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

Abstract

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; OR_GCA = 1.19, OR_TAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (P_GCA = 5.52E-04, OR_GCA = 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.

Figure 1

Manhattan plot representation of the results of the HLA region in (A) giant cell arteritis, (B) Takayasu’s arteritis, and (C) the meta-analysis of both forms of vasculitis. The log₁₀ of the P values are plotted against their physical chromosomal position. A red/green color gradient was used to represent the effect size of each analysed polymorphism (red for risk and green for protection). The red line represents the study-wide level of significance (P < 1.13E-06). HLA class I and II subregions are highlighted in grey.