P86 Mendelian randomization points to a potential role of OX40 in mediating the effects of smoking initiation on Palmoplantar Pustulosis

Abstract Palmoplantar pustulosis (PPP) is a rare variant of psoriasis characterized by sterile pustules on the palms and soles. As pathogenic pathways remain poorly understood, no targeted therapeutics are available. Most individuals with PPP are current or past smokers, indicating a likely pathogenic role for cigarette smoking. To explore what pro-inflammatory factors might mediate this relationship, we carried out a two-step Mendelian Randomization analysis. We first examined the influence of smoke on the plasma levels of 160 cytokines and chemokines, using proteome GWAS data generated by the UK biobank. This showed that the levels of 45 plasma proteins were likely to be causally affected by smoking initiation. When these proteins were examined as an exposure in the second step of the analysis, a 1-standard deviation increase in the plasma level of TNFRSF4 (OX40) was predicted to casually influence PPP (Padj = 2.46 × 10−3; odds ratio: 1.50). Consistent results were obtained in sensitivity analyses. As the relatively small size of the PPP GWAS (n = 1456 cases) reduced the power to detect robust associations, a larger dataset will be required to confirm our findings. While our study highlights the difficulty of investigating rare conditions with population-wide methods, it identifies OX40 as an inflammatory protein that could mediate the pathogenic effects of cigarette smoking in PPP.