Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P = 7.54E-07; ORGCA = 1.19, ORTAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA = 5.52E-04, ORGCA = 1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus.
This work was supported by SAF2012– 34435 from the Spanish Ministry of Economy and Competitiveness, BIO-1395 from Junta de Andalucía, and RD12/0009/0004 from the RETICS Program (RIER) of Instituto de Salud Carlos III (ISCIII). FDC was recipient of a grant from the ‘Ramón y Cajal’ programme of the Spanish Ministry of Economy and Competitiveness (RYC-2014–16458). MCC and JHR are supported by Ministerio de Economía y Competitividad (SAF 14/57708R), cofunded by “Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa” [Instituto de Salud Carlos III and Fondo Europeo de desarrollo regional (FEDER) (PIE 13/00033)]. The Vasculitis Clinical Research Consortium has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR057319), the National Center for Research Resources (U54 RR019497), the Office of Rare Diseases Research, and the National Center for Advancing Translational Science. The VCRC is part of the Rare Diseases Clinical Research Network (RDCRN).