4-Aminobutyrate Aminotransferase (ABAT): Genetic and Pharmacological Evidence for an Involvement in Gastro Esophageal Reflux Disease

• Published in: PloS one Vol. 6; no. 4; p. e19095
• Main Authors: Jirholt, Johan, Åsling, Bengt, Hammond, Paul, Davidson, Geoffrey, Knutsson, Mikael, Walentinsson, Anna, Jensen, Jörgen M., Lehmann, Anders, Agreus, Lars, Lagerström-Fermer, Maria
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.04.2011; Public Library of Science (PLoS)
• Subjects: 4-Aminobutyrate transaminase; 4-Aminobutyrate Transaminase - genetics; Acids; Adolescent; Adult; Animals; Association analysis; Biology; Case-Control Studies; Children & youth; Chromosome 16; Disease susceptibility; Dogs; Esophageal sphincter; Esophageal Sphincter, Lower - metabolism; Esophageal Sphincter, Lower - physiopathology; Esophagus; Ethics; Ethnicity; Families & family life; Family medical history; Female; Fourier transforms; GABA; Gastroenterology; Gastroesophageal reflux; Gastroesophageal Reflux - drug therapy; Gastroesophageal Reflux - genetics; Gastroesophageal Reflux - physiopathology; Gene polymorphism; Genes; Genetic aspects; Genetic factors; Genetic Linkage; Genetic Predisposition to Disease; Genomes; Genomics; Genotyping; Human subjects; Humans; Laboratory animals; Linkage analysis; Male; Medicine; Metabolism; Microsatellites; Minority & ethnic groups; Parents; Patients; Pharmacology; Polymorphism; Population; R&D; Reproducibility of Results; Research & development; Risk factors; Sequence Analysis, DNA; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Sphincter; Studies; Twins; Women; γ-Aminobutyric acid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0019095

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.