P137 The role of the IRX1 gene variant rs12653958 in late-onset Raynaud’s phenomenon

Abstract Background/Aims Raynaud’s phenomenon (RP) is characterised by episodic vasospasm resulting in transient, reversible skin colour changes—typically well-demarcated blanching followed by cyanosis and/or erythema. Late-onset RP has been suggested to carry a higher likelihood of underlying pathology and a more severe clinical course. Recent evidence has implicated two single nucleotide polymorphisms (SNPs), ADRA2A (rs7090046 GA) and IRX1 (rs12653958 AG), in the development of RP. This study aimed to investigate whether ADRA2A (rs7090046 GA) and IRX1 (rs12653958 AG) genetic variants are associated with age at RP onset. Methods We included 139 consecutive patients with RP, referred to “Molecular Physiology and Clinical Applications Unit, Department of Physiology, National and Kapodistrian University of Athens” for further evaluation. We subsequently stratified them according to age at disease onset into early and late onset groups (40 and ≥40 years, respectively). Clinical characteristics and laboratory parameters including full autoantibody profile were recorded following thorough chart review. Genotyping of the ADRA2A (rs7090046 GA), and IRX1 (rs12653958 AG) SNPs was performed using PCR-restriction fragment length polymorphism (RFLP) on DNA extracted from whole peripheral blood in 123 RP patients and 132 healthy controls (HCs). Comparisons were performed using chi-square test. Results Patients with RP onset at age ≥40 demonstrated a higher prevalence of the homozygous GG genotype of the IRX1 rs12653958 variant compared to both early-onset RP patients and HCs aged ≥40 (12.8% vs. 0.0% vs. 3.9%; p-values 0.009 and 0.04, ORs (95%)CI: 2.2 (1.8-2.8) and 3.6 (1.0-13.5), respectively). No such associations were detected for the ADRA2A (rs7090046) SNP (4.2% vs 6% vs 4.7%, p-values 0.68 and 1, respectively). When comparing the prevalence of the homozygous GG and AA genotypes for IRX1 and ADRA2A SNPs, respectively, between young onset RP and HC 40 years, no significant differences were detected (0% vs 4.5% p = 0.003), history of cancer (30.4% vs. 8.2%; p = 0.002), arthritis (28.6% vs. 11.5%; p = 0.02), muscle weakness (7.1% vs. 0.0%; p = 0.034), and β2-glycoprotein I IgM positivity (10.0% vs. 0.0%; p = 0.028). Conclusion Our findings indicate that late-onset RP may represent a distinct, genetically influenced subtype. The observed association with IRX1 variants provides potential clues to the pathogenesis and emphasises the need for further investigation in larger patient cohorts. Disclosure A.I. Karampela: None. S. Raftopoulou: None. C. Stylianopoulos: Other; Lilly, employee. V. Koulouri: None. C. Skarlis: None. C. Mavragani: None.