ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2851

The Relationship of ARMS2 Genotype with Idiopathic Inflammatory Vasculitis

Christopher Mecoli1, Fan Wang2, Christopher Pappas3, Peter C. Grayson4, David Cuthbertson5, Simon Carette6, Christian Pagnoux6, Gary S. Hoffman7, Nader A. Khalidi8, Curry L. Koening9, Carol A. Langford10, Carol McAlear11, Paul A. Monach12, Larry W. Moreland13, Philip Seo14, Ulrich Specks15, Steven R. Ytterberg16, Rui Feng17, Gregory Hageman3 and Peter A. Merkel1, 1University of Pennsylvania, Philadelphia, PA, 2University of Pennsylvania, Philadelphia, OK, 3University of Utah School of Medicine, Salt Lake City, UT, 4NIAMS Systemic Autoimmunity Branch, National Institutes of Health, Bethesda, MD, 5Department of Biostatistics, University of South Florida, Tampa, FL, 6Division of Rheumatology, University of Toronto, Toronto, ON, Canada, 7Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, OH, 8Division of Rheumatology, St. Joseph’s Hospital, McMaster University, Hamilton, ON, Canada, 9Division of Rheumatology, University of Utah, Salt Lake City, UT, 10Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, OH, 11Division of Rheumatology, Vasculitis Center, University of Pennsylvania, Philadelphia, PA, 12Section of Rheumatology, Vasculitis Center, Boston University School of Medicine, Boston, MA, 13Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, 14Rheumatology Division, Johns Hopkins Vasculitis Center, Johns Hopkins University, Baltimore, MD, 15Frederichs Dr NW, Mayo Clinic, Rochester, MN, 16Division of Rheumatology, Mayo Clinic, Rochester, MN, 17Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Vasculitis III

Session Type: Abstract Submissions (ACR)

Background/Purpose: Patients with age-related macular degeneration (AMD), a leading cause of irreversible blindness, have a 10-fold increased prevalence of abdominal aortic aneurysms. Single nucleotide polymorphisms (SNPs) in a number of genes, including Complement Factor H (CFH) on chromosome 1 and age-related macular susceptibility protein 2 (ARMS2) and HTRA Serine Peptidase 1 (HTRA1) on chromosome 10, are strongly associated with increased risk for developing AMD. These AMD-associated loci are also strongly associated with vasculopathies, including choroidal neovascularization, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation in both Caucasians and Japanese. These finding raise intriguing possibilities of a potential association between vascular pathology and AMD-associated genes. This study tested the hypothesis that AMD-associated gene variants may also be involved in the development of vasculitis, especially the large-vessel vasculitides (LVV), giant cell arteritis (GCA) and Takayasu’s arteritis (TAK).

Methods: A candidate gene study was performed to investigate the relationship between AMD-associated variants and vasculitis. In a preliminary study, SNPs within CFH (rs1061170), Complement Component 3 (C3; rs2230199), IL2/IL21 (rs1065489), ARMS2 (rs10490924) and HTRA1 (rs11200638) were examined for association with six phenotypes of vasculitis: GCA, TAK, granulomatosis with polyangiitis (Wegener’s, GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA), and polyarteritis nodosa (PAN). Among these 5 SNPs rs10490924 had the strongest association with the vasculitides and this SNP was pursued in the full analysis. The study included samples from 1196 patients with vasculitis and 1248 healthy controls matched for age, sex, race, and ethnicity. Additive p-values were calculated for each subtype of vasculitis.

Results: The main results of the study are reported in the Table. The controls had a minor allele frequency (MAF) of 21% for rs10490924. Overall there was a significant association of all vasculitis types with rs10490924 (p=0.0449). Large-vessel vasculitides were significantly associated with rs10490924 (p-value of 0.0177). The GCA and MPA groups were each independently associated with rs10490924 (p-values of 0.0199 and 0.039, respectively).

Conclusion: This candidate gene study demonstrated a significant association between variants in ARMS2 and idiopathic forms of vasculitis, including large-vessel vasculitides. While further validation is needed, this study suggests the possibility of a common pathogenesis between aortic pathology in AMD and large-vessel vasculitis.

                                                                                                   Association of rs10490924 with Vasculitis

Type of vasculitis

Cases, n

MAF in cases

MAF in controls

Additive OR

Additive p-value

(95% C.I.)

GPA

584

0.23

0.21

1.11 (0.93-1.32)

0.2478

MPA

88

0.28

0.21

1.46 (1.03-2.08)

0.0390

EGPA

133

0.2

0.21

0.92 (0.67-1.26)

0.6222

PAN

62

0.21

0.21

0.99 (0.63-1.55)

0.9522

All Non-LVV
(4 Vasculitides)

867

0.23

0.21

1.10 (0.95-1.29)

0.2086

TAK

116

0.25

0.21

1.26 (0.92-1.72)

0.1461

GCA

213

0.25

0.21

1.43 (1.07-1.92)

0.0199

All LVV (TAK+GCA)

329

0.25

0.21

1.30 (1.05-1.60)

0.0177

All 6 Vasculitides

1196

0.23

0.21

1.15 (1.00-1.32)

0.0449

Disclosure:

C. Mecoli,
None;

F. Wang,
None;

C. Pappas,
None;

P. C. Grayson,
None;

D. Cuthbertson,
None;

S. Carette,
None;

C. Pagnoux,
None;

G. S. Hoffman,
None;

N. A. Khalidi,
None;

C. L. Koening,
None;

C. A. Langford,
None;

C. McAlear,
None;

P. A. Monach,
None;

L. W. Moreland,
None;

P. Seo,
None;

U. Specks,
None;

S. R. Ytterberg,
None;

R. Feng,
None;

G. Hageman,

Voyant Biotherapeutics LLC & Optherion Inc.,

5;

P. A. Merkel,

Genentech and Biogen IDEC Inc.,

2,

Bristol-Myers Squibb,

2,

GlaxoSmithKline,

2,

Actelion Pharmaceuticals US,

2,

Actelion Pharmaceuticals US,

5,

Sanofi-Aventis Pharmaceutical,

5,

Chemocentryx,

5.

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