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

Extent: 9p.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 (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.Johan Jirholt, Bengt Åsling, Paul Hammond, Geoffrey Davidson, Mikael Knutsson, Anna Walentinsson, Jörgen M. Jensen, Anders Lehmann, Lars Agreus and Maria Lagerström-Ferme

Regional differences and coronary microvascular dysfunction in heart failure with preserved ejection fraction

Aims: In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF. Methods and results: We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS-HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine-induced vs. resting flow) &lt; 2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non-significant after adjustment for age, sex, N-terminal pro-brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis). Conclusions: Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions.</p

Regional differences and coronary microvascular dysfunction in heart failure with preserved ejection fraction

Aims: In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF. Methods and results: We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS-HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine-induced vs. resting flow) &lt; 2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non-significant after adjustment for age, sex, N-terminal pro-brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis). Conclusions: Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions.</p

Regional differences and coronary microvascular dysfunction in heart failure with preserved ejection fraction

Abstract Aims In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF. Methods and results We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS‐HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine‐induced vs. resting flow) < 2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non‐significant after adjustment for age, sex, N‐terminal pro‐brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis). Conclusions Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions

Analysis of ABAT inhibition in dogs.

<p>Inhibition of TLESRs (A) and reflux episodes (B) in dogs after administration of the ABAT specific inhibitor Vigabatrin. Administration was performed 2 hours or 2 and 16 hours before measurements. Each group consisted of six dogs. TLESR and reflux events are presented as number of events/45 minutes. P-values were calculated using paired t-test. Open boxes represent the control experiment, filled boxes are after the administration of Vigabatrin, n.s. denotes not significant.</p

Overlapping linkage peak at chromosome 16p for families 122 and 146.

<p>Strongest linkage was obtained for family 146 showing a LOD of 3.9. The other family, 122, showed a linkage of LOD 2.0. The combined linkage curve reaches a maximal LOD score of 5.5.</p

Genetic association in the trio cohort.

<p>A total of 66 SNPs were genotyped in the linked region on chromosome 16 and subsequently analyzed with TDT. The table shows a subset of these located around ABAT. T:U denotes the number of transmitted versus untransmitted alleles. p-val is the nominal p value. p_adj is the p-value adjusted for multiple testing through permutation analysis for the full 66 SNP panel. The trio cohort consists of 177 probands with positive findings from endoscopy evaluation and 175 probands with positive findings from histology evaluation. In total the cohort consist of 219 trios. The eight SNPs marked with an asterisk were also genotyped in the adult case control cohort in addition to rs8046201.</p

A summary of the five linked regions identified in the GERD family collection.

<p>The table shows that suggestive linkage was found on chromosome 5, 6, 16 and 18. Significant linkage was found on chromosome 16. Number of GERD individuals and individuals with unassigned disease status are presented for each family (number of males in parenthesis). The remaining individuals are healthy. The linked region is defined as the utmost markers included in the genetic linkage log of Odds (LOD) score peak while outer markers are defined as the closest genotyped unlinked marker.</p