Search

Background: Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) are far more prevalent in European Americans than in African Americans. Hypothesizing that this racial disparity in prevalence might represent a genetic susceptibility, we used an admixture mapping approach to interrogate disease association with genomic differences between European and African ancestry., Methods: Formalin fixed paraffin embedded samples were identified from 54 African Americans with BE or EAC through review of surgical pathology databases at participating Barrett's Esophagus Translational Research Network (BETRNet) institutions. DNA was extracted from normal tissue, and genotyped on the Illumina OmniQuad SNP chip. Case-only admixture mapping analysis was performed on the data from both all 54 cases and also on a subset of 28 cases with high genotyping quality. Haplotype phases were inferred with Beagle 3.3.2, and local African and European ancestries were inferred with SABER plus. Disease association was tested by estimating and testing excess European ancestry and contrasting it to excess African ancestry., Results: Both datasets, the 54 cases and the 28 cases, identified two admixture regions. An association of excess European ancestry on chromosome 11p reached a 5% genome-wide significance threshold, corresponding to -log10(P) = 4.28. A second peak on chromosome 8q reached -log10(P) = 2.73. The converse analysis examining excess African ancestry found no genetic regions with significant excess African ancestry associated with BE and EAC. On average, the regions on chromosomes 8q and 11p showed excess European ancestry of 15% and 20%, respectively., Conclusions: Chromosomal regions on 11p15 and 8q22-24 are associated with excess European ancestry in African Americans with BE and EAC. Because GWAS have not reported any variants in these two regions, low frequency and/or rare disease associated variants that confer susceptibility to developing BE and EAC may be driving the observed European ancestry association evidence.

Background: Clinicians often face dilemmas with decisions related to formulary choices when two similar drugs are simultaneously available in the market. We studied the comparative safety, effectiveness, and treatment costs of the two first generation direct-acting antiviral agents (DAA), boceprevir and telaprevir as uncertainty existed regarding the drug of choice between these two seemingly equally Hepatitis-C treatment options., Methods: We randomly assigned 50 patients in an open-label, pragmatic randomized controlled trial (RCT) at a VA Medical Center to either boceprevir or telaprevir in combination with peginterferon and ribavirin, stratified by the presence of cirrhosis and prior treatment experience. Tolerability was assessed at each visit and reasons for discontinuation of treatment and severity of adverse events due to PI treatment were adjudicated using a blinded adjudication committee. The primary outcome was difference in tolerability between boceprevir vs. telaprevir. Secondary outcomes included viral response rates and cost-per cure achieved., Results: Higher rates of treatment discontinuations and/or severe DAA associated adverse events were seen in 10/25 (40%) patients randomized to telaprevir compared to 2/25 (8%) patients randomized to boceprevir (RR: 5; 95% CI: 1.2, 20; p<0.01). Cure rates did not appear to be significantly different between groups (telaprevir vs. boceprevir: RR 1.23; 95% CI: 0.76, 1.99; p = 0.39). On an intention-to-treat basis, total cost per cure was $44,329 for boceprevir vs. $57,115 for telaprevir. The significant side effect profile of telaprevir combined with the availability of highly efficacious second generation DAAs led to the early discontinuation of the trial., Conclusion: Telaprevir is associated with a significantly higher rate of severe adverse events leading to treatment discontinuations, hospitalizations or severe anemia and a substantially higher cost per SVR when compared to boceprevir. Real-time, point of care, pragmatic randomized controlled trials are necessary for guidance beyond just acquisition costs and to make evidence-based formulary selections when multiple effective treatments are available. (Clinicaltrials.gov registration: NCT02113631)., Competing Interests: The authors have declared that no competing interests exist.