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

Gastro-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 tran...

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Autores principales:	Johan Jirholt, Bengt Asling, Paul Hammond, Geoffrey Davidson, Mikael Knutsson, Anna Walentinsson, Jörgen M Jensen, Anders Lehmann, Lars Agreus, Maria Lagerström-Fermer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3707b69c97d44eaf978b6be18b2e9934
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spelling	oai:doaj.org-article:3707b69c97d44eaf978b6be18b2e99342021-11-18T06:55:01Z4-aminobutyrate aminotransferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease.1932-620310.1371/journal.pone.0019095https://doaj.org/article/3707b69c97d44eaf978b6be18b2e99342011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21552517/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Gastro-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) (P(adj) = 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 (γ-vinyl GABA) in a dog study, we were able to show a reduction of transient lower esophageal sphincter relaxations (TLESRs) by 57.3 ± 11.4 % (p = 0.007) and the reflux events from 3.1 ± 0.4 to 0.8 ± 0.4 (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.Johan JirholtBengt AslingPaul HammondGeoffrey DavidsonMikael KnutssonAnna WalentinssonJörgen M JensenAnders LehmannLars AgreusMaria Lagerström-FermerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e19095 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Johan Jirholt Bengt Asling Paul Hammond Geoffrey Davidson Mikael Knutsson Anna Walentinsson Jörgen M Jensen Anders Lehmann Lars Agreus Maria Lagerström-Fermer 4-aminobutyrate aminotransferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease.
description	Gastro-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) (P(adj) = 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 (γ-vinyl GABA) in a dog study, we were able to show a reduction of transient lower esophageal sphincter relaxations (TLESRs) by 57.3 ± 11.4 % (p = 0.007) and the reflux events from 3.1 ± 0.4 to 0.8 ± 0.4 (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.
format	article
author	Johan Jirholt Bengt Asling Paul Hammond Geoffrey Davidson Mikael Knutsson Anna Walentinsson Jörgen M Jensen Anders Lehmann Lars Agreus Maria Lagerström-Fermer
author_facet	Johan Jirholt Bengt Asling Paul Hammond Geoffrey Davidson Mikael Knutsson Anna Walentinsson Jörgen M Jensen Anders Lehmann Lars Agreus Maria Lagerström-Fermer
author_sort	Johan Jirholt
title	4-aminobutyrate aminotransferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease.
title_short	4-aminobutyrate aminotransferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease.
title_full	4-aminobutyrate aminotransferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease.
title_fullStr	4-aminobutyrate aminotransferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease.
title_full_unstemmed	4-aminobutyrate aminotransferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease.
title_sort	4-aminobutyrate aminotransferase (abat): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/3707b69c97d44eaf978b6be18b2e9934
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4-aminobutyrate aminotransferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease.

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