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Gut. 2014 Sep;63(9):1401-9. doi: 10.1136/gutjnl-2013-304848. Epub 2013 Nov 20.

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

Author information

1
Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
2
Vesalius Research Center, VIB, Leuven University, Leuven, Belgium Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium.
3
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany.
4
Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
5
Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
6
Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy Unit of Gastroenterology SOD2, Azienda Ospedaliera Universitaria, Careggi, Firenze, Italy.
7
Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy.
8
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany Institute for Genomic Mathematics, University of Bonn, Bonn, Germany Department of Biostatistics, Harvard School of Public Health, Boston, USA.
9
Department of Gastroenterology, German Clinic of Diagnostics, Wiesbaden, Germany.
10
Department of General, Visceral and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany.
11
Department of Gastroenterology, Humanitas Clinical and Research Center-Istituto Clinico Humanitas IRCCS, Milan, Italy.
12
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
13
Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy.
14
Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.

Abstract

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 (r(2)>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.

KEYWORDS:

Achalasia; Genetic Polymorphisms

PMID:
24259423
DOI:
10.1136/gutjnl-2013-304848
[Indexed for MEDLINE]

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