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Background
Systemic lupus erythematosus (SLE) is a systemic inflammatory disease associated with a significantly increased risk of cardiovascular disease (CVD). The risk is up to 50-times increased and is not explained by traditional cardiovascular risk factors. Vitamin D deficiency is more common in SLE than the general population (with a prevalence of 52% in our Manchester lupus cohort) and is a plausible mediator for cardiovascular risk either by a direct effect on endothelial cells or indirectly via increased inflammation.
Vitamin D deficiency is an independent risk factor for cardiovascular CVD in the general population. Endothelial dysfunction precedes the development of CVD and in diabetic patients can be rapidly reversed with vitamin D treatment. Endothelial cells (ECs) express both the vitamin D receptor (VDR) and 1-alpha-hydroxylase, suggesting a direct effect within the vasculature. In addition B lymphocyte function is regulated by vitamin D, which may affect B cell hyperactivity and response to lupus treatment.
Hypothesis
Vitamin D modifies endothelial cell function and drug response in patients with SLE.
Aims/Objectives
1a. Establish the influence of vitamin D on endothelial function in a SLE cohort.
1b. Investigate the action of vitamin D on isolated endothelial cells (ECs) in an in vitro model of SLE.
2. Determine whether vitamin D status modifies response to therapy in patients with active SLE.
Methods
Changes in endothelial function by vitamin D will be assessed using flow-mediated dilatation (FMD) and by studying the function of endothelial progenitor cells (EPCs) ex vivo in a cohort of lupus patients.
Type-1 interferon (IFNα) is the dominant cytokine in SLE and has direct effects on endothelial cell function, offering a tractable model to study the lupus effect on endothelium and how vitamin D acts on damaged endothelial cells.
The importance of vitamin D in modifying response to therapy will be investigated in lupus patients enrolled in a national biologics register.
Scientific/Medical Opportunities
Epidemiological evidence suggests a novel role for vitamin D in the development of CVD. This is of interest in the context of inflammatory disease, where the prevalence of both CVD and vitamin D deficiency are exaggerated. Although an association is clear, studies need to focus on a causal relationship. Demonstrating improvement in endothelial function both in vivo and in vitro will contribute to the understanding of premature CVD in SLE patients and identify novel therapeutic targets. Vitamin D may be a novel modifiable predictor of clinical response to treatment.
4 years
North West England MRC Clinical Pharmacology and Therapuetics Clinical Research Fellowship
BRC Manchester Clinical Research Fellowship
Professor Ian Bruce | Supervisor |
Professor Terence O'Neill | Supervisor |
Professor David Ray | Supervisor |
Dr Yvonne Alexander | Supervisor |
Dr John Reynolds | PhD student |