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

Borrego-Yaniz G, Fuentes-Moreno V, Ortiz-Fernández L, Hernández-Rodríguez J, Mackie SL, Vaglio A, Castañeda S, Solans R, Mestre-Torres J, Khalidi N, Langford CA, Ytterberg S, Beretta L, Govoni M, Emmi G, Cimmino MA, Witte T, Neumann T, Holle J, Schönau V, Pugnet G, Papo T, Haroche J, Mahr A, Mouthon L, Molberg Ø, Diamantopoulos AP, Voskuyl A, Daikeler T, Berger CT, Molloy ES, van Sleen Y, Sorensen L, Luqmani R, Ortego-Centeno N, Brouwer E, Lamprecht P, Klapa S, Salvarani C, Merkel PA, Cid MC, Iles MM, González-Gay MA, Morgan AW, Martin J, Márquez A (2026)

Publication Type: Journal article

Publication year: 2026

Journal

DOI: 10.1016/j.ard.2026.06.008

Abstract

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

Authors with CRIS profile

Involved external institutions

Institute of Parasitology and Biomedicine López-Neyra / Instituto de Parasitología y Biomedicina "López - Neyra" Spain (ES) Università degli Studi di Firenze / University of Florence Italy (IT) University of Leeds United Kingdom (GB) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona Spain (ES) Hospital Universitario de La Princesa Spain (ES) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico Italy (IT) Mayo Clinic United States (USA) (US) Universitätsklinikum Jena Germany (DE) University of Genova / Università degli Studi di Genova Italy (IT) Universität zu Lübeck Germany (DE) Hospital Universitario Fundación Jiménez Díaz Spain (ES) Universidad de Granada Spain (ES) University of Oxford United Kingdom (GB) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) Assistance Publique-Hôpitaux de Paris (AP-HP) France (FR) Università degli Studi di Trieste Italy (IT) McMaster University Canada (CA) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Cleveland Clinic United States (USA) (US) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Universitätsspital Basel Switzerland (CH) Azienda Ospedaliera Universitaria di Ferrara Arcispedale Sant'Anna Italy (IT) St Vincent's University Hospital Ireland (IE) Centre Hospitalier Universitaire (CHU) de Toulouse France (FR) Kantonsspital St.Gallen Switzerland (CH) Azienda Unità Sanitaria Locale die Reggio Emilia Italy (IT) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Université Sorbonne Paris Cité France (FR) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) Penn Medicine United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Akershus University Hospital / Akershus universitetssykehus (Ahus) Norway (NO) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE)

How to cite

APA:

Borrego-Yaniz, G., Fuentes-Moreno, V., Ortiz-Fernández, L., Hernández-Rodríguez, J., Mackie, S.L., Vaglio, A.,... Márquez, A. (2026). Genetic biomarkers of clinical manifestations in giant cell arteritis define distinct patient subgroups. Annals of the Rheumatic Diseases. https://doi.org/10.1016/j.ard.2026.06.008

MLA:

Borrego-Yaniz, Gonzalo, et al. "Genetic biomarkers of clinical manifestations in giant cell arteritis define distinct patient subgroups." Annals of the Rheumatic Diseases (2026).

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