| Literature DB >> 24997987 |
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.
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.Entities:
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Year: 2014 PMID： 24997987 DOI： 10.1038/ng.3029
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330