A genome-wide association meta-analysis links hidradenitis suppurativa to common and rare sequence variants causing disruption of the Notch and Wnt/β-catenin signaling pathways.

Background: The contributions of genetic and environmental risk factors to hidradenitis suppurativa (HS) are both poorly understood.
Objective: To identify sequence variants that associate with HS and determine the contribution of environmental risk factors and inflammatory diseases to HS pathogenesis.
Methods: A genome-wide association meta-analysis of 4814 HS cases (Denmark: 1977; Iceland: 1266; Finland: 800; UK: 569; and US: 202) and 1.2 million controls, searching for sequence variants associated with HS.
Results: We found 8 independent sequence variants associating with HS, 6 common and 2 rare (frequency <1%). Four associations point to candidate causal genes, NCSTN, PSENEN, WNT10A, and TMED10, that all map to the Notch and Wnt/β-catenin signaling pathways, involved in epidermal keratinization.
Limitations: Limited racial diversity may prevent identification of sequence variants of particular importance in non-Caucasian populations.
Conclusions: These findings demonstrate that genes and pathways involved in epidermal keratinization are the genetic backbone of HS pathology.
Competing Interests: Conflicts of interest Dr Andersen reports that his attendance at the Nordic Congress of DermatoVenerology hosted in Copenhagen in 2022 was funded by Eli Lilly. Drs Stefansdottir, Halldorsson, Ferkingstad, Oddsson, Walters, Olafsdottir, Rutsdottir, Saemundsdottir, Melsted, Norddahl, Sulem, Stefansson, Holm, Gudbjartsson, Thorleifsson, Jonsdottir, and Stefansson are employees of deCODE Genetics/Amgen, Inc. Dr Zachariae has been a speaker/consultant for Jansen Cilag, Novartis, Almirall, UCB, Leo Pharma, Galderma, with no relation to the present manuscript. Dr Thomsen has received research support from Abbvie, Janssen, LEO Pharma, Novartis, Sanofi, and UCB; and has been a speaker/consultant for Abbvie, Eli Lilly, Galderma, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi, Symphogen, UCB, and UNION therapeutics, with no relation to the present manuscript. Dr Brodersen's spouse is a principal level employee at LEO Pharma, part of stock incentive program, and currently hold incentive stock options to a value of approx. 7300USD (January 17 2024). Dr Brunak declares that he has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, ALK abello A/S, and managing board memberships in Proscion A/S and Intomics A/S. Dr Erikstrup reports unrestricted departmental grants from Novo Nordisk and Abbott Diagnostics, no personal fees. Dr Eidsmo has received speaker honoraria from Novartis, Lilly, Leo Pharma, and Janssen; and has been a consultant for advisory boards and received research grants from Novartis. Dr Saunte has over the past 3 years received honoraria as a consultant for advisory board meetings by AbbVie, Janssen, Sanofi, Leo Pharma, and Novartis and as a speaker and/or received grants from the following companies: AbbVie, Janssen, Novartis, Sanofi, Jamjoom Pharma, UCB, Pfizer, and Leo Pharma. Dr Jemec has received honoraria from AbbVie, Chemocentryx, Coloplast, Incyte, Inflarx, Novartis, Pierre Fabre, and UCB for participation on advisory boards, and grants from AbbVie, AstraZeneca, Inflarx, Janssen-Cilag, Leo Pharma, Novartis, Regeneron, and Sanofi, for participation as an investigator, and received speaker honoraria from AbbVie, Boehringer Ingelheim, Galderma, and MSD. He has also received unrestricted departmental grants from AbbVie, Leo Pharma, and Novartis. Drs Riis, Dinh, Knowlton, Knight, Nadauld, Banasik, Hansen, Hjalgrim, Sørensen, Mikkelsen, Ullum, Nyegaard, Bruun, Ostrowski, Sigurgeirsson, Orvar, and Pedersen have no conflicts of interest to declare.
(Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)