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.

Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQβ1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQβ1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P = 1.84 × 10 − 04 , Sweden P = 7.44 × 10 − 05 ). Combining all five European data sets -Central Europe, Italy, Spain, Poland and Sweden -the insertion is achalasia associated with P combined = 1.67 × 10 − 35 . In addition, we observe that the frequency of the insertion shows a geospatial north-south gradient. The insertion is less common in northern (around 6-7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.

Although achalasia presents with typical symptoms such as dysphagia, regurgitation, weight loss, and atypical chest pain, the time until first diagnosis often takes years and is frustrating for patients and nevertheless associated with high costs for the healthcare system. A total of 563 patients were interviewed with confirmed diagnosis of achalasia regarding their symptoms leading to diagnosis along with past clinical examinations and treatments. Included were patients who had undergone their medical investigations in Germany. Overall, 527 study subjects were included (male 46%, female 54%, mean age at time of interview 51 ± 14.8 years). Dysphagia was present in 86.7%, regurgitation in 82.9%, atypical chest pain in 79%, and weight loss in 58% of patients before diagnosis. On average, it took 25 months (Interquartile Range (IQR) 9-65) until confirmation of correct diagnosis of achalasia. Though, diagnosis was confirmed significantly quicker (35 months IQR 9-89 vs. 20 months IQR 8-53; p < 0.01) in the past 15 years. The majority (72.1%) was transferred to three or more specialists. Almost each patient underwent at least one esophagogastroduodenoscopy (94.2%) and one radiological assessment (89.3%). However, esophageal manometry was performed in 70.4% of patients only. The severity of symptoms was independent with regard to duration until first diagnosis (Eckardt score 7.14 ± 2.64 within 12 months vs. 7.29 ± 2.61 longer than 12 months; P = 0.544). Fifty-five percent of the patients primarily underwent endoscopic dilatation and 37% a surgical myotomy. Endoscopic dilatation was realized significantly faster compared to esophageal myotomy (1 month IQR 0-4 vs. 3 months IQR 1-11; p < 0.001). Although diagnosis of achalasia was significantly faster in the past 15 years, it still takes almost 2 years until the correct diagnosis of achalasia is confirmed. Alarming is the fact that although esophageal manometry is known as the gold standard to differentiate primary motility disorders, only three out of four patients had undergone this diagnostic pathway during their diagnostic work-up. Better education of medical professionals and broader utilization of highly sensitive diagnostic tools, such as high-resolution manometry, are strictly necessary in order to correctly diagnose affected patients and to offer therapy faster.

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Our data point to a role of viral infections in the development of achalasia. In addition, they provide evidence for a relationship between achalasia and allergic, as well as autoimmune, disorders. Furthermore, pregnancy seems to be a disease-triggering factor in female HLA-DQβ1 insertion carriers, which points to hormonal and/or immunosuppressive factors influencing disease development.