- Title
- Vitamin D and folate: nutrigenetic relationships with environmental ultraviolet radiation
- Creator
- Jones, Patrice
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2020
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Vitamin D and folate have many biological functions, with suboptimal levels and activity of these nutrients associated with increased risk of numerous health problems, including cardiovascular disease (CVD), adverse pregnancy outcomes and several forms of cancer. Multiple environmental and genetic factors determine the status and activity of these nutrients, such as dietary and ultraviolet radiation (UVR) exposures, and variation in genes underpinning vitamin D and/or folate-driven processes. These factors are commonly studied in isolation but may interact to further influence the roles of vitamin D and folate in health and disease, with further examination into these potential interactions important. UVR is an everyday exposure linked to vitamin D and folate through the vitamin D-folate hypothesis. This is a major evolutionary theory proposing that early humans evolved varying skin colours to maintain levels of vitamin D and folate, which are disparately impacted by UVR. The vitamin D-folate hypothesis is relevant to our current understanding of health and disease, as it indicates that UVR and skin pigmentation may be closely interrelated with other environmental and genetic determinants of vitamin D and/or folate functioning. However, the full extent of the relationship between these factors, and their potential health consequences, remains unclear. The presented studies were conducted to further investigate the relationships between UVR, vitamin D and folate levels, and related genetic variants, and to assess the potential interactive effects of these factors in predicting health outcomes. These studies adopted a mixed-methods approach and were designed to capitalise on published data, publicly available databases, and a large well-characterised elderly Australian cohort (The Retirement Health & Lifestyle Study (RHLS) cohort; n=650) to achieve the project aims. The studies presented in the first half of this thesis (Chapters 2-4) utilised genotypic data from published studies and/or databases to evaluate the relationships between the frequency of genetic variants in folate and vitamin D genes, and UVR environment. It was hypothesised that variation in these genes was associated with UVR environment and the evolution of skin pigmentation. Therefore, these studies focused on evaluating cohorts from Europe, Asia, Africa, and surrounding areas encompassing humankind’s earliest migration patterns, where early humans first evolved varying skin colour in response to UVR. Presented results demonstrate novel relationships between the frequency of multiple common folate genetic variants (n=19) within nine folate genes (MTRR, MTR, MTHFR, CBS, SHMT1, MTHFD1, RFC1, BHMT, TYMS) and surrogate measures of UVR environment; latitude and skin phototype. Additionally, an examination of numerous vitamin D genetic variants (n=46) found the distribution of variants in genes related to vitamin D UVR-production and transport (DHCR7/NADSYN1 and GC) to coincide with changes in UVR environment, with population-specific distribution patterns observed for variants in several other vitamin D genes that warrant further examination (CYP2R1, CYP11A1, CYP27A1, CYP24A1, VDR, and RXRα). The novel findings of relationships between folate and vitamin D variants and markers of UVR environment and/or skin phototypes led to the studies in the latter half of this thesis (Chapters 5-7), which evaluated if these relationships were indicative of interactions between environmental and genetic factors that may predict health outcomes. The RHLS cohort was a suitable focus for these studies, given elderly Australians are vulnerable to adverse UVR-related impacts. By leveraging data and blood samples available from the RHLS cohort, the fourth study presented examined the independent and interactive effects of environmental UVR and skin pigmentation genetic variants on markers of folate status (serum and red blood cell folate, and homocysteine (Hcy) levels). Data from this study reports negative associations between environmental UVR and all examined measures of folate status. This important finding highlights UVR as a potential determinant of folate status in elderly Australians. Reported effects of skin pigmentation variants (MC1R-rs1805007 and IRF4-rs12203592) on folate status were non-significant following adjustments but provide an incentive for further studies considering how skin pigmentation genes may modify the relationship between UVR and folate status. The reported inverse relationship between UVR and Hcy was a novel finding. Given Hcy is a risk factor for CVD, this association had potentially important clinical consequences and required further investigation. Therefore, it was also assessed whether the relationship between UVR and Hcy was mediated by folate and/or vitamin D levels and related genetic variants. Novel interactions between vitamin D levels, folate variant MTHFD1-rs2236225, and UVR in predicting Hcy are reported, with the association between environmental UVR and Hcy shown to be dependent on inadequate vitamin D levels and/or carriage of the MTHFD1-rs2236225 variant. It was hypothesised that these interactions may influence another important CVD risk factor; blood pressure (BP). Prior investigations had linked vitamin D, folate, and UVR-related factors to BP changes, with their potential interactive effects yet to be explored. The final presented study, therefore, examined interactions between vitamin D and folate levels, related genetic variants and UVR in determining BP in the RHLS cohort. UVR indices, and vitamin D and folate genetic variants independently predicted BP, with no interactions reported. However, several reported associations were lost following adjustments with Hcy, suggesting the effects of UVR and/or genetic variants may relate to their effects on Hcy. The findings presented in this thesis significantly extend our understanding of the relationships between vitamin D, folate, UVR, and related genetic factors, and their associated health outcomes. Results provide important insight into how the folate and vitamin D systems may be mediated by environmental UVR and genetic factors. These data may have implications for personalised nutrition and be used to inform future studies examining the roles of folate and vitamin D in human health and disease.
- Subject
- folate; vitamin D; ultraviolet radiation; nutrigenetics; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1422022
- Identifier
- uon:37796
- Rights
- Copyright 2020 Patrice Jones
- Language
- eng
- Full Text
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| View Details Download | ATTACHMENT01 | Thesis | 26 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 574 KB | Adobe Acrobat PDF | View Details Download |