813 Rare coding variants in NOX4 link high superoxide levels to psoriatic arthritis mutilans

Introduction: Psoriatic arthritis mutilans(PAM) is the rarest and most severe subtype of psoriatic arthritis(PsA) characterized by severe destruction of the distal joints. Until today, very little is known about the genetics behind PAM. Materials and methods:We performed massively parallel sequencing of 61 well-characterized patients’ genomes from the PAM Nordic cohort. We genotyped additional psoriasis, psoriatic arthritis, and control cohorts. We studied the effects of the specific variants found in vivo by using zebrafish models and in vitro by stable cell lines and osteoclast differentiation. Results:Using next-generation sequencing, we detected three very rare variants in the NADPH oxidase 4 gene(NOX4). NOX4 is an enzyme involved in ROS production, which leads to bone resorption. In silico analysis predicts that all variants are deleterious, probably damaging, and have a CADD score of 31 and 25. We measured ROS by EPR in peripheral blood from controls (n=9), psoriasis(n=7), PsA(n=8), a carrier of one of the variants with PsA, and a PAM patient. We found a significant increase in ROS in the PAM patient and the PsA mutation carrier compared to all the other groups. When we test the effect of the mutations in zebrafish, we observe that all three variants increase ROS generation, which is in accordance with our results in patients and in stable cell lines. Differentiation to osteoclast compared to a healthy control shows higher ROS generation as well as higher NOX4 expression by western blots. Conclusions: Herein, we propose NOX4 as the first disease-causing gene for PAM. Our research links high levels of ROS NOX4 variants to the development of PAM, opening the possibility for a potential therapeutic target.