Genetic biomarkers of clinical manifestations in giant cell arteritis define distinct patient subgroups.

Authors

Gonzalo Borrego-Yaniz, Vera Fuentes-Moreno, Lourdes Ortiz-Fernández, José Hernández-Rodríguez, Sarah L Mackie, Augusto Vaglio, Santos Castañeda, Roser Solans, Jaume Mestre-Torres, Nader Khalidi, Carol A Langford, Steven Ytterberg, Lorenzo Beretta, Marcello Govoni, Giacomo Emmi, Marco A Cimmino, Torsten Witte, Thomas Neumann, Julia Holle, Verena Schönau, Gregory Pugnet, Thomas Papo, Julien Haroche, Alfred Mahr, Luc Mouthon, Øyvind Molberg, Andreas P Diamantopoulos, Alexandre Voskuyl, Thomas Daikeler, Christoph T Berger, Eamonn S Molloy, Yannick van Sleen, Louise Sorensen, Raashid Luqmani, Spanish GCA Group, UK GCA Consortium, Vasculitis Clinical Research Consortium, Norberto Ortego-Centeno, Elisabeth Brouwer, Peter Lamprecht, Sebastian Klapa, Carlo Salvarani, Peter A Merkel, María C Cid, Mark M Iles, Miguel A González-Gay, Ann W Morgan, Javier Martin, Ana Márquez

Published in

Annals of the rheumatic diseases. Jul 03, 2026. Epub Jul 03, 2026.

Abstract

Giant cell arteritis (GCA) is a clinically heterogeneous disease, which complicates both diagnosis and management. This study aimed to identify genetic risk factors associated with GCA clinical manifestations and evaluate their utility for defining clinical phenotypes.
Genome-wide genotype data from 3498 patients with GCA and 15,550 controls were analysed to investigate the genetic architecture of GCA manifestations. Logistic regression was used to compare patients with and without each manifestation, as well as each subgroup of patients vs controls. Gene annotation was conducted based on functional information using Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA GWAS). Latent class analysis (LCA) was applied to evaluate the ability of associated variants to classify patients with GCA into genetic subgroups.
We identified 7 human leukocyte antigen (HLA) variants specifically associated with different clinical features. Furthermore, 7 non-HLA associations across 6 clinical manifestations were found. Gene prioritisation highlighted biologically relevant candidate genes for GCA pathogenesis, including IL17A (limb claudication) and IL22RA1 (jaw claudication), both involved in the Th17 pathway, and ATP2A2 (extracranial form), encoding a transporter that promotes aortic aneurysms. Notably, LCA grouped GCA clinical predisposition into 4 classes capturing cranial-predominant, mixed, extracranial, and ischaemic/occlusive patterns, the latter representing a high-risk subgroup for severe ischaemic and ocular complications.
This first genome-wide association study stratified by GCA-specific manifestations deepens our understanding of the genetic basis underlying GCA clinical heterogeneity. Our findings highlight HLA and non-HLA contributors to specific disease phenotypes and support the potential of genetic profiling to guide early diagnosis and personalised management in GCA.

PMID:
42399125
Bibliographic data and abstract were imported from PubMed on 04 Jul 2026.

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