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

Abstract

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) (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 (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.

Ornithine Aminotransferase versus GABA Aminotransferase: Implications for the Design of New Anticancer Drugs

“…For example, potent inhibitors of GABA‐AT have been developed to treat epilepsy and addictions . In addition to the beneficial effects on neurodegenerative diseases, inhibition of GABA‐AT may be useful in immunomodulation and gastroesophageal reflux disease (GERD) …”

“…19 In addition to the beneficial effects on neurodegenerative diseases, inhibition of GABA-AT may be useful in immunomodulation 20 and gastroesophageal reflux disease (GERD). 21 Inhibition of OAT is proposed to be beneficial in treating hyperammonemias by enhancing the urea cycle to clear excess ammonia. 22,23 Recently, human OAT was shown to play a role in regulating mitotic cell division in rapidly growing cells and became a potential target for the development of chemotherapeutic drugs.…”

Role of 4‑aminobutyrate aminotransferase (ABAT) and the lncRNA co‑expression network in the development of myelodysplastic syndrome

“…In humans, gene mutations leading to ABAT deficiency are extremely rare, while a clinical study biochemically confirmed that ABAT deficiency contributes to symptoms related to psychomotor retardation, hypotonia, hyperreflexia, lethargy, and intractable seizures (11). Moreover, ABAT single-nucleotide polymorphisms have been associated with depression (12), sleep homeostasis (13), autism (14) and gastroesophageal reflux disease (15). In regards to human cancer, reduced ABAT expression has been associated with resistance to endocrine therapy of breast cancer, and with poor recurrence-free survival of breast cancer patients (16,17).…”

Metabolite biomarker discovery for metabolic diseases by flux analysis

“…In Gastroesophageal reflux disease (GERD), Obesity patients have a high risk of acquiring the disease [23]. Results show that ABAT is a genetic risk factor for GERD, which strengthens the significance of this gene in Obesity [24]. "ACAS2L" is a known Obesity candidate gene [25] and Obesity is a proved cardiovascular disease risk factor [26].…”

“…And "pi" in reaction 2700 is a key component in the disturbance of Diabetes [31]. While in Obesity, 4-aminobutyrate transaminase (ABAT) has demonstrated the importance in Obesity [24]. Reaction 248 has the name Acyl CoA synthetase.…”