Analysing the association of vitamin D status on selected cardiovascular risk markers using seasonal and genetic variations.

摘要

Vitamin D deficiency is common and has been proposed as a risk factor for cardiovascular disease (CVD), but much of this evidence is inconsistent. The aim of the thesis was to explore the associations between vitamin D status (25(OH)D) and selected risk biomarkers of CVD, in participants of the British 1958 birth cohort free from CVD. Different methodologies were used in an attempt to avoid confounded associations. Mediation analysis was used to infer an association between 25(OH)D and biomarkers from seasonal variations. A genome-wide association study (GWAS) was done to find single nucleotide polymorphisms (SNPs) associated with 25(OH)D. SNPs found by the GWAS and SNPs in candidate genes were evaluated as proxy markers for 25(OH)D, and used in Mendelian randomisation (MR) analysis with the biomarkers. Higher 25(OH)D concentrations were associated with lower levels of tissue plasminogen activator (tPA), after adjusting for lifestyle, socio-economic and adiposity covariates. An association between 25(OH)D and tPA was inferred using mediation analysis. In the GWAS, SNPs from genes involved in the synthesis, hydroxylation and transportation of vitamin D were associated with 25(OH)D. SNPs passing evaluation as proxy markers for 25(OH)D were classified as “synthesis” and “metabolism” based on gene function, with the former considered to be a more robust proxy than the latter. Statistical power to detect an association was limited in MR analysis. However, there was some evidence that 25(OH)D had a protective association with tPA, when metabolism SNPs were used as proxy for 25(OH)D in MR analysis. Findings from the different analyses were inconsistent for CRP, D-dimer and fibrinogen. In conclusion, the findings tentatively suggest that vitamin D has a beneficial influence on CVD through the mechanism of fibrinolysis. However, more evidence is required from large MR studies and randomised controlled trials before the role of vitamin D in CVD is conclusively understood.