Novel pleiotropic loci links vascular and immune pathways in systemic sclerosis and primary Raynaud’s phenomenon

OBJECTIVE: Raynaud's phenomenon (RP) is the first noticeable symptom of systemic sclerosis (SSc), appearing even years before other signs. Vascular and immune pathways, hallmarks in SSc pathogenesis, are implicated in primary RP. Hence, we aimed to define the shared genetic architecture between these conditions to explore pathogenic mechanisms and whether pleiotropic loci could help identify primary RP patients at increased genetic risk of developing SSc. METHODS: We analyzed genome-wide association study (GWAS) summary statistics for primary RP (4,986 cases and 850 981 controls) and SSc (10 654 cases and 18 043 controls). We performed a cross-trait meta-analysis (∼8.6M SNPs) to identify variants associated with both diseases. Functional annotation was used to prioritize potential causal genes. We also constructed a polygenic risk score (PRS) to assess clinical implications. RESULTS: Beyond the well-known HLA associations, we identified five additional pleiotropic loci, including MEOX2 as a novel association for both traits with opposing effects, ADRA2A representing a novel genetic factor for SSc, and IL12A, NFKB1 and TNIP1 as novel loci for primary RP. Functional annotation highlighted vascular and inflammatory pathways. Finally, the PRS model shows modest discrimination (AUC = 0.57). However, it allows the identification of primary RP individuals at high genetic risk of developing SSc (75th percentile, RR 1.29 [95% CI 1.02-1.62]; p= 3.58E-2). CONCLUSION: This study reveals a genetic link between primary RP and SSc, identifying five novel pleiotropic loci and supporting the potential of genetic profiling for early risk assessment and personalized monitoring strategies.

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Lara D. Veeken
Published
2026-04-06
DOI
https://doi.org/10.1093/rheumatology/keag164
Primary Topic
Systemic Sclerosis and Related Diseases
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article
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article

Novel pleiotropic loci links vascular and immune pathways in systemic sclerosis and primary Raynaud’s phenomenon

Anne‐Lise Maudoux, N. Hunzelmann, Ana Campar, Esmeralda Neves et al.
Lara D. Veeken
Systemic Sclerosis and Related Diseases
article

Novel pleiotropic loci links vascular and immune pathways in systemic sclerosis and primary Raynaud’s phenomenon

Anne‐Lise Maudoux, N. Hunzelmann, Ana Campar, Esmeralda Neves, S. Proudman, Mariana Brandão, M. Kerick, Barbara Vigone, Miguel Ángel González-Gay Mantecón, Fátima Farinha, Jacques‐Olivier Pers, C. Rosa-Baez, Inmaculada Rodríguez-Martín, Julie Ducreux, Alfonso Corrales Martínez, Ricardo Blanco Alonso, José Luis Callejas, Marialbert Acosta-Herrera, Alfredo Guillen- del-Castillo, J. K. de Vries-Bouwstra, A Guillén, F J Narvàez, Yannick Allanore, Gianluca Moroncini, Mandana Nikpour, Bernard Lauwerys, M Rubio Rivas, E Vicente, B P C Koeleman, A Gabrielli, B Fernàndez-Gutiérrez, J L Andreu, P Airo, A Fernàndez-Nebro, G Moroncini, A Barton, F Díaz, M C Vonk, Lorenzo Beretta, Marta E Alarcón-Riquelme, F J López-Longo, N Ortego-Centeno, G Orozco, T R D J Radstake, Ana Tavares, F J Blanco Garcia, Christopher P Denton, M Fernàndez de Castro, A Nordin, P Carreira, L Padyukov, M Freire, C Tolosa, António Marinho, Carlos Vasconcelos, B Díaz, L Rodríguez-Rodríguez, J A Roman-Ivorra, V Fonollosa, Ariane L Herrick, L Saez-Comet, R Hesselstrand, Carmen P Simeón-Aznar, P García de la Peña, M A Aguirre, N Oreiro, C Fonseca, A B Madroñero, A Kreuter, J H W Distler, Carlos Rangel-Peláez, T Witte, C Lunardi, Shervin Assassi, Divi Cornec, A Pros, P Fanlo-Mateo, Lourdes Ortiz-Fernández, M V Egurbide, F J García-Hernàndez, V Ortiz-Santamaría, Sandrine Jousse-Joulin, M A Gonzàlez-Gay, Oliver Distler, L Trapiella, Alain Saraux, A E Voskuyl, I Castellvi, A Hoffmann-Vold, C Magro, Javier Martín, Valérie Devauchelle-Pensec, J J Alegre Sancho, M Rodríguez Carballeira, Maureen D Mayes, E Beltràn, Raquel Faria, G Riemekasten, R García Portales, G Espinosa
article en

Abstract

OBJECTIVE: Raynaud's phenomenon (RP) is the first noticeable symptom of systemic sclerosis (SSc), appearing even years before other signs. Vascular and immune pathways, hallmarks in SSc pathogenesis, are implicated in primary RP. Hence, we aimed to define the shared genetic architecture between these conditions to explore pathogenic mechanisms and whether pleiotropic loci could help identify primary RP patients at increased genetic risk of developing SSc. METHODS: We analyzed genome-wide association study (GWAS) summary statistics for primary RP (4,986 cases and 850 981 controls) and SSc (10 654 cases and 18 043 controls). We performed a cross-trait meta-analysis (∼8.6M SNPs) to identify variants associated with both diseases. Functional annotation was used to prioritize potential causal genes. We also constructed a polygenic risk score (PRS) to assess clinical implications. RESULTS: Beyond the well-known HLA associations, we identified five additional pleiotropic loci, including MEOX2 as a novel association for both traits with opposing effects, ADRA2A representing a novel genetic factor for SSc, and IL12A, NFKB1 and TNIP1 as novel loci for primary RP. Functional annotation highlighted vascular and inflammatory pathways. Finally, the PRS model shows modest discrimination (AUC = 0.57). However, it allows the identification of primary RP individuals at high genetic risk of developing SSc (75th percentile, RR 1.29 [95% CI 1.02-1.62]; p= 3.58E-2). CONCLUSION: This study reveals a genetic link between primary RP and SSc, identifying five novel pleiotropic loci and supporting the potential of genetic profiling for early risk assessment and personalized monitoring strategies.

Lara D. Veeken
Délégation Paris 5 (FR), Marche Polytechnic University (IT), The University of Sydney (AU), Royal Adelaide Hospital (AU), University of Zurich (CH), Université Paris Cité (FR), Manchester Academic Health Science Centre (GB), Leiden University Medical Center (NL), The Royal Free Hospital (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Sorbonne Paris Cité (FR), Manchester University NHS Foundation Trust (GB), University Hospital of Zurich (CH), Victorian Aboriginal Health Service (AU), Instituto de Investigación Biosanitaria de Granada (ES), Vall d'Hebron Hospital Universitari (ES), Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (ES), Instituto de Parasitología y Biomedicina "López - Neyra" (ES), University Hospital Cologne (DE), The University of Texas Health Science Center (US), University College London (GB)
Peace, Justice and strong institutions, Reduced inequalities
Openalex Percentile: Top 25%
Systemic Sclerosis and Related Diseases
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