Academic Journal
A genome-wide meta-analysis of palmoplantar pustulosis implicates T(H)2 responses and cigarette smoking in disease pathogenesis
| العنوان: | A genome-wide meta-analysis of palmoplantar pustulosis implicates T(H)2 responses and cigarette smoking in disease pathogenesis |
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| المؤلفون: | Hernandez-Cordero, A., Thomas, L., Smail, A., Lim, Z. Q., Saklatvala, J. R., Chung, R., Curtis, C. J., Baum, P., Visvanathan, S., Burden, A. D., Cooper, H. L., Dunnill, G., Griffiths, C. E. M., Levell, N. J., Parslew, R., Reynolds, N. J., Wahie, S., Warren, R. B., Wright, A., Simpson, M., Hveem, K., Barker, J. N., Dand, N., Løset, M., Smith, C. H., Capon, F. |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2024 |
| المجموعة: | RD&E Research Repository (Royal Devon and Exeter NHS Foundation Trust) |
| مصطلحات موضوعية: | Mendelian randomization, Palmoplantar pustulosis, T(h)2, cigarette smoking, genome-wide association study |
| الوصف: | BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. Although 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: We sought 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 3 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 association signals. We also 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 < 5 × 10(-6)) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and T(H)2-mediated diseases such as atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in 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 T(H)2 responses and cigarette smoking. ; Published version, accepted version (12 month embargo), submitted version ; Journal content freely available via Open Access. Some content may be unavailable ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(24)00553-0; Hernandez-Cordero A, Thomas L, Smail A, Lim ZQ, Saklatvala JR, Chung R, et al. A genome-wide meta-analysis of palmoplantar pustulosis implicates T(H)2 responses and cigarette smoking in disease pathogenesis. The Journal of allergy and clinical immunology. 2024.; The Journal of allergy and clinical immunology; https://hdl.handle.net/11287/623328 |
| DOI: | 10.1016/j.jaci.2024.05.015 |
| الاتاحة: | https://hdl.handle.net/11287/623328 https://doi.org/10.1016/j.jaci.2024.05.015 |
| Rights: | © 2024 The Authors. Published by Elsevier Inc. All rights reserved. |
| رقم الانضمام: | edsbas.FD4F16E5 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.jaci.2024.05.015 |
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