic repository which will provide resources to all WGET investigators and to explore the relationship between the WG diathesis and genetic polymorphisms in candidate molecules, selected for their role in pathophysiology. We also propose to discover new polymorphisms in such molecules and apply these to this cohort. Accordingly, our specific aims are: 1) To establish a renewable biological resource of all WG patients screened and enrolled in the WGET clinical trial, including two ethnically and geographically matched controls for each patient; 2) To determine if known variations in genes involved in the innate inflammatory response, in lymphocyte activation and in target antigen biology influence the susceptibility to or severity of WG; 3) Recognizing that the knowledge base about biologically significant genetic variants will increase, we will determine, through direct discovery and through continual evaluation of SNP databases, if newly identified variation in gene categories outline in Specific Aim 2 influence the susceptibility to or severity of WG.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-SSS-J (03))
Program Officer
Serrate-Sztein, Susana
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Sreih, Antoine G; Ezzedine, Rana; Leng, Lin et al. (2018) Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis. Arthritis Rheumatol 70:2077-2086
Merkel, Peter A; Xie, Gang; Monach, Paul A et al. (2017) Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis. Arthritis Rheumatol 69:1054-1066
Xie, Gang; Roshandel, Delnaz; Sherva, Richard et al. (2013) Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum 65:2457-68
Chung, Sharon A; Xie, Gang; Roshandel, Delnaz et al. (2012) Meta-analysis of genetic polymorphisms in granulomatosis with polyangiitis (Wegener's) reveals shared susceptibility loci with rheumatoid arthritis. Arthritis Rheum 64:3463-71
Cao, Yali; Schmitz, John L; Yang, Jiajin et al. (2011) DRB1*15 allele is a risk factor for PR3-ANCA disease in African Americans. J Am Soc Nephrol 22:1161-7
Kelley, James M; Monach, Paul A; Ji, Chuanyi et al. (2011) IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis. Proc Natl Acad Sci U S A 108:20736-41
Mahr, Alfred D; Edberg, Jeffrey C; Stone, John H et al. (2010) Alpha?-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis. Arthritis Rheum 62:3760-7