Type of publication:
Journal article [preprint]
Author(s):
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.; Loset M.; Smith C.H.; Capon F.; Abraham T.; Ali M.; August S.; Baudry D.; Becher G.; Bewley A.; Brown V.; Cornelius V.; Ghaffar S.; Ingram J.; Kavakleiva S.; *Kelly S.; Khorshid M.; Lachmann H.; Ladoyanni E.; McAteer H.; McKenna J.; Meynell F.; Patel P.; Pink A.; Powell K.; Pushparajah A.; Sinclair C.; Wachsmuth R.;
Citation:
medRxiv. (no pagination), 2024. Date of Publication: 17 Jan 2024.
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. Objective(s): To identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis. Method(s): 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. Result(s): 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. Conclusion(s): The first genome-wide association study of PPP points to a pathogenic role for deregulated Th2 responses and cigarette smoking.
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