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
59 Citations (Scopus)


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 languageEnglish
JournalNature Genetics
Issue number8
Pages (from-to)901-904
Number of pages4
Publication statusPublished - 08.2014


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