SynthesisThe Lancet. Rheumatology2026
Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study.
Synthesis in The Lancet. Rheumatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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26 authors.
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Abstract
backgroundSystemic 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.
methodsBased 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.
findingsAfter quality control filtering, we included 10 653 patients with systemic sclerosis (1556 male and 9097 female) and 18 043 controls (6990 male and 11 053 female). We identified eight sex-specific loci associated with systemic sclerosis: one novel male-specific locus (BCL11A odds ratio [OR] 1·32 [95% CI 1·20-1·45], p=8·39 × 10
interpretationWe 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.
fundingInstituto de Salud Carlos III, EU's Seventh Framework Program, and European Federation of Pharmaceutical Industries and Associations companies.
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