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. © 2014 Nature America, Inc.

Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia / Gockel, I.; Becker, J.; Wouters, M. M.; Niebisch, S.; Gockel, H. R.; Hess, T.; Ramonet, D.; Zimmermann, J.; Vigo, A. G.; Trynka, G.; De Leon, A. R.; De La Serna, J. P.; Urcelay, E.; Kumar, V.; Franke, L.; Westra, H. -J.; Drescher, D.; Kneist, W.; Marquardt, J. U.; Galle, P. R.; Mattheisen, M.; Annese, V.; Latiano, A.; Fumagalli, U.; Laghi, L.; Cuomo, R.; Sarnelli, G.; Muller, M.; Eckardt, A. J.; Tack, J.; Hoffmann, P.; Herms, S.; Mangold, E.; Heilmann, S.; Kiesslich, R.; Von Rahden, B. H. A.; Allescher, H. -D.; Schulz, H. G.; Wijmenga, C.; Heneka, M. T.; Lang, H.; Hopfner, K. -P.; Nothen, M. M.; Boeckxstaens, G. E.; De Bakker, P. I. W.; Knapp, M.; Schumacher, J.. - In: NATURE GENETICS. - ISSN 1061-4036. - 46:8(2014), pp. 901-904. [10.1038/ng.3029]

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

Annese V.;
2014-01-01

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. © 2014 Nature America, Inc.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/166150
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