Between GERD and NERD: the relevance of weakly acidic reflux

Nonerosive reflux disease (NERD) is a common condition and the most frequent phenotype of gastroesophageal reflux disease (GERD). NERD is extremely heterogeneous and includes patients with negative endoscopy but abnormal esophageal acid exposure and/or positive reflux-symptom association analysis (hypersensitive esophagus). This segregation is only possible owing to the use of impedance-pH monitoring. Indeed, weakly acidic reflux represents one of the most common causes of refractory symptoms in patients evaluated off antisecretory therapy and, more importantly, during antisecretory drug treatment. Patients with heartburn who do not have any type of reflux underlying their symptoms (functional heartburn) must be excluded from the category of GERD. The drawbacks of impedance-pH are mainly due to the day-to-day variability of the test and the fact that the accuracy of the symptom-reflux correlation scores is often far from perfect. Some histopathological characteristics, such as dilated intercellular spaces, can be helpful in distinguishing patients with NERD through esophageal biopsies. Patients with NERD in whom acid is the main pathogenetic factor respond successfully to proton pump inhibitor therapy, while those with hypersensitive esophagus to weakly acidic reflux could be treated with reflux inhibitors or surgery, although further controlled studies are required

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern.

BACKGROUNDThe presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODSTo identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTSWe identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONSIn this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDINGThis project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 - STATS). For detailed funding information per study, see the Supplemental Acknowledgments