4-aminobutyrate aminotrasferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease

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dc.contributor.authorJirholt, J.
dc.contributor.authorAsling, B.
dc.contributor.authorHammond, P.
dc.contributor.authorDavidson, G.
dc.contributor.authorKnutsson, M.
dc.contributor.authorWalentinsson, A.
dc.contributor.authorJensen, J.
dc.contributor.authorLehmann, A.
dc.contributor.authorAgreus, L.
dc.contributor.authorLagerstrom-Fermer, M.
dc.contributor.editorDubé, M.-P.
dc.date.issued2011
dc.descriptionExtent: 9p.
dc.description.abstractGastro-esophageal reflux disease (GERD) is partly caused by genetic factors. The underlying susceptibility genes are currently unknown, with the exception of COL3A1. We used three independent GERD patient cohorts to identify GERD susceptibility genes. Thirty-six families, demonstrating dominant transmission of GERD were subjected to whole genome microsatellite genotyping and linkage analysis. Five linked regions were identified. Two families shared a linked region (LOD 3.9 and 2.0) on chromosome 16. We used two additional independent GERD patient cohorts, one consisting of 219 trios (affected child with parents) and the other an adult GERD case control cohort consisting of 256 cases and 485 controls, to validate individual genes in the linked region through association analysis. Sixty six single nucleotide polymorphism (SNP) markers distributed over the nine genes present in the linked region were genotyped in the independent GERD trio cohort. Transmission disequilibrium test analysis followed by multiple testing adjustments revealed a significant genetic association for one SNP located in an intron of the gene 4-aminobutyrate aminotransferase (ABAT) (Padj = 0.027). This association did not replicate in the adult case-control cohort, possibly due to the differences in ethnicity between the cohorts. Finally, using the selective ABAT inhibitor vigabatrin (c-vinyl GABA) in a dog study, we were able to show a reduction of transient lower esophageal sphincter relaxations (TLESRs) by 57.3611.4 % (p = 0.007) and the reflux events from 3.160.4 to 0.860.4 (p = 0.007). Our results demonstrate the direct involvement of ABAT in pathways affecting lower esophageal sphincter (LES) control and identifies ABAT as a genetic risk factor for GERD.
dc.description.statementofresponsibilityJohan Jirholt, Bengt Åsling, Paul Hammond, Geoffrey Davidson, Mikael Knutsson, Anna Walentinsson, Jörgen M. Jensen, Anders Lehmann, Lars Agreus and Maria Lagerström-Fermer
dc.identifier.citationPLoS One, 2011; 6(4):e19095:1-e19095:9
dc.identifier.doi10.1371/journal.pone.0019095
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/2440/72056
dc.language.isoen
dc.publisherPublic Library of Science
dc.rights© 2011 Jirholt et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pone.0019095
dc.subjectEsophageal Sphincter, Lower
dc.subjectAnimals
dc.subjectDogs
dc.subjectHumans
dc.subjectGastroesophageal Reflux
dc.subjectGenetic Predisposition to Disease
dc.subject4-Aminobutyrate Transaminase
dc.subjectCase-Control Studies
dc.subjectReproducibility of Results
dc.subjectSequence Analysis, DNA
dc.subjectAdolescent
dc.subjectAdult
dc.subjectFemale
dc.subjectMale
dc.subjectGenetic Linkage
dc.title4-aminobutyrate aminotrasferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease
dc.typeJournal article
pubs.publication-statusPublished

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