Document resource
Introduction Raynaud’s phenomenon (RP) is often the first manifestation of systemic sclerosis (SSc), affecting 90% of SSc patients compared to only 5% of the general population. In addition, vascular and immune pathways, hallmarks in SSc pathogenesis, are also implicated in primary RP. Hence, we aimed to define the shared genetic architecture between these conditions to uncover underlying pathogenic mechanisms and identify primary RP individuals at high risk of developing SSc.Material and Methods To identify genetic variants associated with both diseases, we performed a cross-trait meta-analysis including ~8.6 million variants and 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 then conducted functional annotation of the associated variants to prioritize potential causal genes. Additionally, we calculated polygenic risk score (PRS) to assess the predictive utility of the identified variants.Results We observed a significant genetic correlation between SSc and primary RP (rg = 0.315 ± 0.105, p-value = 0.003), highlighting their shared genetic component. In addition, we identified five non-HLA pleiotropic loci, including MEOX2 as a novel association for both traits ( figure 1). Notably, MEOX2-associated variants showed a protective effect for primary RP but increased risk for SSc. We hypothesized that reduced MEOX2 expression could improve microvascular perfusion in primary RP, while exacerbating SSc via enhanced NF-κB signaling. Moreover, functional annotation revealed new candidate genes in vascular and inflammatory pathways, such as IL12A, NFKB1, TNIP1 for primary RP and ADRA2A for SSc. Finally, PRS comparison showed a significant difference between primary RP and SSc with secondary RP (mean PRS primary RP: -3.51E-3 vs mean PRS SSc with secondary RP: 7.01E-5; p-value = 7.52E-3), indicating that the PRS could distinguish between primary RP and SSc patients. Classification in the highest-risk PRS group was significantly associated with SSc comorbidity (p-value = 3.58E-2), corresponding to an increased relative risk of 1.29 [95% CI: 1.02 - 1.62] for developing SSc among primary RP individuals.Conclusions This study uncovers a genetic link between primary RP and SSc, identifying MEOX2 as a potential key contributor to their pathogenesis. Additionally, our results support the potential utility for early risk stratification of the genetic markers identified in the cross-trait meta-analysis and represent an initial step toward integrating genetic information into future personalized approaches for monitoring patients with primary RP.Abstract OC.41 Figure 1Manhattan plot for the cross-trait meta-analysis of primary RP and SSc. Chromosomes are displayed on the x-axis, while statistical significance is represented on the y-axis in -log10(p-value) format. The red line denotes the genome-wide significance threshold (p = 5 x 10’), and the blue dashed line marks the suggestive significance threshold (p = 5 x 10’5). Variants shown in gray are significant but do not meet the predefined criteria (nominal significance in each trait and a lower p-value in the meta-analysis compared to each individual trait). Loci that meet these criteria are labeled