Background: Sex differences can influence clinical features, disease progression, and treatment responses in psoriatic arthritis (PsA). Understanding these differences at a genetic level may help for developing personalized treatment approaches and improving disease management.

Objectives: This study utilizes data from the UK Biobank to identify sex-specific genetic variants that contribute to the susceptibility to PsA, thereby enhancing our understanding of the disease’s underlying mechanisms.

Methods: Data were extracted from the UK Biobank, including 459 female and 497 male PsA patients. To minimize population stratification, only Caucasian participants were included, resulting in 444 female and 423 male PsA patients, along with 226,198 female and 191,928 male Caucasian controls. A genome-wide association study (GWAS) was conducted, comparing 97,013,422 SNPs between males and females among PsA patients and controls, focusing exclusively on autosomes. Only SNPs with allele frequencies greater than 0.005 in affected cases and controls were included, and associations were considered significant at P < × 10^-6. Comprehensive pathway enrichment analysis was performed using pathDIP (extended pathways) and considering only significant genes unique to males and females, and those in common; significance determined as q-value, FDR: BH-method < 0.05.

Results: In males, 2,596 significant SNPs were identified across 104 genes, and in females, 4,542 significant SNPs were associated with 108 genes, when comparing PsA cases and sex matched controls. Among these significant genes, 72 were shared between sexes, including PSORS1C1 , the strongest genetic associated locus for psoriatic disease. Additionally, 32 unique genes were identified in males, including ERAP-1 and TRAF3IP2 , whereas 35 unique genes were identified in females, including HLA-DRB1 and HLA-DQA1 . Notably, selected sex-specific genes have been previously documented to exhibit sex-specific differences in immune responses. The pathway enrichment analysis using genes enriched in males included Uniprot: Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis (0.000956038), SIGNOR: Sonic Hedgehog (0.00973283), and Uniprot: Protein modification; protein ubiquitination (0.0438678). Female-specific pathways included: Uniprot: Protein modification; protein ubiquitination (0.00828116), and SIGNOR: T cell activation (0.00143735), Inflammasome Activation (0.00896164), Insulin Signaling (0.0290307), IL6 Signaling (0.0349914), and TNF-alpha Signaling (0.0445199).

Conclusions: The identification of unique genes in each sex, alongside shared genetic markers, highlights the complexity of PsA’s genetic landscape. These findings suggest that sex-specific weighted genetic factors may play a role in the expression of PsA. Further research is needed to validate these results and explore their clinical and molecular implications, which could ultimately lead to more tailored therapeutic strategies for PsA patients.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.