A genome-wide meta-analysis of palmoplantar pustulosis implicates TH2 responses and cigarette smoking in disease pathogenesis

Ariana Hernandez-Cordero; Laurent Thomas; Alice Smail; Zhao Qin Lim; Jake R. Saklatvala; Raymond Chung; Charles J. Curtis; Patrick Baum; Sudha Visvanathan; A. David Burden; Hywel L. Cooper; Giles Dunnill; Christopher E.M. Griffiths; Nick J. Levell; Richard Parslew; Nick J. Reynolds; Shyamal Wahie; Richard B. Warren; Andrew Wright; Thamir Abraham; Muhmad Ali; Suzannah August; David Baudry; Gabrielle Becher; Anthony Bewley; Victoria Brown; Victoria Cornelius; Sharizan Ghaffar; John Ingram; Svetlana Kavakleiva; Susan Kelly; Mohsen Khorshid; Helen Lachmann; Effie Ladoyanni; Helen McAteer; John McKenna; Freya Meynell; Prakash Patel; Andrew Pink; Kingsley Powell; Angela Pushparajah; Catriona Sinclair; Rachel Wachsmuth; Michael Simpson; Kristian Hveem; Jonathan N. Barker; Nick Dand; Mari Løset; Catherine H. Smith; Francesca Capon

doi:10.1016/j.jaci.2024.05.015

A genome-wide meta-analysis of palmoplantar pustulosis implicates T_H2 responses and cigarette smoking in disease pathogenesis

, Ariana Hernandez-Cordero, Laurent Thomas, Alice Smail, Zhao Qin Lim, Jake R. Saklatvala, Raymond Chung, Charles J. Curtis, Patrick Baum, Sudha Visvanathan, A. David Burden, Hywel L. Cooper, Giles Dunnill, Christopher E.M. Griffiths, Nick J. Levell, Richard Parslew, Nick J. Reynolds, Shyamal Wahie, Richard B. Warren, Andrew WrightThamir Abraham, Muhmad Ali, Suzannah August, David Baudry, Gabrielle Becher, Anthony Bewley, Victoria Brown, Victoria Cornelius, Sharizan Ghaffar, John Ingram, Svetlana Kavakleiva, Susan Kelly, Mohsen Khorshid, Helen Lachmann, Effie Ladoyanni, Helen McAteer, John McKenna, Freya Meynell, Prakash Patel, Andrew Pink, Kingsley Powell, Angela Pushparajah, Catriona Sinclair, Rachel Wachsmuth, Michael Simpson, Kristian Hveem, Jonathan N. Barker, Nick Dand, Mari Løset, Catherine H. Smith, Francesca Capon (Lead / Corresponding author)

Undergraduate Medicine

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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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. 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_H2-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_H2 responses and cigarette smoking.

Original language	English
Pages (from-to)	657-665.e9
Number of pages	18
Journal	Journal of Allergy and Clinical Immunology
Volume	154
Issue number	3
Early online date	28 May 2024
DOIs	https://doi.org/10.1016/j.jaci.2024.05.015
Publication status	Published - 4 Sept 2024

Keywords

cigarette smoking
genome-wide association study
Mendelian randomization
Palmoplantar pustulosis
T2

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.jaci.2024.05.015Licence: CC BY

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Cite this

, 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., ... Capon, F. (2024). A genome-wide meta-analysis of palmoplantar pustulosis implicates T_H2 responses and cigarette smoking in disease pathogenesis. Journal of Allergy and Clinical Immunology, 154(3), 657-665.e9. https://doi.org/10.1016/j.jaci.2024.05.015

@article{252d5c4d214a40e69ab4c0e1b1c0ed3e,

title = "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. 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 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. ConclusionsThe first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.",

keywords = "cigarette smoking, genome-wide association study, Mendelian randomization, Palmoplantar pustulosis, T2",

author = "Ariana Hernandez-Cordero and Laurent Thomas and Alice Smail and Lim, \{Zhao Qin\} and Saklatvala, \{Jake R.\} and Raymond Chung and Curtis, \{Charles J.\} and Patrick Baum and Sudha Visvanathan and Burden, \{A. David\} and Cooper, \{Hywel L.\} and Giles Dunnill and Griffiths, \{Christopher E.M.\} and Levell, \{Nick J.\} and Richard Parslew and Reynolds, \{Nick J.\} and Shyamal Wahie and Warren, \{Richard B.\} and Andrew Wright and Thamir Abraham and Muhmad Ali and Suzannah August and David Baudry and Gabrielle Becher and Anthony Bewley and Victoria Brown and Victoria Cornelius and Sharizan Ghaffar and John Ingram and Svetlana Kavakleiva and Susan Kelly and Mohsen Khorshid and Helen Lachmann and Effie Ladoyanni and Helen McAteer and John McKenna and Freya Meynell and Prakash Patel and Andrew Pink and Kingsley Powell and Angela Pushparajah and Catriona Sinclair and Rachel Wachsmuth and Michael Simpson and Kristian Hveem and Barker, \{Jonathan N.\} and Nick Dand and Mari L{\o}set and Smith, \{Catherine H.\} and Francesca Capon",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = sep,

day = "4",

doi = "10.1016/j.jaci.2024.05.015",

language = "English",

volume = "154",

pages = "657--665.e9",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier",

number = "3",

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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, 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, Simpson, M, Hveem, K, Barker, JN, Dand, N, Løset, M & Smith, CH & Capon, F 2024, 'A genome-wide meta-analysis of palmoplantar pustulosis implicates T_H2 responses and cigarette smoking in disease pathogenesis', Journal of Allergy and Clinical Immunology, vol. 154, no. 3, pp. 657-665.e9. https://doi.org/10.1016/j.jaci.2024.05.015

TY - JOUR

T1 - A genome-wide meta-analysis of palmoplantar pustulosis implicates TH2 responses and cigarette smoking in disease pathogenesis

AU - Hernandez-Cordero, Ariana

AU - Thomas, Laurent

AU - Smail, Alice

AU - Lim, Zhao Qin

AU - Saklatvala, Jake R.

AU - Chung, Raymond

AU - Curtis, Charles J.

AU - Baum, Patrick

AU - Visvanathan, Sudha

AU - Burden, A. David

AU - Cooper, Hywel L.

AU - Dunnill, Giles

AU - Griffiths, Christopher E.M.

AU - Levell, Nick J.

AU - Parslew, Richard

AU - Reynolds, Nick J.

AU - Wahie, Shyamal

AU - Warren, Richard B.

AU - Wright, Andrew

AU - Abraham, Thamir

AU - Ali, Muhmad

AU - August, Suzannah

AU - Baudry, David

AU - Becher, Gabrielle

AU - Bewley, Anthony

AU - Brown, Victoria

AU - Cornelius, Victoria

AU - Ghaffar, Sharizan

AU - Ingram, John

AU - Kavakleiva, Svetlana

AU - Kelly, Susan

AU - Khorshid, Mohsen

AU - Lachmann, Helen

AU - Ladoyanni, Effie

AU - McAteer, Helen

AU - McKenna, John

AU - Meynell, Freya

AU - Patel, Prakash

AU - Pink, Andrew

AU - Powell, Kingsley

AU - Pushparajah, Angela

AU - Sinclair, Catriona

AU - Wachsmuth, Rachel

AU - Simpson, Michael

AU - Hveem, Kristian

AU - Barker, Jonathan N.

AU - Dand, Nick

AU - Løset, Mari

AU - Smith, Catherine H.

AU - Capon, Francesca

PY - 2024/9/4

Y1 - 2024/9/4

N2 - 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 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. ConclusionsThe first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.

AB - 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 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. ConclusionsThe first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.

KW - cigarette smoking

KW - genome-wide association study

KW - Mendelian randomization

KW - Palmoplantar pustulosis

KW - T2

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U2 - 10.1016/j.jaci.2024.05.015

DO - 10.1016/j.jaci.2024.05.015

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AN - SCOPUS:85196665197

SN - 0091-6749

VL - 154

SP - 657-665.e9

JO - Journal of Allergy and Clinical Immunology

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