SYSTEMIC sclerosis may develop through different genetic pathways in males and females, according to a large genome-wide association study that identified eight sex-specific susceptibility loci and highlighted potential targets for precision medicine approaches.
Sex Differences in Systemic Sclerosis
Systemic sclerosis is an immune-mediated inflammatory disease with striking sex differences in prevalence and severity, affecting females far more frequently while often causing more severe disease in males. Although previous genome-wide association studies identified susceptibility genes, sex-aware analyses have remained limited. Researchers therefore investigated whether autosomal genetic risk differs between sexes in systemic sclerosis.
Large GWAS Analysis in Systemic Sclerosis Cohorts
This sex-stratified genome-wide association meta-analysis included patients with systemic sclerosis recruited through previous GWAS datasets and an international multicentre collaboration. Eligible adults met 2013 American College of Rheumatology and European Alliance of Associations for Rheumatology classification criteria or early systemic sclerosis criteria proposed by LeRoy and Medsger.
After quality-control filtering, analyses included 10,653 patients with systemic sclerosis comprising 1,556 males and 9,097 females, alongside 18,043 controls including 6,990 males and 11,053 females. Researchers performed sex-stratified autosomal analyses, functional annotation of loci, sex-differential expression analysis, and drug repurposing investigations.
Novel Sex-Specific Loci Identified in Systemic Sclerosis
Investigators identified eight sex-specific loci associated with systemic sclerosis. One novel male-specific locus involved BCL11A with odds ratio 1.32 (95% CI 1.20 to 1.45; p=8.39 × 10−9). Two novel female-specific loci included IRF4 with odds ratio 0.78 (95% CI 0.71 to 0.85; p=2.36 × 10−8) and RPL3-PDGFB with odds ratio 1.19 (95% CI 1.12 to 1.26; p=3.18 × 10−8). Five additional previously recognised loci were newly characterised as female-specific. Functional analyses implicated 39 candidate genes, with IL12RB2, ARHGAP31, UBL7, CSK, and MPI showing sex-differential expression in systemic sclerosis. Drug repurposing analysis identified fostamatinib and dasatinib as potential treatment candidates.
Implications for Precision Medicine
The findings provide the first evidence that systemic sclerosis possesses sex-specific autosomal genetic architecture, potentially explaining observed clinical differences between males and females. Researchers highlighted interferon signalling and IL12RB2 as particularly important pathways. These results support development of sex-aware precision medicine strategies and reinforce the importance of incorporating sex-stratified analyses into future rheumatology research.
Reference
Rodriguez-Martin I et al. Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study. The Lancet Rheumatology. 2026;DOI:10.1016/S2665-9913(25)00376-5.
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