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

Ines Gockel¹, Jessica Becker², Mira M Wouters³, Stefan Niebisch⁴, Henning R Gockel⁴, Timo Hess⁵, David Ramonet⁶, Julian Zimmermann⁶, Ana González Vigo⁷, Gosia Trynka⁸, Antonio Ruiz de León⁹, Julio Pérez de la Serna⁹, Elena Urcelay⁷, Vinod Kumar⁸, Lude Franke⁸, Harm-Jan Westra⁸, Daniel Drescher⁴, Werner Kneist⁴, Jens U Marquardt¹⁰, Peter R Galle¹⁰, Manuel Mattheisen¹¹, Vito Annese¹², Anna Latiano¹³, Uberto Fumagalli¹⁴, Luigi Laghi¹⁵, Rosario Cuomo¹⁶, Giovanni Sarnelli¹⁶, Michaela Müller¹⁷, Alexander J Eckardt¹⁷, Jan Tack³, Per Hoffmann¹⁸, Stefan Herms¹⁸, Elisabeth Mangold⁵, Stefanie Heilmann⁵, Ralf Kiesslich¹⁹, Burkhard H A von Rahden²⁰, Hans-Dieter Allescher²¹, Henning G Schulz²², Cisca Wijmenga⁸, Michael T Heneka⁶, Hauke Lang⁴, Karl-Peter Hopfner²³, Markus M Nöthen⁵, Guy E Boeckxstaens³, Paul I W de Bakker²⁴, Michael Knapp²⁵, Johannes Schumacher²

Affiliations

¹ 1] Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany. [2].
² 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3].
³ Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium.
⁴ Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
⁵ 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
⁶ Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany.
⁷ Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
⁸ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁹ Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
¹⁰ First Department of Internal Medicine, University Medical Center, University of Mainz, Mainz, Germany.
¹¹ 1] Department of Biomedicine, Aarhus University, Aarhus, Denmark. [2] Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.
¹² Department of Gastroenterology, Careggi Hospital, University of Florence, Florence, Italy.
¹³ Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
¹⁴ Department of Surgery, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
¹⁵ Department of Gastroenterology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
¹⁶ Department of Clinical Medicine and Surgery, Division of Gastroenterology, Federico II University Hospital School of Medicine, Naples, Italy.
¹⁷ Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany.
¹⁸ 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.
¹⁹ Department of Internal Medicine, Hospital St. Marien, Frankfurt, Germany.
²⁰ Department of General, Visceral, Vascular and Pediatric Surgery, University of Würzburg, Würzburg, Germany.
²¹ Center of Internal Medicine, Hospital Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany.
²² Department of General and Abdominal Surgery, Protestant Hospital Castrop-Rauxel, Castrop-Rauxel, Germany.
²³ 1] Department of Biochemistry, Gene Center, Ludwig Maximilians University, Munich, Germany. [2] Center for Integrated Protein Sciences, Munich, Germany.
²⁴ 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.
²⁵ 1] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. [2].

PMID: 24997987
DOI: 10.1038/ng.3029

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

Ines Gockel et al. Nat Genet. 2014 Aug.

. 2014 Aug;46(8):901-4.

doi: 10.1038/ng.3029. Epub 2014 Jul 6.

Authors

Affiliations

¹ 1] Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany. [2].
² 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3].
³ Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium.
⁴ Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
⁵ 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
⁶ Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany.
⁷ Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
⁸ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁹ Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
¹⁰ First Department of Internal Medicine, University Medical Center, University of Mainz, Mainz, Germany.
¹¹ 1] Department of Biomedicine, Aarhus University, Aarhus, Denmark. [2] Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.
¹² Department of Gastroenterology, Careggi Hospital, University of Florence, Florence, Italy.
¹³ Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
¹⁴ Department of Surgery, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
¹⁵ Department of Gastroenterology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
¹⁶ Department of Clinical Medicine and Surgery, Division of Gastroenterology, Federico II University Hospital School of Medicine, Naples, Italy.
¹⁷ Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany.
¹⁸ 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.
¹⁹ Department of Internal Medicine, Hospital St. Marien, Frankfurt, Germany.
²⁰ Department of General, Visceral, Vascular and Pediatric Surgery, University of Würzburg, Würzburg, Germany.
²¹ Center of Internal Medicine, Hospital Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany.
²² Department of General and Abdominal Surgery, Protestant Hospital Castrop-Rauxel, Castrop-Rauxel, Germany.
²³ 1] Department of Biochemistry, Gene Center, Ludwig Maximilians University, Munich, Germany. [2] Center for Integrated Protein Sciences, Munich, Germany.
²⁴ 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.
²⁵ 1] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. [2].

PMID: 24997987
DOI: 10.1038/ng.3029

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.

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References

1. Hum Genet. 2010 Oct;128(4):353-64 - PubMed
1. Nat Genet. 2011 Nov 06;43(12):1193-201 - PubMed
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Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia

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

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