Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study

Area of Science:

• Genetics
• Immunology
• Rheumatology

Background:

• Systemic sclerosis (SSc) is an immune-mediated inflammatory disease with significant sex disparities in prevalence and severity.
• Genome-wide association studies (GWAS) have identified genetic risk factors for SSc, but sex-specific genetic analyses are limited.
• This study addresses the gap by investigating autosomal sex-specific genetic factors in SSc.

Purpose of the Study:

• To conduct a sex-stratified autosomal meta-analysis of GWAS in systemic sclerosis.
• To identify sex-specific genetic loci associated with SSc.
• To explore the functional implications and potential therapeutic targets for SSc based on sex-specific genetic findings.

Main Methods:

• A sex-stratified autosomal meta-analysis of GWAS data from 10,653 SSc patients and 18,043 controls was performed.
• Sex-specific loci were identified and functionally annotated.
• Sex-differential gene expression analysis and drug repurposing analysis were conducted.

Main Results:

• Eight sex-specific loci associated with SSc were identified, including one novel male-specific locus (BCL11A) and two novel female-specific loci (IRF4, RPL3-PDGFB).
• Five previously known loci were characterized as female-specific.
• Functional analyses implicated 39 candidate genes, with five showing sex-differential expression; fostamatinib and dasatinib were identified as potential repurposing candidates.

Conclusions:

• This study provides the first evidence of a sex-specific genetic architecture in systemic sclerosis.
• The findings offer insights into the molecular basis of SSc sex differences, implicating IL12RB2 and interferon signaling.
• These results support the development of sex-aware precision medicine strategies for SSc.