Given the rapid increase in incidence of esophageal adenocarcinoma in developed countries over the past four decades, it is likely that a gene-environment interaction is taking place. Barrett's esophagus, a premalignant lining of the esophagus, is the most robust risk factor for this highly lethal cancer. To better assess the role of genetics in Barrett's esophagus, we have conducted: 1) Family studies that demonstrate a) Relatives of Barrett's probands have an over 2-fold increase in risk for Barrett's esophagus compared to controls, and; b) Relatives of Barrett's probands without frequent gastroesophageal reflux symptoms are 4-fold more likely to have erosive esophagitis compared to non-symptomatic controls; 2) Twin studies showing the heritable attributable risk of GERD symptoms to be 31%; and, with the support of an initial K23 award, began the 3) Barrett's Esophagus Genomic Study to collect high prevalence Barrett's esophagus kindreds for linkage analysis. We now propose to conduct a pilot study, using the 67 most-informative Barrett's esophagus kindreds collected to date, for a genome wide scan to begin to identify candidate loci of importance for the phenotypes of Barrett's esophagus, reflux esophagitis, hiatal hernia and GERD symptoms.
The first aim i s to continue to obtain DNA from family members for linkage analysis. We have already collected blood specimens from 54 probands and 194 relatives. Endoscopy and phlebotomy remains to be completed in 55 relatives to fully inform our linkage analysis. These families may provide sufficient information to begin to map the responsible gene(s).
The second aim i s to carry out a genome screen to map the chromosomal location of the gene(s) responsible for the phenotypes of interest.
The third aim i s to fine map the genetic region(s) identified through linkage analysis, to identify the smallest genomic segment that contains the gene(s). Candidate loci identified by this study will be tested in consecutive patients prospectively enrolled in the Mayo Clinic Rochester, Esophageal Adenocarcinoma and Barrett's Esophagus Registry, in a future study.
