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

Mendelian randomization Th2 cigarette smoking genome-wide association study palmoplantar pustulosis

Journal

The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002

Informations de publication

Date de publication:
28 May 2024
Historique:
received: 24 01 2024
revised: 22 04 2024
accepted: 15 05 2024
medline: 31 5 2024
pubmed: 31 5 2024
entrez: 30 5 2024
Statut: aheadofprint

Résumé

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. To identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis. 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 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<5X10 The first genome-wide association study of PPP points to a pathogenic role for deregulated Th2 responses and cigarette smoking.

Sections du résumé

BACKGROUND 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 OBJECTIVE
To identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis.
METHODS 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 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 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
CONCLUSIONS CONCLUSIONS
The first genome-wide association study of PPP points to a pathogenic role for deregulated Th2 responses and cigarette smoking.

Identifiants

DOI: 10.1016/j.jaci.2024.05.015 PMID: 38815935
pubmed: 38815935
pii: S0091-6749(24)00553-0
doi: 10.1016/j.jaci.2024.05.015
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Auteurs

Ariana Hernandez-Cordero (A)

Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK.

Laurent Thomas (L)

Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway;; HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, NTNU- Norwegian University of Science and Technology, Trondheim, Norway;; BioCore- Bioinformatics Core Facility, NTNU-Norwegian University of Science and Technology, Trondheim, Norway;; Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Alice Smail (A)

Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK.

Zhao Qin Lim (ZQ)

Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK;; Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore.

Jake R Saklatvala (JR)

Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK.

Raymond Chung (R)

NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.

Charles J Curtis (CJ)

NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.

Patrick Baum (P)

Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.

Sudha Visvanathan (S)

Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA.

A David Burden (AD)

School of Infection and Immunity, University of Glasgow, Glasgow, UK.

Hywel L Cooper (HL)

Portsmouth Dermatology Unit, Portsmouth Hospitals Trust, Portsmouth, UK.

Giles Dunnill (G)

Bristol Royal Infirmary, Bristol, UK.

Christopher Em Griffiths (CE)

NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK;; Department of Dermatology, King's College Hospital, King's College London, London, UK.

Nick J Levell (NJ)

Norwich Medical School, University of East Anglia, Norwich, UK.

Richard Parslew (R)

Department of Dermatology, Royal Liverpool Hospitals, Liverpool, UK.

Nick J Reynolds (NJ)

Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle NIHR Biomedical Research Centre and the Department of Dermatology, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Shyamal Wahie (S)

University Hospital of North Durham, Durham; Darlington Memorial Hospital, Darlington, UK.

Richard B Warren (RB)

NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK;; Dermatology Centre, Northern Care Alliance NHS Foundation Trust, Manchester, UK.

Andrew Wright (A)

St Lukes Hospital, Bradford, UK; Centre for skin science, University of Bradford, Bradford, UK.

Michael Simpson (M)

Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK.

Kristian Hveem (K)

HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, NTNU- Norwegian University of Science and Technology, Trondheim, Norway;; Department of Innovation and Research, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Jonathan N Barker (JN)

St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, UK.

Nick Dand (N)

Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK.

Mari Loset (M)

HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, NTNU- Norwegian University of Science and Technology, Trondheim, Norway;; Department of Dermatology, Clinic of Orthopedy, Rheumatology and Dermatology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Catherine H Smith (CH)

St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, UK.

Francesca Capon (F)

Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK;. Electronic address: francesca.capon@kcl.ac.uk.

Classifications MeSH