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The SLC6A14 gene on chromosome X modifies disease presentation in individuals with cystic fibrosis (CF). Population studies have revealed distinct proximal and distal SNP clusters associated with gastrointestinal and lung phenotypes, respectively. Given the co-localization of cis-eQTLs within the corresponding associated chromosomal regions, where less SLC6A14 expression aligns with improved phenotypic outcomes, we sought to understand the SNP contributions to SLC6A14 expression regulation. Using reporter gene assays, we show that the proximal cluster, aligning with pancreas eQTLs, provides variation in promoter activity that is allele-dependent. The more expansive distal cluster, aligning with primary nasal cell eQTLs, was surveyed and found to harbour an enhancer feature that augmented expression in conjunction with the promoter in cells of lung origin. The rs4446858 SNP present within the enhancer aligns with the binding motif of the IRF1 transcription factor, where the alternate C allele was found to respond to direct addition of IRF1 or its increase following IFN-γ stimulation, resulting in increased SLC6A14 expression. Our data support a conclusion that SLC6A14 expression in airway tissue is regulated, in part, by immune-responsive genetic features, likely involving goblet cells. While our findings support previous model system studies indicating beneficial acute effects of SLC6A14 expression, they also highlight a distinction between immune-related responses and cumulative effects of long term disease reflected as lung function in individuals with CF. Our studies emphasize the challenges of elucidating complex genetic loci where there are multiple levels of regulatory influence with competing contributions.