A genome-wide meta-analysis of palmoplantar pustulosis implicates T(H)2 responses and cigarette smoking in disease pathogenesis
Hernandez-Cordero, Ariana Thomas, Laurent Smail, Alice Lim, Zhao Q Saklatvala, Jake R Chung, Raymond Curtis, Charles J Baum, Patrick Visvanathan, Sudha Burden, David A
Hernandez-Cordero, Ariana
Thomas, Laurent
Smail, Alice
Lim, Zhao Q
Saklatvala, Jake R
Chung, Raymond
Curtis, Charles J
Baum, Patrick
Visvanathan, Sudha
Burden, David A
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Affiliation
Kings College London; Trondheim University Hospital; KK Womens and Childrens Hospital; The Dudley Group NHSFoundation Trust et al
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Publication date
2024-09-01
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Abstract
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. We sought to identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis. 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. 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 TH2-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. The first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.
Citation
Hernandez-Cordero A, Thomas L, Smail A, Lim ZQ, Saklatvala JR, Chung R, Curtis CJ, Baum P, Visvanathan S, Burden AD, Cooper HL, Dunnill G, Griffiths CEM, Levell NJ, Parslew R, Reynolds NJ, Wahie S, Warren RB, Wright A; APRICOT and PLUM Study Team; Simpson M, Hveem K, Barker JN, Dand N, L�set M, Smith CH, Capon F. A genome-wide meta-analysis of palmoplantar pustulosis implicates TH2 responses and cigarette smoking in disease pathogenesis. J Allergy Clin Immunol. 2024 Sep;154(3):657-665.e9. doi: 10.1016/j.jaci.2024.05.015. Epub 2024 May 28.