Genetic variation in the lymphotoxin-α (LTA)/tumour necrosis factor-α (TNFα) locus as a risk factor for idiopathic achalasia

Mira M. Wouters, Diether Lambrechts, Jessica Becker, Isabelle Cleynen, Jan Tack, Ana G. Vigo, Antonio Ruiz De León, Elena Urcelay, Julio Pérez De La Serna, Wout Rohof, Vito Annese, Anna Latiano, Orazio Palmieri, Manuel Mattheisen, Michaela Mueller, Hauke Lang, Uberto Fumagalli, Luigi Laghi, Giovanni Zaninotto, Rosario CuomoGiovanni Sarnelli, Markus M. Nöthen, Séverine Vermeire, Michael Knapp, Ines Gockel, Johannes Schumacher, Guy E. Boeckxstaens

Research output: Contribution to journalArticlepeer-review


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 riskassociated. 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 (p2>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 (TNFa) 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.

Original languageEnglish
Pages (from-to)1401-1409
Number of pages9
Issue number9
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Gastroenterology


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