A genome-wide meta-analysis of palmoplantar pustulosis implicates T_H2 responses and cigarette smoking in disease pathogenesis - 21/06/24

Doi : 10.1016/j.jaci.2024.05.015

Ariana Hernandez-Cordero, MSc ^a, Laurent Thomas, PhD ^b,^c,^d,^e, Alice Smail, MPhil ^a, Zhao Qin Lim, MSc ^a,^f, Jake R. Saklatvala, PhD ^a, Raymond Chung, MSc ^g, Charles J. Curtis, MRes ^g, Patrick Baum, PhD ^h, Sudha Visvanathan, PhD ⁱ, A. David Burden, MD ^j, Hywel L. Cooper, BM ^k, Giles Dunnill, MD ^l, Christopher E.M. Griffiths, MD ^m,ⁿ, Nick J. Levell, MD ^o, Richard Parslew, MD ^p, Nick J. Reynolds, MD ^q, Shyamal Wahie, MD ^r,^s, Richard B. Warren, PhD ^m,^t, Andrew Wright, MB ChB ^u,^v, the
APRICOT and PLUM Study Team
Thamir Abraham ^z, Muhmad Ali ^aa, Suzannah August ^bb, David Baudry ^cc, Gabrielle Becher ^dd, Anthony Bewley ^ee, Victoria Brown ^ff, Victoria Cornelius ^gg, Sharizan Ghaffar ^hh, John Ingram ⁱⁱ, Svetlana Kavakleiva ^jj, Susan Kelly ^kk, Mohsen Khorshid ^ll, Helen Lachmann ^mm, Effie Ladoyanni ⁿⁿ, Helen McAteer ^oo, John McKenna ^pp, Freya Meynell ^qq, Prakash Patel ^rr, Andrew Pink ^ss, Kingsley Powell ^tt, Angela Pushparajah ^uu, Catriona Sinclair ^vv, Rachel Wachsmuth ^ww
^z Peterborough City Hospital, Peterborough
^aa Worthing Hospital, Worthing
^bb Poole Hospital NHS Foundation Trust, Poole
^cc Guy’s Hospital, London
^dd West Glasgow Ambulatory Care Hospital, Glasgow
^ee Whipps Cross Hospital, Leytonstone
^ff St Albans City Hospital, St Albans
^gg Imperial College London, London
^hh Ninewells Hospital and Medical School, Dundee
ⁱⁱ University Hospital of Wales, Cardiff
^jj Royal Lancaster Infirmary, Lancaster
^kk The Royal Shrewsbury Hospital, Shrewsbury
^ll Basildon Hospital, Essex
^mm Royal Free Hospital, London
ⁿⁿ Russells Hall Hospital, Dudley
^oo Psoriasis Association, Northampton
^pp Leicester Royal Infirmary, Leicester
^qq Guy’s Hospital, London
^rr Guy’s Hospital, London
^ss Guy’s Hospital, London
^tt Guy’s Hospital, London
^uu Guy’s Hospital, London
^vv Broomfield Hospital, Essex
^ww Royal Devon and Exeter NHS Foundation Trust, Exeter

Michael Simpson, PhD ^a, Kristian Hveem, MD, PhD ^c,^w, Jonathan N. Barker, MD ^x, Nick Dand, PhD ^a, Mari Løset, PhD ^c,^y, Catherine H. Smith, MD ^x, Francesca Capon, PhD ^a,^⁎
^a Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King’s College London, London, United Kingdom
^b Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
^c HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
^d BioCore-Bioinformatics Core Facility, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
^e Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
^f Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore
^g 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, United Kingdom
^h Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
ⁱ Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn
^j School of Infection and Immunity, University of Glasgow, Glasgow, United Kingdom
^k Portsmouth Dermatology Unit, Portsmouth Hospitals Trust, Portsmouth, United Kingdom
^l Bristol Royal Infirmary, Bristol, United Kingdom
^m NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
ⁿ Department of Dermatology, King’s College Hospital, King’s College London, London, United Kingdom
^o Norwich Medical School, University of East Anglia, Norwich, United Kingdom
^p Department of Dermatology, Royal Liverpool Hospitals, Liverpool, United Kingdom
^q 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, United Kingdom
^r University Hospital of North Durham, Durham, United Kingdom
^s Darlington Memorial Hospital, Darlington, United Kingdom
^t Dermatology Centre, Northern Care Alliance NHS Foundation Trust, Manchester, United Kingdom
^u St Lukes Hospital, Bradford, United Kingdom
^v Centre for Skin Science, University of Bradford, Bradford, United Kingdom
^w Department of Innovation and Research, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
^x St John’s Institute of Dermatology, School of Basic and Medical Biosciences, King’s College London, London, United Kingdom
^y Department of Dermatology, Clinic of Orthopedy, Rheumatology and Dermatology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

^∗Corresponding author: Francesca Capon, PhD, 9th Floor, Tower Wing, Guy’s Hospital, London SE1 9RT, UK.9th FloorTower WingGuy’s HospitalLondonSE1 9RTUK

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Friday 21 June 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. 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.