BACKGROUND: Achalasia is a primary oesophageal motility disorder. Although aetiology remains mainly unknown, a genetic risk variant, rs28688207 in HLA-DQB1, showed strong achalasia association suggesting involvement of immune-mediated processes in the pathogenesis. High-resolution manometry recognises three types of achalasia. The aim of our study was to perform the first genotype-phenotype analysis investigating the frequency of rs28688207 across the high-resolution manometry subtypes. METHODS: This was a cross-sectional retrospective study. Achalasia patients from tertiary centres in the Czech Republic (n = 163), Germany (n = 114), Greece (n = 70) and controls were enrolled. All subjects were genotyped for the rs28688207 insertion. The Kruskal-Wallis test was used for the genotype-phenotype analysis. RESULTS: A total of 347 achalasia patients (type I - 89, II - 210, III - 48) were included. The overall frequency of the rs28688207 was 10.3%. The distribution of the insertion was significantly different across the high-resolution manometry subtypes (p = 0.038), being most prevalent in type I (14.6%), followed by type II (9.5%) and III (6.3%). CONCLUSION: The frequency of the HLA-DQB1 insertion differs among high-resolution manometry achalasia subtypes. The insertion is most prevalent in type I, suggesting that immune-mediated mechanisms triggered by the insertion may play a more prominent role in the pathogenesis of this subtype.

Department of Genomics University of Bonn Bonn Germany

Department of Hepatogastroenterology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Visceral Transplant Thoracic and Vascular Surgery University Hospital of Leipzig Leipzig Germany

Faculty of Medicine Ostrava University Ostrava Czech Republic

Foregut Surgery Department Hippokration General Hospital of Athens Athens Greece

Institute for Medical Biometry Informatics and Epidemiology University of Bonn Bonn Germany

Institute of Human Genetics University of Bonn Bonn Germany

Institute of Physiology Charles University Prague Prague Czech Republic

William Harvey Research Institute University of London London UK

Zobrazit více v PubMed

Schumacher J, Gockel I, Lang H, et al. Achalasia: Will genetic studies provide insights? Human Genet 2010; 128: 353–364. PubMed

Boeckxstaens GE. The lower oesophageal sphincter. Neurogastroenterol Motil 2005; 17: S13–S21. PubMed

Goldblum JR, Whyte RI, Orringer MB, et al. Achalasia. A morphologic study of 42 resected specimens. Am J Surg Pathol 1994; 18: 327–337. PubMed

Goldblum JR, Rice TW, Richter JE. Histopathologic features in esophagomyotomy specimens from patients with achalasia. Gastroenterology 1996; 111: 648–654. PubMed

Lach B, Shamji FM. Inflammatory aetiology of primary oesophageal achalasia: An immunohistochemical and ultrastructural study of Auerbach's plexus. Histopathology 1999; 35: 445–453. PubMed

Clark SB, Rice TW, Tubbs RR, et al. The nature of the myenteric infiltrate in achalasia: An immunohistochemical analysis. Am J Surg Pathol 2000; 24: 1153–1158. PubMed

Gockel I, Bohl JR, Doostkam S, et al. Spectrum of histopathologic findings in patients with achalasia reflects different etiologies. J Gastroenterol Hepatol 2006; 21: 727–733. PubMed

Pandolfino JE, Fox MR, Bredenoord AJ, et al. High-resolution manometry in clinical practice: Utilizing pressure topography to classify oesophageal motility abnormalities. Neurogastroenterol Motil 2009; 21: 796–806. PubMed PMC

Bredenoord AJ, Fox M, Kahrilas PJ, et al. Chicago classification criteria of esophageal motility disorders defined in high resolution esophageal pressure topography. Neurogastroenterol Motil 2012; 24: S57–S65. PubMed PMC

Pandolfino JE, Kwiatek MA, Nealis T, et al. Achalasia: A new clinically relevant classification by high-resolution manometry. Gastroenterology 2008; 135: 1526–1533. PubMed PMC

Gockel I, Becker J, Wouters MM, et al. Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia. Nat Genet 2014; 46: 901–904. PubMed

Senju S, Kimura A, Yasunami M, et al. Allele-specific expression of the cytoplasmic exon of HLA-DQB1 gene. Immunogenetics 1992; 36: 319–325. PubMed

Becker J, Haas SL, Mokrowiecka A, et al. The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north-south gradient among Europeans. Eur J Hum Genet 2016; 24: 1228–1231. PubMed PMC

Dimitriou M, Rallidis LS, Theodoraki EV, et al. Exclusive olive oil consumption has a protective effect on coronary artery disease: Overview of the THISEAS study. Public Health Nutr 2016; 19: 1081–1087. PubMed PMC

International High Resolution Manometry Working Group. The Chicago Classification of Esophageal Motility Disorders, v3.0. Neurogastroenterol Motil 2015; 27: 160–174. PubMed PMC

Marchini J, Howie B, Myers S, et al. A new multipoint method for genome-wide association studies via imputation of genotypes. Nat Genet 2007; 39: 906–913. PubMed

Genomes Project Consortium. A global reference for human genetic variation. Nature 2015; 526: 68–74. PubMed PMC

Becker J, Niebisch S, Ricchiuto A, et al. Comprehensive epidemiological and genotype-phenotype analyses in a large European sample with idiopathic achalasia. Eur J Gastroenterol Hepatol 2016; 28: 689–695. PubMed

Kahrilas PJ, Boeckxstaens G. The spectrum of achalasia: Lessons from studies of pathophysiology and high-resolution manometry. Gastroenterology 2013; 145: 954–965. PubMed PMC

Jin L, Hahn A, Drake J. Immunological functions of the membrane proximal region of MHC Class II Molecules. F1000Res 2016; 17: 5–5. PubMed PMC

Doostkam S, Eckardt VF, Junginger T. Spectrum of histopathologic findings in patients with achalasia reflects different etiologies. J Gastroenterol Hepatol 2006; 21: 727–733. PubMed

Kilic A, Krasinskas AM, Owens SR, et al. Variations in inflammation and nerve fiber loss reflect different subsets of achalasia patients. J Surg Res 2007; 143: 177–182. PubMed

Sodikoff JB, Lo AA, Shetuni BB, et al. Histopathologic patterns among achalasia subtypes. Neurogastroenterol Motil 2016; 28: 139–145. PubMed PMC

Borchers AT, Uibo R, Gershwin ME. The geoepidemiology of type 1 diabetes. Autoimmun Rev 2010; 9: A355–A365. PubMed

Kiryluk K, Li Y, Sanna-Cherchi S, et al. Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis. PLoS Genet 2012; 8: e1002765–e1002765. PubMed PMC

Sarnelli G, Grosso M, Palumbo I, et al. Allele-specific transcriptional activity of the variable number of tandem repeats of the inducible nitric oxide synthase gene is associated with idiopathic achalasia. United European Gastroenterol J 2017; 5: 200–207. PubMed PMC

Prevalence of neurodegenerative/demyelinating disorders in patients with achalasia