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.
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 Gonz?lez, Vigo; Gosia, Trynka; Antonio Ruiz de, Le?n; Julio P?rez 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; Cuomo, Rosario; Sarnelli, Giovanni; Michaela, M?ller; 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., N?then; Guy E., Boeckxstaens; Paul I. W., de Bakker; Michael, Knapp; Johannes, Schumacher. - 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
CUOMO, ROSARIO;SARNELLI, GIOVANNI;
2014
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.| File | Dimensione | Formato | |
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