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Original article
Genetic variation in the lymphotoxin-α (LTA)/tumour necrosis factor-α (TNFα) locus as a risk factor for idiopathic achalasia
  1. Mira M Wouters1,
  2. Diether Lambrechts2,3,
  3. Jessica Becker4,5,
  4. Isabelle Cleynen1,
  5. Jan Tack1,
  6. Ana G Vigo6,
  7. Antonio Ruiz de León6,
  8. Elena Urcelay6,
  9. Julio Pérez de la Serna6,
  10. Wout Rohof7,
  11. Vito Annese8,9,
  12. Anna Latiano8,
  13. Orazio Palmieri8,
  14. Manuel Mattheisen4,5,10,11,
  15. Michaela Mueller12,
  16. Hauke Lang13,
  17. Uberto Fumagalli14,
  18. Luigi Laghi14,
  19. Giovanni Zaninotto15,
  20. Rosario Cuomo16,
  21. Giovanni Sarnelli16,
  22. Markus M Nöthen4,5,
  23. Séverine Vermeire1,
  24. Michael Knapp17,
  25. Ines Gockel13,
  26. Johannes Schumacher4,5,
  27. Guy E Boeckxstaens1
  1. 1Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
  2. 2Vesalius Research Center, VIB, Leuven University, Leuven, Belgium
  3. 3Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium
  4. 4Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
  5. 5Institute of Human Genetics, University of Bonn, Bonn, Germany
  6. 6Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
  7. 7Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
  8. 8Division of Gastroenterology, IRCCS ‘Casa Sollievo della Sofferenza’ Hospital, San Giovanni Rotondo, Italy
  9. 9Unit of Gastroenterology SOD2, Azienda Ospedaliera Universitaria, Careggi, Firenze, Italy
  10. 10Institute for Genomic Mathematics, University of Bonn, Bonn, Germany
  11. 11Department of Biostatistics, Harvard School of Public Health, Boston, USA
  12. 12Department of Gastroenterology, German Clinic of Diagnostics, Wiesbaden, Germany
  13. 13Department of General, Visceral and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany
  14. 14Department of Gastroenterology, Humanitas Clinical and Research Center—Istituto Clinico Humanitas IRCCS, Milan, Italy
  15. 15Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
  16. 16Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy
  17. 17Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
  1. Correspondence to Dr Mira Wouters, Translational Research Center for Gastrointestinal Disorders, Herestraat 49, O&NI, box 701, Leuven B-3000, Belgium; mira.wouters{at}


Background Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility.

Methods 391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p<0.05) were validated in an Italian (160 achalasia patients, 278 HVs) and Spanish cohort (281 achalasia patients, 296 HVs). 16 SNPs in linkage disequilibrium (LD) with rs1799724 (r2>0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran–Armitage trend test.

Results The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-β-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication.

Conclusions Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia.

  • Achalasia
  • Genetic Polymorphisms

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