title: Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia.
abstract: 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.
authors.affiliation: 1] Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany. [2].
authors.forename: Ines
authors.initials: I
authors.lastname: Gockel
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3].
authors.forename: Jessica
authors.initials: J
authors.lastname: Becker
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Mira M
authors.initials: MM
authors.lastname: Wouters
authors.affiliation: Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Niebisch
authors.affiliation: Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Henning R
authors.initials: HR
authors.lastname: Gockel
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Hess
authors.affiliation: Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ramonet
authors.affiliation: Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Zimmermann
authors.affiliation: Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Ana González
authors.initials: AG
authors.lastname: Vigo
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.affiliation: Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Antonio Ruiz
authors.initials: AR
authors.lastname: de León
authors.affiliation: Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Julio Pérez
authors.initials: JP
authors.lastname: de la Serna
authors.affiliation: Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Lude
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authors.lastname: Franke
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Harm-Jan
authors.identifier: 000000017038567X
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Drescher
authors.affiliation: Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Kneist
authors.affiliation: First Department of Internal Medicine, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Jens U
authors.initials: JU
authors.lastname: Marquardt
authors.affiliation: First Department of Internal Medicine, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.affiliation: 1] Department of Biomedicine, Aarhus University, Aarhus, Denmark. [2] Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.
authors.forename: Manuel
authors.identifier: 000000028442493X
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Department of Gastroenterology, Careggi Hospital, University of Florence, Florence, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Annese
authors.affiliation: Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Latiano
authors.affiliation: Department of Surgery, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
authors.forename: Uberto
authors.initials: U
authors.lastname: Fumagalli
authors.affiliation: Department of Gastroenterology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Laghi
authors.affiliation: Department of Clinical Medicine and Surgery, Division of Gastroenterology, Federico II University Hospital School of Medicine, Naples, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Cuomo
authors.affiliation: Department of Clinical Medicine and Surgery, Division of Gastroenterology, Federico II University Hospital School of Medicine, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sarnelli
authors.affiliation: Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany.
authors.forename: Alexander J
authors.initials: AJ
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authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Jan
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authors.lastname: Tack
authors.affiliation: 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.
authors.forename: Per
authors.identifier: 000000026573983X
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann
authors.affiliation: Department of Internal Medicine, Hospital St. Marien, Frankfurt, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kiesslich
authors.affiliation: Department of General, Visceral, Vascular and Pediatric Surgery, University of Würzburg, Würzburg, Germany.
authors.forename: Burkhard H A
authors.initials: BH
authors.lastname: von Rahden
authors.affiliation: Center of Internal Medicine, Hospital Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Allescher
authors.affiliation: Department of General and Abdominal Surgery, Protestant Hospital Castrop-Rauxel, Castrop-Rauxel, Germany.
authors.forename: Henning G
authors.initials: HG
authors.lastname: Schulz
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.affiliation: Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Lang
authors.affiliation: 1] Department of Biochemistry, Gene Center, Ludwig Maximilians University, Munich, Germany. [2] Center for Integrated Protein Sciences, Munich, Germany.
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Hopfner
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Boeckxstaens
authors.affiliation: 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.
authors.forename: Paul I W
authors.identifier: 0000000177357858
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: 1] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. [2].
authors.forename: Michael
authors.initials: M
authors.lastname: Knapp
authors.affiliation: 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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mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D004931:Esophageal Achalasia / Q000235:genetics* / Q000276:immunology; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics*; D059848:HLA-DQ alpha-Chains / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide
chemical_list: D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen