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: Vasculitis

Session Information

Session 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
Type of vasculitis	Cases, n	MAF in cases	MAF in controls	(95% C.I.)	Additive p-value
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.,

P. A. Merkel,

Genentech and Biogen IDEC Inc.,

Bristol-Myers Squibb,

GlaxoSmithKline,

Actelion Pharmaceuticals US,

Sanofi-Aventis Pharmaceutical,

Chemocentryx,

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