A Meta-Immunochip Analysis Suggests IL12B As a Common Susceptibility Factor for Large-Vessel Vasculitides

Francisco David Carmona¹, Patrick Coit², Güher Saruhan-Direskeneli³, Maria C. Cid⁴, Roser Solans⁵, Santos Castañeda⁶, Augusto Vaglio (on behalf of the Italian GCA Study Group)⁷, Haner Direskeneli (on behalf of the Turkish Takayasu Study Group)⁸, Peter A. Merkel⁹, Carlo Salvarani¹⁰, Miguel A. Gonzalez-Gay¹¹, Javier Martín¹², Amr H. Sawalha² and Spanish GCA consortium, ¹Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, PTS-Granada, Granada, Spain, ²Division of Rheumatology, University of Michigan, Ann Arbor, MI, ³Department of Physiology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey, ⁴Autoimmune and Systemic Diseases, Hospital Clínic. IDIBAPS. University of Barcelona, Barcelona, Spain, ⁵Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain, ⁶Rheumatology, H.U. La Princesa, Madrid, Spain, ⁷Medicina Clinica e Nefrologia, Università di Parma, Parma, Italy, ⁸Department of Rheumatology, Marmara University, School of Medicine, Istanbul, Turkey, ⁹Penn Vasculitis Center, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, ¹⁰Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy, ¹¹Reumatologia, Hospital Universitario Marqués de Valdecilla, IDIVAL, University of Cantabria, Santander, Spain, ¹²Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Armilla (Granada), Spain

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Genetics and giant cell arteritis

Session Information

Date: Tuesday, November 10, 2015

Title: Vasculitis III

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Large-vessel vasculitides (LVV) comprise giant cell arteritis (GCA) and Takayasu arteritis (TAK). They are characterized by self-sustaining inflammatory damage of the wall of large-sized vessels such as the aorta. Using previously published Immunochip data, we carried out an inter-disease meta-analysis of these two disorders in order to identify common susceptibility genetic factors predisposing to LVV development.

Methods: Two cohorts from Spain (759 cases/1,505 controls) and Italy (238 cases/1,270 controls) included in an Immunochip study on GCA, were combined with two additional cohorts from Turkey (327 cases/481 controls) and USA (110 cases/558 controls) included in an Immunochip study on TAK. In total, 1,434 LVV cases and 3,814 unaffected controls were analysed. We compared in every cohort the variation frequencies of cases and controls by logistic regression under a fixed-effects model using the ten first principal components as covariates. We then used the inverse variance weighted meta-analysis method to test for common association signals. Only those variants showing a nominally significant association with both diseases separately (P<0.05), as well as no significant heterogeneity in the overall meta-analysis (Q>0.05), were considered as putative shared risk variants.

Results: Strong association signals were observed within the HLA class II region (lead SNP rs9268923, P=6.50E-16, OR=1.49), although associations at the genome-wide level of significance were also detected in HLA class I (rs10947210, P=2.25E-08, OR=1.66). The highest non-HLA peak corresponded to a genetic variant nearby the IL12B gene (rs6871626, P=4.67E-07, OR=1.28), which is in complete linkage disequilibrium (r²=1) with the reported TAK-associated IL12B SNP rs56167332. Other suggestive signals were observed within GRIN2A (rs1448258, P=2.69E-06, OR=1.24), a member of the glutamate-gated ion channel protein family, and GPSM1 (rs28489139, P=1.38E-05, OR=1.45), a receptor-independent activator of G protein signaling.

Conclusion: A strong contribution of HLA class I and II variants to LVV predisposition was evident. Outside the HLA region, our data indicated that IL12B may be a common susceptibility factor for both GCA and TAK, and suggested other putative shared loci between these vasculitides including GRIN2A and GPSM1.

Disclosure: F. D. Carmona, None; P. Coit, None; G. Saruhan-Direskeneli, None; M. C. Cid, None; R. Solans, None; S. Castañeda, None; A. Vaglio (on behalf of the Italian GCA Study Group), None; H. Direskeneli (on behalf of the Turkish Takayasu Study Group), None; P. A. Merkel, None; C. Salvarani, None; M. A. Gonzalez-Gay, None; J. Martín, None; A. H. Sawalha, None.

To cite this abstract in AMA style:

Carmona FD, Coit P, Saruhan-Direskeneli G, Cid MC, Solans R, Castañeda S, Vaglio (on behalf of the Italian GCA Study Group) A, Direskeneli (on behalf of the Turkish Takayasu Study Group) H, Merkel PA, Salvarani C, Gonzalez-Gay MA, Martín J, Sawalha AH. A Meta-Immunochip Analysis Suggests IL12B As a Common Susceptibility Factor for Large-Vessel Vasculitides [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/a-meta-immunochip-analysis-suggests-il12b-as-a-common-susceptibility-factor-for-large-vessel-vasculitides/. Accessed .

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