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Genomic Variations Impact on Differential Phenotypes of Cystic Fibrosis
Thesis   Open access

Genomic Variations Impact on Differential Phenotypes of Cystic Fibrosis

Anastasia Ward
Southern Cross University
Doctor of Philosophy (PhD), Southern Cross University
2025
DOI:
https://doi.org/10.25918/thesis.599
Appears in  Recent Southern Cross PhD Theses
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Ward A PhD 20258.09 MBDownloadView
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Abstract

Cystic Fibrosis Genetic polymorphism Gene variations In-silico Pain Disease severity
Background: Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although monogenic, considerable phenotypic variability is observed even among individuals with the same CFTR genotype. Variability in the respiratory, gastroenterological, reproductive, and musculoskeletal phenotypes has been attributed not only to CFTR mutations, but also to genetic variations in non-CFTR genes, known as gene modifiers (GMs). To date, there is a lack of research on genomic variations in GMs, and their contribution to treatment response and pain-related outcomes in CF remains largely unexplored. Objective: The objectives of this research were to (i) explore the current literature surrounding GMs in CF; (ii) investigate the prevalence, severity, associated clinical characteristics, and measurement of pain in people living with CF (pwCF); (iii) identify potential GMs that may contribute to pain in CF; and (iv) analyse the impact of genomic variants within identified GMs associated with pain phenotypes in CF. Methods: (i) A systematic review was conducted to examine the current literature on the impacts of GMs on disease progression, severity and therapeutic response; (ii) a case-control study was conducted to investigate the prevalence, severity and associated clinical symptoms of pain in pwCF; (iii) in silico analyses including pathway enrichment analysis, protein-protein interactions and drug-gene network investigations, were conducted to identify candidate genes of interest; and (iv) a bioinformatics workflow incorporating computational modelling and analysis of specific variations within the identified genes. Results: The systematic review described over 80 GMs associated with CF. Notably, it also highlighted the gap in research on GMs affecting the pain profile in CF. The nationwide survey described a significantly higher prevalence of pain symptoms, clustering and reported that pain is undermanaged and underreported in pwCF. The investigation of novel GMs potentially associated with pain in CF identified seven GMs of interest. Among these, transforming growth factor beta 1 (TGFB1), tumour necrosis factor (TNF), and ATP-binding cassette subfamily B member 1 (ABCB1) emerged as key candidates with multiple potentially pathogenic variants. Conclusion: This thesis presents new evidence on genomic variations in GMs involved in pain pathways and provides a detailed overview of the pain phenotype and its clinical manifestations in pwCF. By exploring the potential impact of genomic variations in GMs on pain, this research improves our understanding of the molecular mechanisms involved in pain development, which may lead to future therapeutic targets for improved health outcomes.

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