POS1222 COMPUTATIONAL TRANSCRIPTOMIC ANALYSIS REVEALS DYSREGULATION OF THE NAD<sup>+</sup>PATHWAY IN CHRONIC INFLAMMATORY RHEUMATIC DISEASES
Authors: B. Vellón-García, M. Pérez-Rodriguez, M. Llamas-López, Á. A. Puerto-Nuñez, L. M. Sánchez-Mendoza, J. A. González-Reyes, J. A. Moreno, M. I. Burón, A. Llamas-Urbano, J. M. Martínez-Moreno, Y. Hanaee, I. Arias-de la Rosa, C. López-Medina, E. Collantes-Estevez, N. Barbarroja, A. Escudero-Contreras, C. Lopez-Pedrera, J. M. Villalba, C. Perez-Sanchez
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Recent studies suggest that the NAD+ pathway may play a crucial role in pathogenic processes associated with accelerated aging-related diseases, including chronic inflammatory rheumatic diseases (CIRD). Therefore, exploring the elements involved in NAD<sup>+</sup> metabolism could unveil new therapeutic pathways for these conditions. <h3>Objectives:</h3> To analyze the expression of key players in the NAD<sup>+</sup> pathway in CIRD using computational tools to identify common and distinctive alterations. <h3>Methods:</h3> We analyzed eight public transcriptomic datasets from Gene Expression Omnibus and ArrayExpress in PBMCs and whole blood of healthy donors (HDs) and four different CIRDs: rheumatoid arthritis (RA), spondyloarthritis (SpA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), comprising a total of 460 patients. Using R software, we obtained the differential expression of a selected panel of 50 genes primarily involved in the synthesis, transport, and degradation of NAD<sup>+</sup> from microarray and RNAseq datasets. Comparative statistical analyses identified shared and distinctive altered NAD<sup>+</sup> pathway genes among the different CIRDs. <h3>Results:</h3> The bioinformatic analysis revealed a significant alteration of genes related to the NAD<sup>+</sup> pathway, particularly in RA (24) and SSc (22), compared to SLE (10) and SpA (13). Notably, increased expression of NAD<sup>+</sup> consumption genes, such as Poly (ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs), was consistently identified in RA and SSc, with these diseases sharing the highest number of altered genes (17). These findings suggest a potential decline in NAD<sup>+</sup> levels, a phenomenon previously associated with various pathological conditions. Interestingly, the simultaneous alteration of three genes—PARP1, SIRT5, and NAD<sup>+</sup> kinase (NADK)—was observed in all four CIRDs analyzed compared to healthy donors (HDs), highlighting their potential significant role in the pathogenesis of these disorders. <h3>Conclusion:</h3> RA and SSc exhibited significant alterations in genes related to NAD<sup>+</sup> metabolism, potentially impacting the crucial functions of this canonical biological pathway and driving pathological phenotypes. Further analysis of these molecular mechanisms could contribute to identifying new therapeutic targets in these and other CIRD. <h3>REFERENCES: NIL.</h3> <h3>Acknowledgements:</h3> CPS and CLP: Supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking 3TR, Projects no. PI21/0591 &amp; CD21/00187 funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. Project no. RD21/0002/0033 funded by ISCIII and funded by the European Union-NextGeneration EU, via Plan de Recuperación, Transformacion y Resiliencia (PRTR) and MINECO (RYC2021-033828-I, and PID2022-141500OA-I00). JMV: RTI2018-100695-B-I00, PID2021-126280OB-I00, JA grants P18-RT-4264, 1263735-R and BIO-276, PRE2019-08743, P18-RT-4264, BIO-276 and PID2021-126280OB-I00. <h3>Disclosure of Interests:</h3> <b>None declared.</b>