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; 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.
Highlights
Giant cell arteritis (GCA) and Takayasu’s arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features
GCA cases had a significant enrichment of non-HLA risk alleles for TAK when compared to controls (PGCA = 3.53E-03) and vice-versa (PTAK = 3.60E-02), with no correlation observed within the HLA region (PGCA = 0.27 and PTAK = 0.70). This cross-disease analysis of Immunochip data represents the first interrogation of the genetic overlap between GCA and TAK
In TAK the most affected vessels correspond with the aorta and its major branches, whereas in GCA the main lesions are usually localised in more peripheral arteries and GCA is sometimes associated with the development of polymyalgia rheumatica[11]
Summary
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. Group includes giant cell arteritis (GCA) and Takayasu’s arteritis (TAK), which mainly involve arteries of large calibre such as the aorta and its major branches[2] These two forms of vasculitis develop predominantly in women, with GCA generally affecting people over 50 years of age in Western countries, especially those of European origin, and TAK affecting younger patients with a higher prevalence in Turkey, Japan, India, and China[3,4]. The use of the same platform in these studies has facilitated the identification of shared aetiopathogenic pathways amongst these disorders, supporting the hypothesis of a common genetic background underlying autoimmunity[8]
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