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

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.

The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north–south gradient among Europeans

“…The ethnic homogeneity of the Central European patients and controls has been previously shown. 2 The distribution of females and males within each sample is presented in Supplementary Table 1. In all patients, achalasia diagnosis was made according to a standardized procedure, including esophageal manometry and/or esophagography.…”

“…4 Previously, we have demonstrated that the imputation of the insertion show a high accuracy (concordance rate = 99.7%). 2 The data of the HLA-DQβ1 insertion was deposited to the European Genome-phenome Archive (EGA, http://www.ebi.ac.uk/ega/) and is available under accession number EGAS00001001515.…”

“…1 Most recently, an insertion of eight amino acids in the cytoplasmic tail of HLA-DQβ1 and two amino acid substitutions in the extracellular part of HLA-DQα1 and HLA-DQβ1 have been identified as being independently disease associated. 2 Although on the cellular level the function of the identified achalasia risk variants remains speculative, the findings show that the HLA-DQ receptor and thereby autoimmune processes represent a major risk factor for idiopathic achalasia.…”

“…In addition, we analyzed the insertion in 171 achalasia patients and 732 controls from Sweden. Beside the two cohorts from Poland and Sweden, we included samples from Central Europe (1042 patients and 3670 controls), Spain (273 patients and 327 controls) and Italy (165 patients and 1263 controls) that were part of our previous study, 2 but have not been analyzed separately so far. Finally, we assessed the frequency and epidemiological consequences of the HLA-DQβ1 insertion on the population level among the five different European cohorts.…”

A case report of achalasia

“…Achalasia is diagnosed in adults most frequently in the age group of 25 to 60 years with a male to female ratio in 1:1. [3,4] In this case, the patient is a 48 years old male active smoker. Patients usually suffered from dysphagia, regurgitation, difficulty in swallowing foods, chest pain, heartburn and weight loss.…”