- Title
- Genotype-phenotype relationships relevant to the lifecycle with special reference to vitamin nutrition
- Creator
- Martin, Charlotte
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2016
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background: Nutrition is a key modifiable lifestyle factor that can influence the development and progression of chronic diseases such as cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and cancer. Increased life expectancy has led to these chronic disorders becoming more prevalent, and as a result a strong focus on nutrition in ageing research has occurred in an attempt to achieve ‘healthy ageing’ at a population level. Nutrition is not only important in old age, but also critical at the early phase of the human lifecycle, as adverse influences during intrauterine growth and early development can potentially effect long-term health outcomes; a hypothesis known as the developmental origins of health and disease. Context: Folate and vitamin D are two micronutrients which are important throughout the human lifecycle. Folate has a central role in one-carbon metabolism, and is responsible for methionine and nucleotide synthesis. A deficiency in folate can therefore lead to DNA hypomethylation and instability, and as a result an increase in cancer risk. Insufficient folate is also associated with elevated levels of homocysteine (Hcy), a vasculo-toxic amino acid linked to a number of disorders including CVD and neural tube defects. Folate-related one-carbon metabolism contains polymorphic proteins that can modify this vitamin’s absorption and metabolism, therefore influencing disease risk. Vitamin D synthesis is primarily driven by exposure of the skin to solar ultraviolet radiation (UVR). Vitamin D plays an important role not only in skeletal maintenance, but also various other biological actions due to the presence of the vitamin D receptor (VDR) in almost all organs and tissues within the human body. Genetic polymorphisms within the VDR gene exist, and are associated with a variety of disorders, including CVD and cancer. Both folate and vitamin D are UV-sensitive micronutrients and are hypothesised to have roles in the evolution of skin pigmentation, and are considered to have a wide influence on human health. Dermal penetration of UVR is dependent on melanin pigmentation, and is a critical factor in influencing the photolysis of folate - a photo-labile compound, while promoting the photosynthesis of vitamin D. Folate and vitamin D have been investigated for their relationship to exposomal factors such as UVR and diet, and have been examined from a lifecycle perspective. In order to better understand these two UV-sensitive vitamins, and their biological role across the human lifecycle and in a putative evolutionary context, this thesis examines several clinical and molecular parameters within a large study population. The present study also retrospectively examines whether total solar irradiance (TSI) during the first trimester of pregnancy, and photoperiod at the time of conception influences folate and VDR gene occurrence, and if any such affected genes influence late life biochemical/clinical phenotypes. Additionally, relationships between TSI, photoperiod and clinical phenotypes, and between dietary intake and clinical phenotypes have been explored. Methodology: Retirement village and community dwelling participants (n = 650) aged 65 years and over were recruited from the Central Coast, New South Wales, Australia. Information regarding medical history and dietary intake (food and supplement) was collected, and blood pressure, anthropometrics (body mass index (BMI) and waist-to-hip ratio (WHR)), and fasting blood samples were taken. Participants also completed a Hospital and Anxiety Depression Scale (HADS) questionnaire and Mini Mental State Examination (MMSE). Genotyping of 16 folate- and thiol-related gene variants and 7 vitamin D-related genetic polymorphisms was performed using polymerase chain reaction and restriction length fragment polymorphism analysis. TSI was calculated for the first 90 days following conception for each participant, while photoperiod at conception was calculated using each participants estimated date of conception and place of birth. Dietary intake was analysed to establish a daily average nutrient intake for each participant. Due to the large dataset, stepwise regression modelling was most frequently used, and while an initial alpha level of 0.05 was set, a Bonferroni correction for multiple comparisons was also performed. Results: Influence of early life exposomal factors on late life phenotypic outcomes and genotype – Several key findings were observed between TSI and polymorphism occurrence; for example the observation between TSI exposure in post-conceptional weeks 5 and 10 and G472A-COMT genotype occurrence (p = 0.0004, 0.0014, respectively; r² for model = 0.0417). Exposomal effects were also examined to determine whether early life events leave a signature on late life adulthood diseases, with observations of TSI on late life phenotypes showing numerous significant relationships. Selected findings include relationships between TSI exposure at post-conceptional weeks 1, 2, and 12 and HADS-A (anxiety) (p = 0.0006, 0.0140, and 0.0084, respectively; r² for model = 0.0311), and post-conceptional weeks 3, 5, and 9 and bowel cancer (p = 0.0371, 0.0400, and 0.0035, respectively; r² for model = 0.0690). Examination of the mean distribution of TSI exposure during these post-conceptional weeks was shown to influence the subsequent later life occurrence of the anxiety and bowel cancer phenotype. A significant relationship was also found between peri-conceptional photoperiod and cognitive decline (p = 0.0347; r² = 0.0098). Distribution of day length found that participants with cognitive decline (based on their MMSE score), experienced a shorter mean peri-conceptional photoperiod. Gene-related & non-gene associations with late life phenotypes – Analysis of the relationship between folate-, thiol- and vitamin D-related genetic polymorphisms and late life clinical phenotypes (hypertension, stroke, myocardial infarction, T2DM, several cancers, psychometric indices, and osteoporosis) revealed many significant associations. For example the folate-related genetic polymorphism A2756G-MS increased risk of hypertension, and was also significantly associated with Hcy. Additionally, both the A2756G-MS and C677T-MTHFR were associated with increased risk of depression based on HADS-D score. Many non-genetic associations were also uncovered, including those between BMI, WHR, biochemical indices and clinical phenotypes. For example, a significant positive association was found between BMI score and prostate cancer. Examination of nutrient-phenotype relationships also showed many significant associations, including low alcohol intake and cognitive decline. Relationships involving clinical phenotypes and folate and vitamin D intake, which are of particular interest in the present study, were also observed and fully discussed. Interpretative overview: Many of the findings in the present study support existing literature, while other relationships observed are novel and warrant further investigation. Overall, the present study has shown that genes encoding vitamin-related proteins appear to be responsive to environmental stimuli early in the lifecycle, with particular gene-variants being more sensitive than others. Additionally, these vitamin-related genes were also found to be associated with clinical phenotypes often observed later in life. Examination of the associations between nutrient intake and clinical phenotypes confirm the importance of nutrition for optimal health. There was new supportive evidence to suggest that anthropometric indices may play a role in clinical phenotype risk. Conclusion: Management, and ultimately prevention of chronic disease is now a global priority due to the heavy burden these have on our healthcare system. While the present study has identified numerous potentially interesting correlations, they do not represent causal relationships. The aetiology of chronic disease is multifactorial, and a single gene variant and/or nutrient interaction is not indicative of causation. However, the potential of using personalised nutrition to tailor an individualised diet based on known nutrient-gene interactions may assist in decreasing the risk of nutrient-related chronic diseases.
- Subject
- nutrigenetics; nutrigeneomics; human lifecycle; ageing
- Identifier
- http://hdl.handle.net/1959.13/1315286
- Identifier
- uon:22931
- Rights
- Copyright 2016 Charlotte Martin
- Language
- eng
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