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

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. ### Competing Interest Statement F.C. has received grants and consultancy fees from Boehringer-Ingelheim. A.D.B. has received consultancy fees from Boehringer-Ingelheim. C.E.M.G. has received research grants and/or honoraria from Abbvie, Almirall, Anaptysbio, Boehringer-Ingelheim, Bristol Meyers Squibb, Evelo, GSK, Inmagene, Janssen, Lilly, ONO Pharmaceuticals, Novartis, Pfizer and UCB. P.B. and S.V. are Boehringer-Ingelheim employees. S.W. has had non-financial support (sponsorship to attend dermatology conferences) from Janssen, Abbvie, Novartis, Almirall and UCB. J.N.B. declares paid activities as an advisor and speaker for AbbVie, Amgen, Boehringer-Ingelheim, Bristol Myers Squibb, Johnson & Johnson, Lilly, Novartis. ### Funding Statement This work was supported by NIHR BioResource Centre Maudsley, National Institute for Health Research Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London. We gratefully acknowledge capital equipment funding from the Maudsley Charity (Grant Ref. 980) and Guy's and St Thomas's Charity (Grant Ref. STR130505). The work was also supported by the NIHR Manchester Biomedical Research Centre (NIHR203308). The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St Olavs hospital and the Faculty of Medicine and Health Sciences, NTNU. The APRICOT trial was funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership (grant EME 13/50/17 to C.H.S., F.C., J.N.B., C.E.M.G., N.J.R. and A.D.B). This study was supported by Boehringer-Ingelheim and by the Psoriasis Association (grants BSTOP50/5 to CHS and PhD studentship ST3/20 to AHC). ZQL was supported by the Talent Development Fund of KK Women's and Children's Hospital, Singapore. NJR is a NIHR Senior Investigator and is also supported by NIHR Newcastle Biomedical Research Centre, NIHR Newcastle In Vitro Diagnostics Co-operative and NIHR Newcastle Patient Safety Research Collaboration. The views expressed are those of the author(s) and not necessarily those of the NHS, Department of Health or King's College London. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Norwegian Data Protection Authority and the Regional Committee for Medical and Health Research Ethics in Central Norway; the London Bridge Research Ethics Committee in the UK; and the Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The FinnGen data are publicly available. The UK data will be submitted to the GWAS catalogue. * AD : atopic dermatitis; eQTL : expression quantitative trait locus; GWAS : genome-wide association study; LD : linkage disequilibrium; PBMC : peripheral blood mononuclear cells; PPP : palmoplantar pustulosis; UC : ulcerative colitis.