Manuel Mattheisen

Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Ines Gockel, 1] Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany. [2].
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  • Jessica Becker, 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. [3].
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  • Mira M Wouters, Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium.
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  • Stefan Niebisch, Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany., Denmark
  • Henning R Gockel, Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany., Denmark
  • Timo Hess, 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany., Denmark
  • David Ramonet, Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany., Denmark
  • Julian Zimmermann, Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany., Denmark
  • Ana González Vigo, Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain., Denmark
  • Gosia Trynka, Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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  • Antonio Ruiz de León, Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain., Denmark
  • Julio Pérez de la Serna, Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain., Denmark
  • Elena Urcelay, Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
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  • Vinod Kumar, Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Denmark
  • Lude Franke, Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Denmark
  • Harm-Jan Westra, Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Denmark
  • Daniel Drescher, Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany., Denmark
  • Werner Kneist, Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany., Denmark
  • Jens U Marquardt, First Department of Internal Medicine, University Medical Center, University of Mainz, Mainz, Germany., Denmark
  • Peter R Galle, First Department of Internal Medicine, University Medical Center, University of Mainz, Mainz, Germany., Denmark
  • Manuel Mattheisen
  • Vito Annese, Department of Gastroenterology, Careggi Hospital, University of Florence, Florence, Italy.
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  • Anna Latiano, Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
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  • Uberto Fumagalli, Department of Surgery, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
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  • Luigi Laghi, Department of Gastroenterology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
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  • Rosario Cuomo, Department of Clinical Medicine and Surgery, Division of Gastroenterology, Federico II University Hospital School of Medicine, Naples, Italy.
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  • Giovanni Sarnelli, Department of Clinical Medicine and Surgery, Division of Gastroenterology, Federico II University Hospital School of Medicine, Naples, Italy.
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  • Michaela Müller, Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany., Denmark
  • Alexander J Eckardt, Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany., Denmark
  • Jan Tack, Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium.
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  • Per Hoffmann, 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.
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  • Stefan Herms, 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.
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  • Elisabeth Mangold, 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
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  • Stefanie Heilmann, 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany., Denmark
  • Ralf Kiesslich, Department of Internal Medicine, Hospital St. Marien, Frankfurt, Germany., Denmark
  • Burkhard H A von Rahden, Department of General, Visceral, Vascular and Pediatric Surgery, University of Würzburg, Würzburg, Germany., Denmark
  • Hans-Dieter Allescher, Center of Internal Medicine, Hospital Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany., Denmark
  • Henning G Schulz, Department of General and Abdominal Surgery, Protestant Hospital Castrop-Rauxel, Castrop-Rauxel, Germany., Denmark
  • Cisca Wijmenga, Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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  • Michael T Heneka, Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany.
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  • Hauke Lang, Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
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  • Karl-Peter Hopfner, 1] Department of Biochemistry, Gene Center, Ludwig Maximilians University, Munich, Germany. [2] Center for Integrated Protein Sciences, Munich, Germany., Denmark
  • Markus M Nöthen, 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
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  • Guy E Boeckxstaens, Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium.
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  • Paul I W de Bakker, 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.
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  • Michael Knapp, 1] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. [2].
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  • Johannes Schumacher, 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. [3].

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.

Original languageEnglish
JournalNature Genetics
ISSN1061-4036
DOIs
Publication statusPublished - 6 Jul 2014

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