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Background: Although globus pharyngeus is not rare in clinical practice, little is known about its associated gene polymorphism. We investigated the association between the SLC6A4 polymorphism and globus pharyngeus and its response to treatment with antidepressants. Methods: A total of 84 patients were diagnosed with globus pharyngeus according to Rome III, and 160 healthy controls were genotyped for the SLC6A4 polymorphism using polymerase chain reaction amplification and agarose gel electrophoresis. All patients with globus were studied using high-resolution manometry pre-therapy. Globus patients were randomized into paroxetine or amitriptyline groups for a 6-week treatment and asked to complete the following pre- and post-therapy questionnaires: the Glasgow Edinburgh Throat Scale (GETS), the Pittsburgh Sleep Quality Index, and the Hamilton Rating Scale Anxiety/Depression. Treatment response was defined as a >50% reduction in the GETS scores. Results: A significant difference was observed in the globus S/S genotype with anxiety compared to that without anxiety (χ2 = 14.579, p = 0.006). The L/S genotype showed a significant difference between high upper esophageal sphincter pressure (>104 mm Hg) and non-high upper esophageal sphincter pressure patients (χ2 = 14.433, p = 0.006). A significant association between the S/S genotype and the response to antidepressant treatment was also observed, while patients with sleep disorders or depression showed no association. Conclusion: A significant association was observed between the S/S genotype of the SLC6A4 polymorphism and globus pharyngeus, suggesting that SLC6A4 is a potential candidate gene involved in the pathogenesis of globus pharyngeus. [ABSTRACT FROM AUTHOR]