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Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis

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Merkel PA1, Xie G2, Monach PA3, Ji X4, Ciavatta DJ5, Byun J4, Pinder BD2, Zhao A2, Zhang J6, Tadesse Y2, Qian D4, Weirauch M7, Nair R8, Tsoi A8, Pagnoux C9, Carette S9, Chung S10, Cuthbertson D11, Davis JC Jr10, Dellaripa PF12, Forbess L13, Gewurz-Singer O8, Hoffman GS14, Khalidi N15, Koening C16, Langford CA14, Mahr AD17, McAlear C1, Moreland L18, Seo EP19, Specks U20, Spiera RF21, Sreih A1, St Clair EW22, Stone JH23, Ytterberg SR20, Elder JT24, Qu J25, Ochi T26, Hirano N26, Edberg JC27, Falk RJ5, Amos CI4, Siminovitch KA6; Vasculitis Clinical Research Consortium. Arthritis Rheumatol. 2017 May;69(5):1054-1066. doi: 10.1002/art.40034. Epub 2017 Apr 6.


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1 University of Pennsylvania, Philadelphia.

2 Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada.

3 Boston University and VA Boston Healthcare System, Boston, Massachusetts.

4 Dartmouth College, Lebanon, New Hampshire.

5 University of North Carolina, Chapel Hill.

6 Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada.

7 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

8 University of Michigan, Ann Arbor.

9 Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.

10 University of California, San Francisco.

11 University of South Florida, Tampa.

12 Brigham and Women's Hospital, Boston, Massachusetts.

13 Cedars-Sinai Medical Center, West Hollywood, California.

14 Cleveland Clinic, Cleveland, Ohio.

15 McMaster University, Hamilton, Ontario, Canada.

16 University of Utah, Salt Lake City.

17 Hôpital Saint-Louis, Paris, France.

18 University of Pittsburgh, Pittsburgh, Pennsylvania.

19 Johns Hopkins University, Baltimore, Maryland.

20 Mayo Clinic, Rochester, Minnesota.

21 Hospital for Special Surgery, New York, New York.

22 Duke University Medical Center, Durham, North Carolina.

23 Massachusetts General Hospital, Boston.

24 University of Michigan and Ann Arbor VA Hospital, Ann Arbor, Michigan.

25 Wenzhou Medical University, Wenzhou, China.

26 University of Toronto and Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

27 University of Alabama at Birmingham.



To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).


A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function.


Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA-DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA-DPB1 gene and HLA-DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)-reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%.


This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.