A genome-wide meta-analysis of palmoplantar pustulosis implicates Th2 responses and cigarette smoking in disease pathogenesis

ABSTRACT Background Palmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. While the disease can present with concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets. Objectives To identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis. Methods We performed a genome-wide association meta-analysis of three North-European cohorts (n=1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the resulting association signals. We undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP. Results We found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive ( P <5X10 -6 ) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and Th2-mediated diseases like atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and enriched for T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP. Conclusions The first genome-wide association study of PPP points to a pathogenic role for deregulated Th2 responses and cigarette smoking. Clinical implications The results of the first PPP GWAS support the therapeutic potential of agents that inhibit Th2 responses and target inflammatory pathways activated by cigarette smoking. Capsule The genetic analysis of ∼1,400 PPP cases and 400,000 healthy controls points to a causal role of abnormal Th2 responses and cigarette smoking. This supports the therapeutic utility of Th2 inhibition.