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

• DOI: 10.1038/ng.3029
• Publication Date: 2014-07-06T17:59:20Z
• Authors: 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...; 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 ...; Hans-Dieter Alles...; 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
• Keywords: Male; Models, Molecular; 0301 basic medicine; 610; Genetic Predisposition; Polymorphism, Single Nucleotide; HLA-DQ alpha-Chains; 03 medical and health sciences; HLA-DQ Antigens; 616; HLA-DQ beta-Chains; Humans; Genetic Predisposition to Disease; Alleles; Genetic Association Studies; Achalasia; genetic; Immunity; Achalasia; ASSOCIATION; 3. Good health; Esophageal Achalasia; INSIGHTS; Logistic Models; Amino Acid Substitution; Haplotypes; Case-Control Studies; Female; MHC; genetic

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.