ASSOCIATION BETWEEN A VARIANT OF THE SRP55 SPLICING FACTOR GENE AND SYSTEMIC SCLEROSIS IN AN ITALIAN POPULATION

Background: In systemic sclerosis (SSc), alternative splicing of the last exon (exon 8) of vascular endothelial growth factor (VEGF)-A pre-mRNA is a key element in the switch from proangiogenic to antiangiogenic VEGF-A isoforms. The mRNA-binding protein serine/arginine protein 55 (SRp55, also known as SFRS6) is a key regulatory splicing factor that promotes distal splice-site selection in the exon 8 region of VEGF-A pre-mRNA and subsequent upregulation of the exon 8b-containing VEGF 165 b antiangiogenic isoform. Overexpression of both VEGF 165 b and SRp55 has been implicated in SSc-related angiogenesis impairment and peripheral vascular damage. Moreover, differential splicing of the VEGF-A gene has been shown to be critical for development of pulmonary fibrosis. Of note, previous studies reported the lack of sequence variations in the VEGF-A alternatively spliced region, while a single nucleotide polymorphism (SNP) in the SRp55 gene (rs2235611) has been associated with susceptibility to disturbed ocular angiogenesis in proliferative diabetic retinopathy. Objectives: This case-control pilot study examined the possible implication of SRp55 rs2235611 SNP in the genetic predisposition to SSc susceptibility and clinical phenotype. Methods: A total population of 872 white Italian individuals (414 SSc patients, 458 controls) was studied. All patients were classified as limited and diffuse cutaneous SSc (lcSSc and dcSSc, respectively) and were clinically evaluated for the presence of autoantibodies (anticentromere, anti-Scl70 antibodies), pulmonary fibrosis and digital ulcers. The SRp55 rs2235611 SNP was genotyped by TaqMan Real-Time PCR. Results: SRp55 rs2235611 genotype distribution and allele frequency were similar in SSc and healthy controls, though a trend toward significance was observed for genotype distribution (p=0.07). The SRp55 rs2235611 AA genotype significantly influenced the predisposition to SSc (OR 2.55, 95% CI 1.11 to 5.57, p = 0.03), and to both lcSSc (OR 2.80, 95% CI 1.16 to 6.84, p = 0.02) and dcSSc (OR 3.42, 95% CI 1.20 to 9.72, p = 0.02) subtypes. The SRp55 rs2235611 A minor allele and AA genotype showed a significant risk association with susceptibility to SSc-related pulmonary fibrosis (A allele: OR 1.39, 95% CI 1.00 to 1.93, p = 0.046; AA genotype: OR 3.95, 95% CI 1.48 to 10.54, p = 0.006). A trend toward an association between the AA genotype and anti-Scl70 antibody-positive SSc was also found (OR 2.82, 95% CI 0.95 to 8.37, p = 0.06). Both rs2235611 A allele and AA genotype were significantly associated with the SSc subset without digital ulcers (A allele: OR 1.33, 95% CI 1.01 to 1.75, p = 0.04; AA genotype: OR 3.26, 95% CI 1.32 to 8.03, p = 0.01). Conclusion: The SRp55 rs2235611 polymorphism is associated with susceptibility to SSc and, in particular, with SSc-related pulmonary fibrosis and peripheral vascular phenotype, consistent with a role of VEGF-A pre-mRNA alternative splicing in the development of pulmonary fibrosis and impairment of angiogenesis. Further replication studies are warranted to confirm our findings in independent SSc cohorts. Disclosure of Interests: Eloisa Romano: None declared, Mirko Manetti: None declared, Joanna Kosalka-Wegiel: None declared, Bianca Saveria Fioretto: None declared, Irene Rosa: None declared, Elena Sticchi: None declared, Serena Guiducci: None declared, Silvia Bellando-Randone: None declared, Lidia Ibba-Manneschi: None declared, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Bristol-Myers Squibb, Speakers bureau: Acetelion, Lilly, Boehringer Ingelheim Citation: Ann Rheum Dis, volume 79, supplement 1, year 2020, page 1081Session: Systemic sclerosis, myositis and related syndromes - etiology, pathogenesis and animal models (Poster Presentations)