Abstract
Noncommunicable diseases (NCDs), or chronic diseases, result from a complex interplay between genetic, physiological, environmental, and behavioural factors. This category of diseases represents a silent epidemic, as it accounts for 74% of global mortality, which equates to approximately 41 million deaths annually. In recognition of the impact of NCDs, the United Nations has identified their reduction through its sustainable development goals as a crucial health-related target to improve the overall well-being of the global population.NCDs encompass a range of chronic conditions, such as cardiovascular disease (CVD), cancer, diabetes, mental health disorders and chronic respiratory diseases. The burden that NCDs impose on individuals, families, society and healthcare systems worldwide is substantial and continuously increasing. Urgent strategies are necessary to address and mitigate the NCD pandemic.
Efforts to prevent and control NCDs that are implemented worldwide are focused on reducing the consumption of tobacco, harmful amounts of alcohol and unhealthy food, and increasing levels of physical activity. These population-based interventions involve mass communication campaigns intended to promote healthy lifestyles. Yet, it is essential to note that these diseases have heritable components, and extensive studies have been conducted among European populations to understand the genetic factors associated with NCDs. Individuals with different genetic architectures may exhibit divergent responses to preventive measures and have differing risks of developing NCDs. People respond differently to these interventions, and some may experience adverse reactions. However, the current approach to treatment and prevention relies on a “one size fits all” model, which does not account for individual differences.
Precision medicine offers the promise of treatments that are tailored to individual patients. This approach ensures that each person receives treatment appropriate to them and reduces the occurrence of adverse reactions. Through the adoption of a precision medicine approach, high-risk individuals can be identified promptly, and this enables the provision of appropriate preventive and therapeutic options. Advances in mapping the human genome, facilitated by initiatives such as the Human Genome Project, have contributed significantly to our understanding of the genetic basis of NCDs. The presence of specific gene mutations or combinations of alleles indicates a genetic predisposition or susceptibility to certain diseases. Genome-wide association studies (GWAS) have played a crucial role in the identification of approximately 160 loci that are associated with CVD, and this achievement has greatly enhanced our knowledge of this condition. Other research explores the genetic underpinnings of various chronic diseases. Projects such as the Encyclopedia of DNA Elements (ENCODE) involve annotation of the non-coding regions of the genome, which provide valuable insights into gene regulation mechanisms.
The integration of genetic information into clinical practice has revolutionised disease management across various stages. Genetic data is now utilised for risk assessment, screening, diagnosis, prognosis and treatment decisions. For instance, in breast and ovarian cancer, genotyping is used to assess susceptibility, predict the likelihood of recurrence, and guide treatment strategies. Similarly, the identification of novel biological pathways that are related to type 2 diabetes has paved the way for early interventions, prevention measures, and effective management of disease progression. For example, a common variant of the TCF7L2 gene, which encodes for the transcription factor 7-like gene, confers a higher risk of diabetes (odds ratio 1.8:1) to carriers of the variant compared with non-variant carriers. Furthermore, genome-based tools have been applied in pharmaceutical clinical practice to facilitate more precise and tailored disease management approaches.
Despite notable advances in the understanding of complex diseases such as schizophrenia, the prevention and management of these conditions remain challenging. The heightened risk and prevalence of such diseases have traditionally been ascribed to social determinants, lifestyle factors (including poor dietary choices, sedentary habits, and substance use), and the impacts of psychotropic medications. Although sedentary behaviours have been explored as potential risk factors for NCDs, numerous unanswered questions persist. For instance, do sedentary behaviours causally influence NCD risk or vice versa? Do different sedentary behaviours, such as mentally passive and active sedentary activities, have different effects on NPD risk? Chapter 2 of this thesis is an explanation of our employment of bidirectional Mendelian randomisation (MR) models, which revealed compelling evidence of potential causal relationships.
Recent strides in pharmacogenomics have revolutionised drug-dose precision, and thereby mitigated toxicity risks and enhanced treatment effectiveness. The paradigm of CYP2C9 or VKORC1 and warfarin epitomises how pharmacogenomics can steer personalised dosing regimens. Despite these advances, it remains a daunting challenge to tailor molecular subtypes and targeted therapies to specific cancers and mental health conditions; attempts yield unfavourable outcomes for many patients. The conventional approach of developing novel drugs based on disease-associated genes is notoriously protracted and resource-intensive, spanning an average of 13 years and requiring an investment of approximately $870 million from inception to market launch. Consequently, the repurposing of approved drugs towards novel uses has emerged as a more cost-efficient avenue. Large-scale human genetic investigations are now pivotal in shaping drug development initiatives. Through the amalgamation of genomic and phenotypic data, sophisticated algorithms have been devised to uncover new applications and redirect the focus of hundreds of medications, and this move has markedly expedited the drug discovery trajectory. In this landscape, drug target MR has emerged as a pivotal analytical instrument in drug exploration.
MR harnesses genetic variants as impartial instrumental variables to scrutinise the repercussions of exposures on outcomes. MR can be regarded as a natural experiment, as it leverages the fortuitous allocation of germline genetic variants during meiosis and untangles confounding variables. Chapter 3 of this thesis contains an explanation of the use of MR methodology to simulate the pharmacological modulation of anti-diabetic and non-steroidal anti-inflammatory (NSAI) drugs to target cancers and mental health conditions and of the evaluation of the effects of such changes on the targeted diseases. This innovative application underscores the potential of MR to elucidate the intricate interplay between drug targeting, disease susceptibility and treatment outcomes, and it offers valuable insights for future therapeutic strategies.
The integration of genetic information into population-wide interventions has been found to enhance the effectiveness of these behavioural modification efforts. The combination of population-based randomised controlled trials (RCTs) with MR analysis can improve the external validity and generalisability of findings. This study design enables the extrapolation of population-wide interventions to a target population based on genetic information, making the study outcomes more applicable in real-world settings. However, many population-based RCTs have limitations in terms of sample sizes and generalisability. To overcome these limitations, a combination of MR analysis and RCT-based meta-analysis is beneficial. This combined analysis incorporates genetic data and aggregated evidence from multiple RCTs to produce more robust and precise estimates of intervention effects than would the use of one of these techniques alone. MR analysis helps to address confounding and reverse causality, while RCT-based meta-analysis provides direct causal evidence from real-world interventions. Chapter 4 of this thesis seeks to provide valuable insights into the effectiveness of nutritional interventions and to elucidate the biological mechanisms that underlie cognitive health. This is achieved through the integration of MR analysis and RCT-based meta-analysis to leverage the strengths of each.
In conclusion, this thesis offers a comprehensive exploration of the genetic foundations of NCDs. Its author endeavours to assess the effectiveness of both pharmacological interventions through the use of the MR approach to explore opportunities to repurpose anti-diabetic and NSAI drugs, and non-pharmacological interventions through rigorous evaluation of RCT-based meta-analyses. Through the harmonious integration of these diverse methodologies, the aspiration is to make substantial contributions to the understanding of disease causation, advancements in drug discovery, and the significance of non-pharmacological strategies in the holistic management of NCDs.
| Date of Award | 27 Dec 2024 |
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| Original language | English |
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| Supervisor | Kei Hang Katie CHAN (Supervisor) |