Novel pleiotropic loci link vascular and immune pathways in systemic sclerosis and primary Raynaud's phenomenon.

OBJECTIVE: Raynaud's phenomenon (RP) is the first noticeable symptom of systemic sclerosis (SSc), appearing even years before other signs. Vascular and immune pathways, hallmarks in SSc pathogenesis, are implicated in primary RP. Hence, we aimed to define the shared genetic architecture between these conditions to explore pathogenic mechanisms and whether pleiotropic loci could help identify primary RP patients at increased genetic risk of developing SSc.

METHODS: We analysed genome-wide association study (GWAS) summary statistics for primary RP (4 986 cases and 850 981 controls) and SSc (10 654 cases and 18 043 controls). We performed a cross-trait meta-analysis (∼8.6M single nucleotide polymorphisms) to identify variants associated with both diseases. Functional annotation was used to prioritise potential causal genes. We also constructed a polygenic risk score (PRS) to assess clinical implications.

RESULTS: Beyond the well-known HLA associations, we identified five additional pleiotropic loci, including MEOX2 as a novel association for both traits with opposing effects, ADRA2A representing a novel genetic factor for SSc, and IL12A, NFKB1 and TNIP1 as novel loci for primary RP. Functional annotation highlighted vascular and inflammatory pathways. Finally, the PRS model shows modest discrimination (area under the curve = 0.57). However, it allows the identification of primary RP individuals at high genetic risk of developing SSc (75th percentile, relative risk =1.29 [95% CI 1.02, 1.62]; P-value= 3.58 × 10-2).

CONCLUSION: This study reveals a genetic link between primary RP and SSc, identifying five novel pleiotropic loci and supporting the potential of genetic profiling for early risk assessment and personalised monitoring strategies.