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

Ines Gockel; Jessica Becker; Mira M. Wouters; Stefan Niebisch; Henning R. Gockel; Timo Hess; David Ramonet; Julian Zimmermann; Ana González Vigo; Gosia Trynka; Antonio Ruiz De León; Julio Pérez De La Serna; Elena Urcelay; Vinod Kumar; Lude Franke; Harm Jan Westra; Daniel Drescher; Werner Kneist; Jens U. Marquardt; Peter R. Galle; Manuel Mattheisen; Vito Annese; Anna Latiano; Uberto Fumagalli; Luigi Laghi; Rosario Cuomo; Giovanni Sarnelli; Michaela Müller; Alexander J. Eckardt; Jan Tack; Per Hoffmann; Stefan Herms; Elisabeth Mangold; Stefanie Heilmann; Ralf Kiesslich; Burkhard H.A. Von Rahden; Hans Dieter Allescher; Henning G. Schulz; Cisca Wijmenga; Michael T. Heneka; Hauke Lang; Karl Peter Hopfner; Markus M. Nöthen; Guy E. Boeckxstaens; Paul I.W. De Bakker; Michael Knapp; Johannes Schumacher

doi:10.1038/ng.3029

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

Ines Gockel, Jessica Becker, Mira M. Wouters, Stefan Niebisch, Henning R. Gockel, Timo Hess, David Ramonet, Julian Zimmermann, Ana González Vigo, Gosia Trynka, Antonio Ruiz De León, Julio Pérez De La Serna, Elena Urcelay, Vinod Kumar, Lude Franke, Harm Jan Westra, Daniel Drescher, Werner Kneist, Jens U. Marquardt, Peter R. GalleManuel Mattheisen, Vito Annese, Anna Latiano, Uberto Fumagalli, Luigi Laghi, Rosario Cuomo, Giovanni Sarnelli, Michaela Müller, Alexander J. Eckardt, Jan Tack, Per Hoffmann, Stefan Herms, Elisabeth Mangold, Stefanie Heilmann, Ralf Kiesslich, Burkhard H.A. Von Rahden, Hans Dieter Allescher, Henning G. Schulz, Cisca Wijmenga, Michael T. Heneka, Hauke Lang, Karl Peter Hopfner, Markus M. Nöthen, Guy E. Boeckxstaens, Paul I.W. De Bakker, Michael Knapp, Johannes Schumacher^*

^*Corresponding author for this work

Clinic of Internal Medicine I

98 Citations (Scopus)

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 × 10⁹) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.

Original language	English
Journal	Nature Genetics
Volume	46
Issue number	8
Pages (from-to)	901-904
Number of pages	4
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3029
Publication status	Published - 08.2014

Funding

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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10.1038/ng.3029

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Gockel, I., Becker, J., Wouters, M. M., Niebisch, S., Gockel, H. R., Hess, T., Ramonet, D., Zimmermann, J., Vigo, A. G., Trynka, G., De León, A. R., De La Serna, J. P., Urcelay, E., Kumar, V., Franke, L., Westra, H. J., Drescher, D., Kneist, W., Marquardt, J. U., ... Schumacher, J. (2014). Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia. Nature Genetics, 46(8), 901-904. https://doi.org/10.1038/ng.3029

@article{728e179039e84a99b858a9c680739d9d,

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 × 109) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.",

author = "Ines Gockel and Jessica Becker and Wouters, \{Mira M.\} and Stefan Niebisch and Gockel, \{Henning R.\} and Timo Hess and David Ramonet and Julian Zimmermann and Vigo, \{Ana Gonz{\'a}lez\} and Gosia Trynka and \{De Le{\'o}n\}, \{Antonio Ruiz\} and \{De La Serna\}, \{Julio P{\'e}rez\} and Elena Urcelay and Vinod Kumar and Lude Franke and Westra, \{Harm Jan\} and Daniel Drescher and Werner Kneist and Marquardt, \{Jens U.\} and Galle, \{Peter R.\} and Manuel Mattheisen and Vito Annese and Anna Latiano and Uberto Fumagalli and Luigi Laghi and Rosario Cuomo and Giovanni Sarnelli and Michaela M{\"u}ller and Eckardt, \{Alexander J.\} and Jan Tack and Per Hoffmann and Stefan Herms and Elisabeth Mangold and Stefanie Heilmann and Ralf Kiesslich and \{Von Rahden\}, \{Burkhard H.A.\} and Allescher, \{Hans Dieter\} and Schulz, \{Henning G.\} and Cisca Wijmenga and Heneka, \{Michael T.\} and Hauke Lang and Hopfner, \{Karl Peter\} and N{\"o}then, \{Markus M.\} and Boeckxstaens, \{Guy E.\} and \{De Bakker\}, \{Paul I.W.\} and Michael Knapp and Johannes Schumacher",

note = "Funding Information: 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. P{\"o}tzsch (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), T{\"u}bingen) 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.",

year = "2014",

month = aug,

doi = "10.1038/ng.3029",

language = "English",

volume = "46",

pages = "901--904",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "8",

}

Gockel, I, Becker, J, Wouters, MM, Niebisch, S, Gockel, HR, Hess, T, Ramonet, D, Zimmermann, J, Vigo, AG, Trynka, G, De León, AR, De La Serna, JP, Urcelay, E, Kumar, V, Franke, L, Westra, HJ, Drescher, D, Kneist, W, Marquardt, JU, Galle, PR, Mattheisen, M, Annese, V, Latiano, A, Fumagalli, U, Laghi, L, Cuomo, R, Sarnelli, G, Müller, M, Eckardt, AJ, Tack, J, Hoffmann, P, Herms, S, Mangold, E, Heilmann, S, Kiesslich, R, Von Rahden, BHA, Allescher, HD, Schulz, HG, Wijmenga, C, Heneka, MT, Lang, H, Hopfner, KP, Nöthen, MM, Boeckxstaens, GE, De Bakker, PIW, Knapp, M & Schumacher, J 2014, 'Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia', Nature Genetics, vol. 46, no. 8, pp. 901-904. https://doi.org/10.1038/ng.3029

TY - JOUR

T1 - Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia

AU - Gockel, Ines

AU - Becker, Jessica

AU - Wouters, Mira M.

AU - Niebisch, Stefan

AU - Gockel, Henning R.

AU - Hess, Timo

AU - Ramonet, David

AU - Zimmermann, Julian

AU - Vigo, Ana González

AU - Trynka, Gosia

AU - De León, Antonio Ruiz

AU - De La Serna, Julio Pérez

AU - Urcelay, Elena

AU - Kumar, Vinod

AU - Franke, Lude

AU - Westra, Harm Jan

AU - Drescher, Daniel

AU - Kneist, Werner

AU - Marquardt, Jens U.

AU - Galle, Peter R.

AU - Mattheisen, Manuel

AU - Annese, Vito

AU - Latiano, Anna

AU - Fumagalli, Uberto

AU - Laghi, Luigi

AU - Cuomo, Rosario

AU - Sarnelli, Giovanni

AU - Müller, Michaela

AU - Eckardt, Alexander J.

AU - Tack, Jan

AU - Hoffmann, Per

AU - Herms, Stefan

AU - Mangold, Elisabeth

AU - Heilmann, Stefanie

AU - Kiesslich, Ralf

AU - Von Rahden, Burkhard H.A.

AU - Allescher, Hans Dieter

AU - Schulz, Henning G.

AU - Wijmenga, Cisca

AU - Heneka, Michael T.

AU - Lang, Hauke

AU - Hopfner, Karl Peter

AU - Nöthen, Markus M.

AU - Boeckxstaens, Guy E.

AU - De Bakker, Paul I.W.

AU - Knapp, Michael

AU - Schumacher, Johannes

N1 - Funding Information: 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.

PY - 2014/8

Y1 - 2014/8

N2 - 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 × 109) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.

AB - 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 × 109) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.

UR - https://www.scopus.com/pages/publications/84906101114

U2 - 10.1038/ng.3029

DO - 10.1038/ng.3029

M3 - Journal articles

C2 - 24997987

AN - SCOPUS:84906101114

SN - 1061-4036

VL - 46

SP - 901

EP - 904

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

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