POS0676 GENETIC BIOMARKERS FOR TOFACITINIB TREATMENT RESPONSE IN PATIENTS WITH RHEUMATOID ARTHRITIS.
Authors: S. Janahiraman, C. L. Too, S. S. Ch’ng, L. H. Eow, E. Mageswaren, A. L. Lim, H. C. Chong, P. S. Ong, A. Mohamed Ismail, S. M. Abd Rahim, C. R. Ng, D. M. Suahilai, A. H. Ramlan, N. S. Shahril, C. O. Leong
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Treatment response to tofacitinib for patients with rheumatoid arthritis (RA) displays considerable heterogeneity. The interindividual variations in clinical response may have a genetic etiology. Understanding of the genetic basis of tofacitinib response will facilitate the translation of genetic discoveries to clinical benefit and personalised therapy. <h3>Objectives:</h3> To identify genetic predictors of tofacitinib response among RA patients. <h3>Methods:</h3> Genotypes of 58 tofacitinib-treated RA patients were determined by whole genome sequencing (WGS). Clinical endpoints were assessed from baseline to 6 months of Tofacitinib treatment based on overall 4-component disease activity (DAS)28. Variants obtained from sequencing were analysed for the association with tofacitinib response using Fisher's Exact test with Odds ratio (OR) and 95% confidence interval (CI) estimation. <h3>Results:</h3> This study showed that four single nucleotide variants (SNV)s reached genome-wide statistical significance level with p value less than 1x10<sup>-7</sup> and thirty-four variants achieved p value less than 1x10<sup>-6</sup> for the outcome measure of tofacitinib response. The strongest evidence for association to satisfactory EULAR DAS28 ESR/CRP response was with rs12149039_C variant of <i>CDH13</i> gene (OR: 62.2, p=8.82x10<sup>-8</sup>) followed by rs880559_C and rs732169_T variant of <i>PCNX</i> gene polymorphism (OR: 24.0, p=4.47x10<sup>-7</sup>). In addition, our data also revealed other genetic variants associated with tofacitinib non-responders when compared with the responders were rs13315685_C variant of <i>SLC12A8</i> gene (OR: 13.89, p=2.03x10<sup>-7</sup>), rs4372384_T variant of <i>GRID1</i> gene (OR: 9.72, p=4.88x10<sup>-7</sup>) and rs9619005_C variant of <i>ADA2</i> gene (OR: 35.03, p=7.46x10<sup>-7</sup>). <i>CDH13, SEMA3F, SSH1, RNF138</i> and <i>ADA2</i> gene have been replicated from previous studies related to inflammatory and destructive process of RA. Moreover, we identified other genetic variants associated with tofacitinib non-responders, which have not been reported previously i.e <i>PCNX2</i> (rs732168 and rs732169), <i>FEZ2</i> (rs78397636), <i>XRCC5</i> (rs9288517), <i>ZNF736</i> (rs57374192, rs117800590), <i>ARHGEF12</i> (rs661139), <i>SLC12A8</i> (rs13315685) and <i>EIF4ENIF1</i> (rs5749279). <h3>Conclusion:</h3> In summary, five out of twelve genetic risk variants were replicated from previous studies to be observed in the tofacitinib response individuals in this study. Other identified genetic variants may suggest novel genetic risk variants involved in tofacitinib response that warrants further investigations and may facilitate the treatment prediction in RA patients. <h3>REFERENCES:</h3> [1] Li Y, Lai-Han Leung E, Pan H, Yao X, Huang Q, Wu M, Xu T, Wang Y, Cai J, Li R, Liu W, Liu L. Identification of potential genetic causal variants for rheumatoid arthritis by whole-exome sequencing. Oncotarget. 2017;8(67):111119-111129. doi: 10.18632/oncotarget.22630. PMID: 29340042; PMCID: PMC5762310. [2] L. Abdel Salam, A. Q. Aldarwesh and H. H. Eleishi, Whole exome sequencing (WES) of methotrexate response/adverse event profile in rheumatoid arthritis patients, The Egyptian Rheumatologist, 2021; 4:287-291 doi:org/10.1016/j.ejr.2020.08.006. [3] Valli A, Kuuliala K, Virtanen A, Kuuliala A, Palmroth M, Peltomaa R, Vidqvist KL, Leirisalo-Repo M, Silvennoinen O, Isomäki P. Tofacitinib treatment modulates the levels of several inflammation-related plasma proteins in rheumatoid arthritis and baseline levels of soluble biomarkers associate with the treatment response. Clin Exp Immunol. 2022; 210(2):141-150. doi: 10.1093/cei/uxac085. PMID: 36124688. <h3>Acknowledgements:</h3> Special thanks to Director General of Health Malaysia for his permission to present this article and International Medical University Research Grant [PHMS I-2021 (04)] for financial support. <h3>Disclosure of Interests:</h3> <b>None declared.</b>