[en] Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQβ1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P=1.73×10(-19)). In addition, two amino acid substitutions in the extracellular domain of HLA-DQα1 at position 41 (lysine encoded by HLA-DQA1*01:03; P=5.60×10(-10)) and of HLA-DQβ1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P=1.20×10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.
Disciplines :
Neurology
Author, co-author :
Gockel, Ines ✱; 1] Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany. [2
Becker, Jessica ✱; 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3
Wouters, Mira M; Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium
Niebisch, Stefan; Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
Gockel, Henning R; Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
Hess, Timo; 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany
Ramonet, David; Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany
Zimmermann, Julian; Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany
Vigo, Ana González; Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
Trynka, Gosia; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
de León, Antonio Ruiz; Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
de la Serna, Julio Pérez; Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
Urcelay, Elena; Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
Kumar, Vinod; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Franke, Lude; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Westra, Harm-Jan ; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Drescher, Daniel; Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
Kneist, Werner; Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
Marquardt, Jens U; First Department of Internal Medicine, University Medical Center, University of Mainz, Mainz, Germany
Galle, Peter R; First Department of Internal Medicine, University Medical Center, University of Mainz, Mainz, Germany
Mattheisen, Manuel ; 1] Department of Biomedicine, Aarhus University, Aarhus, Denmark. [2] Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark
Annese, Vito; Department of Gastroenterology, Careggi Hospital, University of Florence, Florence, Italy
Latiano, Anna; Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Fumagalli, Uberto; Department of Surgery, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Laghi, Luigi; Department of Gastroenterology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Cuomo, Rosario; Department of Clinical Medicine and Surgery, Division of Gastroenterology, Federico II University Hospital School of Medicine, Naples, Italy
Sarnelli, Giovanni; Department of Clinical Medicine and Surgery, Division of Gastroenterology, Federico II University Hospital School of Medicine, Naples, Italy
Müller, Michaela; Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany
Eckardt, Alexander J; Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany
Tack, Jan; Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium
Hoffmann, Per ; 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3] Division of Medical Genetics, University Hospital, Basel, Switzerland. [4] Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland
Herms, Stefan; 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3] Division of Medical Genetics, University Hospital, Basel, Switzerland. [4] Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland
Mangold, Elisabeth; 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany
Heilmann, Stefanie; 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany
Kiesslich, Ralf; Department of Internal Medicine, Hospital St. Marien, Frankfurt, Germany
von Rahden, Burkhard H A; Department of General, Visceral, Vascular and Pediatric Surgery, University of Würzburg, Würzburg, Germany
Allescher, Hans-Dieter; Center of Internal Medicine, Hospital Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany
Schulz, Henning G; Department of General and Abdominal Surgery, Protestant Hospital Castrop-Rauxel, Castrop-Rauxel, Germany
Wijmenga, Cisca; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
HENEKA, Michael ; Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany
Lang, Hauke; Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
Hopfner, Karl-Peter; 1] Department of Biochemistry, Gene Center, Ludwig Maximilians University, Munich, Germany. [2] Center for Integrated Protein Sciences, Munich, Germany
Nöthen, Markus M; 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany
Boeckxstaens, Guy E; Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium
de Bakker, Paul I W ; 1] Department of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands. [2] Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Knapp, Michael ✱; 1] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. [2
Schumacher, Johannes ✱; 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3
We thank all subjects for participating to this study. We acknowledge our collaborating clinical partners, all colleagues who contributed to patient recruitment, and our laboratory technicians and colleagues responsible for database management (for a complete list of all individuals, see the Supplementary Note). I.G., M.K. and J.S. received support for this work from the Deutsche Forschungsgemeinschaft (DFG), individual grants GO 1795/1-1, KN 378/2-1 and SCHU 1596/5-1. M.M.N. received support for this work from the Alfried Krupp von Bohlen und Halbach-Stiftung. M.M.N. is a member of the DFG-funded Excellence Cluster ImmunoSensation. The Heinz Nixdorf Recall cohort was established with the generous support of the Heinz Nixdorf Foundation, Germany. We thank B. Pötzsch (University of Bonn) for help with collecting DNA samples from anonymous blood donors. In addition, we thank the Type I Diabetes Genetics Consortium (T1DGC) for data access and J. Sauter (German Bone Marrow Donor Center (DKMS), Tübingen) for help differentiating HLA-DQA1 alleles. P.I.W.d.B. is the recipient of a Vernieuwingsimpuls VIDI Award from the Netherlands Organization for Scientific Research (NWO project 016.126.354). M.M.W. is supported by a postdoctoral fellowship of the Fund for Scientific Research (FWO) Flanders, Belgium. G.E.B. is supported by a grant from the Research Foundation– Flanders (FWO) (Odysseus program). K.-P.H. is supported by DFG SFB 684 and the Center for Integrated Protein Sciences Munich.
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