Search

Background: Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear., Methods: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma., Results: The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91-7.56), 3.56 (2.85-4.44), and 3.97 (2.47-6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index., Conclusion: Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1., Impact: The novel gene-exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma., (©2015 American Association for Cancer Research.)

Background: Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA., Methods: We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used., Results: We estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 × 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD., Conclusions: We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.

Objectives: It is important to identify factors responsible for the development of Barrett's oesophagus (BO). The effect of proton pump inhibitors (PPIs) on oesophageal clearance of both acid and alkaline reflux in these patients is uncertain and studies comparing BO patients and healthy controls (HCs) have not been performed earlier., Methods: Two groups of patients were studied: 18 HCs and 12 BO patients. Oesophageal motility, acid reflux and duodenogastro-oesophageal reflux (DGOR) were measured using a three-pressure transducer catheter with an antimony pH tip, connected to a sodium ion selective electrode. All patients were studied both on and off PPIs., Results: Without PPI therapy, BO patients had significantly more upright and supine acid reflux and upright DGOR compared with HCs. During acid reflux, HC demonstrated more peristalsis than BO [HC, % peristalsis=64 (9), BO=53 (8), P<0.01], but this was not seen during DGOR. [HC, % peristalsis=68 (14), BO=56 (11)]. In Barrett's patients, DGOR was significantly reduced with PPIs [off PPI, % upright DGOR=61 (17), on PPIs=19 (15), P<0.01], and no oesophageal motility differences were seen compared with results without PPIs., Conclusion: HCs demonstrate better oesophageal motility compared with BO patients to prevent acid and alkaline reflux. When acid reflux occurred, HCs had better coordinated motility to remove it. This increased coordination did not occur during DGOR, suggesting different stimulation mechanisms. PPI reduced DGOR in BO patients, without any change in oesophageal motility.

Objectives: Esophageal reflux is common in the Western world and can lead to a number of diseases, such as esophagitis, Barrett's esophagus, and adenocarcinoma. Barrett's predisposes to adenocarcinoma and endoscopic surveillance may lead to earlier detection of adenocarcinoma. However, clinical methods only identify one patient in 15 with Barrett's esophagus. The aim of this study was to find factors that may help identify patients with Barrett's earlier., Methods: Blood samples and detailed histories were taken from 456 patients with gastroesophageal reflux who were recruited into three study groups: esophagitis, Barrett's esophagus without dysplasia, and Barrett's with dysplasia or adenocarcinoma. PCR was used to determine the frequency of five functional cytokine polymorphisms: interleukin-1 receptor antagonist position +2018 (IL-1 Ra +2018), interleukin-1 beta position -511 (IL-1 beta-511), tumor necrosis factor-alpha position -238 (TNF-alpha-238), interleukin-10 position +1082 (IL-10 +1082), and interleukin-4 receptor position -1902 (IL-4R -1902)., Results: IL-1 Ra +2018 genotype 2/2 was associated with Barrett's more commonly than esophagitis (OR-3.7, p= 0.0345). The IL-10 +1082 genotype 2/2 was more strongly associated with Barrett's and adenocarcinoma than esophagitis (OR-1.76, p= 0.056 and OR 1.96, p= 0.025, respectively). There were no differences for the IL-1 beta-511, IL-4R -1902, and TNF-alpha-238 polymorphisms., Conclusions: Cytokine polymorphisms are more commonly found in patients with Barrett's or adenocarcinoma than those with esophagitis. Together with demographic data, this may help identify those patients with Barrett's who would benefit from surveillance.

Objective: The metaplastic change of Barrett's oesophagus is linked to both acid and duodenal reflux together with impaired motility. Proton pump inhibitors (PPI) reduce acid reflux, but no treatment is available that reduces duodenogastro-oesophageal reflux (DGOR). The aim of this study was to investigate whether adding a prokinetic to PPI treatment could improve oesophageal motility and subsequently reduce reflux., Methods: Two groups of patients with Barrett's oesophagus on PPI therapy (prokinetic, n = 12; placebo, n = 11) were investigated. At visit 1, ambulatory oesophageal manometry was performed, and peristaltic and simultaneous wave percentage and characteristics were measured. DGOR and pH measurements were also performed. After treatment with either the prokinetic cisapride or placebo, all investigations were repeated (visit 2). Analysis of covariance and Spearman's correlation coefficients of changes from visit 1 to visit 2 were used to compare data., Results: There was no significant difference between the two groups with respect to DGOR, DGOR characteristics, or the percentage of peristalsis and simultaneous waves and their characteristics. There was no correlation between DGOR and motility changes. Although no significant differences existed between acid reflux in the two groups, five patients with high supine acid reflux showed a significant reduction after treatment with cisapride., Conclusions: Addition of cisapride to PPI treatment does not appear to improve oesophageal motility or reduce DGOR in patients with Barrett's oesophagus.

Background Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA. Methods We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h²g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two- sided, except in the case of variance-explained estimation where one-sided tests were used. Results We estimated a statistically significant genetic variance explained for BE (h²g = 35%; standard error [SE] = 6%; one-sided P= 1 x 10-9) and for EA (h²g = 25 %; SE = 5%; one-sided P= 2 x 10-7).The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 x 10-6), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD. Conclusions We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases. [ABSTRACT FROM AUTHOR]