15 Background: GERD predisposes to Barrett’s Esophagus (BE), a precursor lesion to esophageal adenocarcinoma (EA). Recently a large genome-wide association study found two germline markers to be associated with BE, FOXF1 rs9936833 (C Allele) and MHC rs9257809 (A allele). An additional study linked FOXF1 rs9936833 to EA. We assessed whether these same polymorphisms are associated with GERD. Methods: Patients with reflux symptoms referred for esophageal manometry/24-hr pH monitoring at University Health Network (Toronto) were enrolled. DNA extracted from blood was genotyped using a Taqman PCR assay. GERD cases were defined as having DeMeester scores of ≥14.7 or prior evidence of reflux esophagitis on endoscopy. DeMeester < 14.7 defined controls. Logistic regression analysis, adjusted for clinical risk factors, was used to calculate odds ratios (95% confidence intervals) for each polymorphism relative to GERD. Results: Of 182 patients, the median age was 50 years, 62% were female and, 52% met the definition for GERD. Males, higher BMI, alcohol consumption, FOXF1, and MHC polymorphisms were each individually associated with GERD. In the multivariate analysis, after adjusting for gender and BMI, FOXF1 rs9936833 remained significant, with an aOR of 1.82 (95%CI: 1.1-3.0; p=0.02) for an increase in each C allele. MHC rs9257809 also remained significant, with an aOR of 9.36 (2.9-30; p<0.001) comparing AA to AG (there were no patients with GG). When both polymorphisms were placed in the same model, the aORs were 2.10 (1.2-3.5; p=0.006) and 11.0 (3.3-36; p<0.001), per increase in each risk allele, respectively. Conclusions: There are strong, significant associations for increased GERD risk by the C allele in FOXF1 rs9936833 and the A allele in MHC rs9257809 among patients complaining of reflux symptoms. FOXF1 is associated with development of gastrointestinal smooth muscle, possibly contributing to the contractibility of the gastroesophageal junction. The MHC polymorphism is in linkage disequilibrium with HLA alleles involved in T-cell regulation, suggesting the possibility of T-cell involvement in reflux esophagitis. WFL and CL are co-first authors. GL and GED are co-senior authors.