Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study
Abstract
BACKGROUND: Systemic sclerosis is an immune-mediated inflammatory disease with marked sex differences in prevalence and severity. Although genome-wide association studies (GWAS) have advanced the understanding of systemic sclerosis genetics, sex-aware approaches remain scarce. We aimed to address this gap by examining autosomal sex-specific genetic factors in systemic sclerosis. METHODS: Based on a chromosomal definition of sex, we conducted a sex-stratified autosomal meta-analysis of GWAS in systemic sclerosis. We retrieved patient-level and control data from a previous GWAS for systemic sclerosis and newly recruited participants from an international multicentre collaboration (data cutoff June 1, 2024). Adult patients (aged ≥18 years) were required to meet the 2013 American College of Rheumatology-European League Against Rheumatism classification criteria or the criteria for early systemic sclerosis proposed by LeRoy and Medsger, 2001. Patients with systemic sclerosis were compared with healthy controls through sex-stratified analyses. Sex-specific loci were functionally annotated and a sex-differential expression analysis was performed to validate the findings. Additionally, we performed a drug repurposing analysis to explore the clinical implications of our findings. People with lived experience of systemic sclerosis were not involved in the study design or conduct. FINDINGS: ), and five previously known loci now characterised as female-specific. Functional analyses implicated 39 candidate genes, of which five (IL12RB2, ARHGAP31, UBL7, CSK, and MPI) showed sex-differential expression in patients with systemic sclerosis. Two approved drugs, fostamatinib and dasatinib, were identified as potential repurposing candidates for systemic sclerosis sex-aware treatment. INTERPRETATION: We report the first evidence of sex-specific genetic architecture in systemic sclerosis. These findings offer insight into the molecular basis of sex differences in the disease, highlighting both IL12RB2 gene and interferon signalling. These results also support the development of sex-aware precision medicine approaches. FUNDING: Instituto de Salud Carlos III, EU's Seventh Framework Program, and European Federation of Pharmaceutical Industries and Associations companies.
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BibTeX
@article{rodriguezmartin2026sexspecific,
title = {{Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study}},
author = {Inmaculada Rodriguez-Martin and Martin Kerick and Carlos Rangel-Peláez and Carlos Rosa-Baez and Gonzalo Borrego-Yaniz and Lourdes Ortiz-Fernández and Alfredo Guillen-Del-Castillo and Carmen Simeón-Aznar and José Luis Callejas and Oliver Distler and Susanna Proudman and Mandana Nikpour and Nicolas Hunzelmann and Nicolas Hunzelmann and Jeska de Vries-Bouwstra and Ariane Herrick and Yannick Allanore and Marta Alarcón-Riquelme and Lorenzo Beretta and Shervin Assassi and Christopher Denton and Maureen Mayes and Javier Martin and Marialbert Acosta-Herrera and P. Carreira and I. Castellvi and R. Ríos and N. Ortego-Centeno and R. García Portales and A. Fernández-Nebro and F.J. García-Hernández and M.A. Aguirre and B. Fernández-Gutiérrez and L. Rodríguez-Rodríguez and P. García de la Peña and E. Vicente and J.L. Andreu and M. Fernández de Castro and F.J. López-Longo and V. Fonollosa and A. Guillén and G. Espinosa and C. Tolosa and A. Pros and E. Beltrán and M. Rodríguez Carballeira and F.J. Narváez and M. Rubio Rivas and V. Ortiz-Santamaría and A.B. Madroñero and M.A. González-Gay and B. Díaz and L. Trapiella and M.V. Egurbide and P. Fanlo-Mateo and L. Saez-Comet and F. Díaz and J.A. Roman-Ivorra and J.J. Alegre Sancho and M. Freire},
journal = {The Lancet Rheumatology},
year = {2026},
month = oct,
doi = {10.1016/s2665-9913(25)00376-5},
url = {https://hal.science/hal-05837544v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study
AU - Inmaculada Rodriguez-Martin
AU - Martin Kerick
AU - Carlos Rangel-Peláez
AU - Carlos Rosa-Baez
AU - Gonzalo Borrego-Yaniz
AU - Lourdes Ortiz-Fernández
AU - Alfredo Guillen-Del-Castillo
AU - Carmen Simeón-Aznar
AU - José Luis Callejas
AU - Oliver Distler
AU - Susanna Proudman
AU - Mandana Nikpour
AU - Nicolas Hunzelmann
AU - Nicolas Hunzelmann
AU - Jeska de Vries-Bouwstra
AU - Ariane Herrick
AU - Yannick Allanore
AU - Marta Alarcón-Riquelme
AU - Lorenzo Beretta
AU - Shervin Assassi
AU - Christopher Denton
AU - Maureen Mayes
AU - Javier Martin
AU - Marialbert Acosta-Herrera
AU - P. Carreira
AU - I. Castellvi
AU - R. Ríos
AU - N. Ortego-Centeno
AU - R. García Portales
AU - A. Fernández-Nebro
AU - F.J. García-Hernández
AU - M.A. Aguirre
AU - B. Fernández-Gutiérrez
AU - L. Rodríguez-Rodríguez
AU - P. García de la Peña
AU - E. Vicente
AU - J.L. Andreu
AU - M. Fernández de Castro
AU - F.J. López-Longo
AU - V. Fonollosa
AU - A. Guillén
AU - G. Espinosa
AU - C. Tolosa
AU - A. Pros
AU - E. Beltrán
AU - M. Rodríguez Carballeira
AU - F.J. Narváez
AU - M. Rubio Rivas
AU - V. Ortiz-Santamaría
AU - A.B. Madroñero
AU - M.A. González-Gay
AU - B. Díaz
AU - L. Trapiella
AU - M.V. Egurbide
AU - P. Fanlo-Mateo
AU - L. Saez-Comet
AU - F. Díaz
AU - J.A. Roman-Ivorra
AU - J.J. Alegre Sancho
AU - M. Freire
PY - 2026
DA - 2026/10/23
JO - The Lancet Rheumatology
DO - 10.1016/s2665-9913(25)00376-5
UR - https://hal.science/hal-05837544v1
AB - BACKGROUND: Systemic sclerosis is an immune-mediated inflammatory disease with marked sex differences in prevalence and severity. Although genome-wide association studies (GWAS) have advanced the understanding of systemic sclerosis genetics, sex-aware approaches remain scarce. We aimed to address this gap by examining autosomal sex-specific genetic factors in systemic sclerosis. METHODS: Based on a chromosomal definition of sex, we conducted a sex-stratified autosomal meta-analysis of GWAS in systemic sclerosis. We retrieved patient-level and control data from a previous GWAS for systemic sclerosis and newly recruited participants from an international multicentre collaboration (data cutoff June 1, 2024). Adult patients (aged ≥18 years) were required to meet the 2013 American College of Rheumatology-European League Against Rheumatism classification criteria or the criteria for early systemic sclerosis proposed by LeRoy and Medsger, 2001. Patients with systemic sclerosis were compared with healthy controls through sex-stratified analyses. Sex-specific loci were functionally annotated and a sex-differential expression analysis was performed to validate the findings. Additionally, we performed a drug repurposing analysis to explore the clinical implications of our findings. People with lived experience of systemic sclerosis were not involved in the study design or conduct. FINDINGS: ), and five previously known loci now characterised as female-specific. Functional analyses implicated 39 candidate genes, of which five (IL12RB2, ARHGAP31, UBL7, CSK, and MPI) showed sex-differential expression in patients with systemic sclerosis. Two approved drugs, fostamatinib and dasatinib, were identified as potential repurposing candidates for systemic sclerosis sex-aware treatment. INTERPRETATION: We report the first evidence of sex-specific genetic architecture in systemic sclerosis. These findings offer insight into the molecular basis of sex differences in the disease, highlighting both IL12RB2 gene and interferon signalling. These results also support the development of sex-aware precision medicine approaches. FUNDING: Instituto de Salud Carlos III, EU's Seventh Framework Program, and European Federation of Pharmaceutical Industries and Associations companies.
SN - 2665-9913
ER -