Studies of homocysteine and vitamin D in older men

Elizabeth Wong

    Research output: ThesisDoctoral Thesis

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    As the world’s population ages, there is an increased prevalence of chronic diseases, which can result in significant disability and consequently, an increased mortality rate. Effective targeting of modifiable risk factors may potentially attenuate the occurrence of these adverse events and improve the quality of life amongst older people.
    Homocysteine and vitamin D status have been separately linked to several age-related declines. However, there is debate as to whether these biomarkers are merely epiphenomena or whether they do indeed play a role in mediating the development or progression of these health events that occur in old age. Existing findings from epidemiological studies and clinical trials have been inconsistent to date. The aim of this thesis was to explore whether these biomarkers were associated with adverse outcomes in several key domains, including abdominal aortic aneurysm (AAA), frailty, mortality, health-related quality of life, and cancers. The study population comprised community-dwelling men aged 70 years and over who had participated in the longitudinal, population-based Health In Men Study.
    Levels of total plasma homocysteine and 25-hydroxyvitamin D [25(OH)D] were measured by immunoassays in this cohort of older men. The principle of Mendelian randomisation was also undertaken to explore the nature of associations between homocysteine and the outcomes, with the measurement of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism by polymerase chain reaction. Outcome measures included aortic diameter (measured using an ultrasound machine), frailty (assessed with the FRAIL scale, comprising questionnaire data and physical measures), mortality (assessed by electronic record linkage), self-perceived physical health (assessed with the SF-36 Health Survey), and incident cancer diagnoses (assessed by electronic record linkage). Statistical techniques included linear and logistic regression, and Cox and competing-risks proportional hazards models.
    Results of these analyses suggest that hyperhomocysteinaemia is associated with prevalent AAA, frailty, all-cause mortality, and self-perceived physical health. Using Mendelian randomisation, the MTHFR TT genotype is not associated with AAA, aortic diameter, or physical health-related quality of life, reflecting limitation of power for such analyses. Hypovitaminosis D is associated with the presence of larger AAAs, with an inverse dose-response relationship between 25(OH)D concentration and aortic diameter in those men with prevalent AAA. It is also associated with prevalent and incident frailty, as well as an increased risk of all-cause mortality. A paradoxical association between lower 25(OH)D concentrations and reduced incidence of prostate cancer was demonstrated, whilst there is no evidence that vitamin D modulates the risk of colorectal or lung cancer in older men.
    These findings suggest that hyperhomocysteinaemia and hypovitaminosis D may be deleterious to several age-related health outcomes in older men. Clinical trials are warranted to investigate whether homocysteine-lowering strategies and vitamin D supplementation can ameliorate or prevent the development of these adverse outcomes. The finding of a paradoxical association between low 25(OH)D concentration and reduced incident prostate cancer is unexpected and emphasises the need for further carefully designed studies to determine whether a causal relationship indeed exists.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2015


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