Role of modifier gene SLC6A14 in Cystic Fibrosis and the path to personalized medicine

Cystic Fibrosis (CF) is the most common fatal genetic disorder in Canada. It is a multi-system disorder caused by mutations in the CFTR gene, expressed in epithelial tissues. Decrease in lung function over time is the most common cause of morbidity and mortality in CF. However, affliction to other organs systems like the gastro-intestinal system, also contributes to significant disease burden. Variation in disease severity among CF patients is well established, attributable to CFTR gene and modifier gene mutations. There are over 2,000 disease causing mutations in the CFTR gene. F508del is the most common CF causing mutation present on at least one allele in 90% of the CF population. However, patients bearing the same F508del mutation on both alleles also exhibit a tremendous variation in disease severity, which has been attributed to modifier gene mutations. Two FDA approved drugs that work directly on CFTR protein – Ivacaftor and Lumacaftor, are shown to have a heterogenous response in CF patients. The heterogeneity in response has also been attributed to modifier genes. With a greater understanding of modifier genes and CFTR genetics, the variation in patient responses to currently available CF therapies could be explained. This has led to efforts for in vitro phenotypic profiling of individual patient derived tissues, in the context of CF. Towards this we developed the apical CFTR conductance assay, to measure CFTR function in vitro using cultured airway epithelia from individual patients. Later we applied this technology to murine intestinal tissue to understand the mechanism of a genetic modifier of Cystic Fibrosis – SLC6A14, which was a top hit in a recent genome wide association study. Using a murine CF model and a SLC6A14 knockout mouse, we discovered that SLC6A14 modifies the intestinal phenotype of CF by regulating the fluid secretory capacity of the CF affected epithelium, via the nitric-oxide pathway. Thus, we explored the biologic basis of SLC6A14 as a modifier of CF. Taken together, the studies described in this thesis will facilitate the path towards personalized medicine in CF.

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