First genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia

作者：Sandeep Grover, Ines Gockel, Anna Latiano, Anna Mokrowiecka, Pouria Dasmeh, Mira M. Wouters, Zuzana Vacková, Stephan Haas, Tania Triantafyllou, Nicole Kreuser, Jessica Trautmann, Stefan Niebisch, Timo Hess, René Thieme, Jessica Bigge, Hubert Louis, Eric Quertinmont, Aline Meirhaeghe, Manon Muntaner, Philippe Amouyel, Guillaume Gourcerol, Stanislas Bruley des Varannes, François Mion, Michael Vieth, Nikolaos Scarmeas, Orazio Palmieri, Francesca Tavano, Roberto De Giorgio, Daniela Galimberti, Andrea Arighi, Beatrice Arosio, Marco J. Bruno, Justyna Wasielica-Berger, Magdalena Gawron-Kiszka, Maria Janiak, Magdalena Siepsiak, Krystian Adrych, Tomasz Marek, A Dâbrowski, Marek Majewski, Piotr Gietka, Maciej Gonciarz, Julio Pérez de la Serna, Laisy Zacarías Martínez, Vilmantas Giedraitis, Lena Kilander, Laura Fratiglioni, Luís Miguel Real, Julius Špičák, Jan Tack, Stefanie Heilmann-Heimbach, Markus M. Nöthen, Martin Ingelsson, Caroline Graff, Agustín Ruiz, Jean‐Charles Lambert, Alfredo Ramı́rez, Alexander J. Eckardt, Michaela Müller, Michael Knapp, Thaddäus T Wissinowski, Jutta Keller, Christiane J. Bruns, Christian Gerges, Horst Neuhaus, Thomas Rösch, Britta Siegmund, Brigitte Schumacher, Marino Venerito, Antonio Ruiz de León, Riccardo Rosati, Vito Annese, Uberto Fumagalli, Luigi Laghi, Elena Urcelay, Fabienne Vavasseur, Sabine Roman, Ping‐Hong Zhou, Quan‐Lin Li, Zuqiang Liu, Burkhard H.A. von Rahden, Dimitris Theodorou, Ewa Malecka-Wojciesko, Carlo Maj, A. Vigo, Jan Martínek, Guy E. Boeckxstaens, Johannes Schumacher · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2024-334498 · 被引用次数：2 · 研究领域：Gastroesophageal reflux and treatments、Dysphagia Assessment and Management、Gastrointestinal motility and disorders

Background Idiopathic achalasia (IA) is characterised by the degeneration of neurons in the myenteric plexus leading to an irreversible impaired oesophageal function. Although immune-mediated mechanisms have been proposed, the underlying aetiopathology of IA remains poorly understood. Objective This study aimed to uncover the genetic risk architecture of IA. Design We carried out the first genome-wide association study (GWAS) on 4602 European patients with IA and 10 766 ethnically-matched controls. Results A single nucleotide polymorphism (SNP) in HLA-DQB1 leading to an 8-amino acid insertion on the protein level conferred strongest IA risk (PQGPPPAG: p=3.27×10 –68 , OR=2.45). Conditional analyses within the HLA locus revealed a complex genetic risk architecture. Three additional amino acid positions showed independent IA association (Omnibus p<5×10 −8 ). These refer to positions 41 and 130 in HLA-DQα1, position 45 in HLA-DQβ1 and position 86 in HLA-DRβ1. Together, these findings highlight the pivotal role of class II HLA genetic variation in IA pathogenesis. Outside HLA, three independent variants showed IA association (p<5×10 −8 ). One leads to an amino acid substitution with functional effect in PTPN22. Another risk variant leads to a downregulated expression of TNFSF8 , TNFSF15 and TNC in immune cells. The third risk SNP is located near ZNF365 , but the exact underlying cellular mechanism remains unknown. Beyond the single marker level, polygenic risk scores reveale...