The relationship of vitamin D status to risk of cardiovascular disease and mortality.

Vitamin D is essential for bone mineralisation, but a growing body of evidence points at a broader role; vitamin D deficiency has been found to be associated with mortality and several diseases ranging from cardiovascular disease to autoimmune diseases and liver diseases. The evidence is, however, inconclusive and the possible pathways remain unresolved. The aims of the thesis were to investigate the association of vitamin D status to 5-year changes in cardiovascular risk factors such as blood pressure, lipid profile, the metabolic syndrome and urine albumin creatinine ratio (UACR); the association of a known genetic determinant of vitamin D status to cardiovascular risk factors; the association of vitamin D status to the incidence of cardiovascular disease (CVD) and all-cause mortality; and the association of vitamin D status to cause-specific mortality. Data from the 3 population-based studies Monica10 (n = 2,656, 1993-94), Inter99 (n = 6,794, 1999-2001) and Health2006 (n = 3,471, 2006-2008) conducted at the Research Centre for Prevention and Health were used. The studies included questionnaires, physical examinations, and blood tests. Vitamin D status was measured at baseline. Participants were genotyped for the most frequent filaggrin mutations. Registry-based diagnoses and causes of death were obtained from The Danish National Patient Register and the Danish Registry of Causes of Death, respectively. Linear, logistic, Cox and instrumental variable regressions were used to model the associations between vitamin D status and cardiovascular risk factors, disease and mortality. With a 10 year mean follow-up time, we found a significant association between vitamin D status and all-cause mortality with a HR=0.95 (p = 0.005) per 10 nmol/l higher vitamin D level. We found no association between vitamin D status and incidence of ischaemic heart disease or stroke (HR = 1.01, p = 0.442 and HR = 1.00, p = 0.920, respectively). We found a baseline level of vitamin D that was 10 nmol/l higher to be associated with a decrease in triglycerides and very low density lipoprotein cholesterol by 0.52% (p = 0.03) and 0.66% (p = 0.005), respectively. The odds ratios per 10 nmol/l higher baseline vitamin D level were 0.95 (p < 0.05) and 0.94 (p = 0.01) for the development of the metabolic syndrome and hypercholesterolaemia, respectively. There was no association between vitamin D and blood pressure. With filaggrin genotype as an instrumental variable, we found a 23.8% (95% confidence interval, CI: 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were no longer statistically significant when applying the Bonferroni-adjusted significance level. The remaining lipids showed non-significant changes in a favourable direction. A doubling of vita-min D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure or anthropometrics. With a total of 832 deaths and a 10.3 year median follow-up time, we found significant associations between vitamin D status and death caused by respiratory diseases, digestive diseases, and endocrine, nutritional and metabolic diseases with hazard ratios (HRs) 0.26 (ptrend = 0.0042), 0.28 (ptrend = 0.0040), and 0.21 (ptrend = 0.035), respectively, for the fourth vitamin D quartile compared to the first. We found non-significantly lower HRs for death caused by mental and behavioural diseases and diseases of the nervous system, but no association between vitamin D status and death caused by diseases of the circulatory system or neoplasms. We found a baseline level of vitamin D that was 10 nmol/l higher was associated with a small but statistically significant decrease in UACR by 0.92% (p = 0.02), but a non-significantly lower PTH. The odds ratio for an increased UACR were 0.96 (p = 0.0006) per 10 nmol/l higher baseline vitamin D level. Our studies support the idea that vitamin D can affect lipid status in a favourable direction as well as the incidence of metabolic syndrome and increased UACR but neither blood pressure nor anthropometrics. Vitamin D status was inversely associated with mortality, but this was not explained by an association with cardiovascular disease. Rather, the association seemed to be caused by an inverse association with death caused by digestive disease, endocrine, metabolic and nutritional diseases, and respiratory disease. Further studies, e.g. RCTs or Mendelian randomisation studies, are needed to clarify whether low vitamin D status is a causal and reversible factor to prevent disease and mortality.