Results
Baseline Characteristics
Selected characteristics of the 5409 men included in the analyses are summarized in Table 1. The mean age of participants at resurvey was 76.9 (SD 4.9) years, and about one-third (1841 men) had a history of prior vascular disease, cancer, or diabetes at resurvey. The majority (87%) were non-smokers, while 78% were self-reported 'current' alcohol drinkers.
Distribution of 25-hydroxyvitamin D Concentrations at Baseline
Plasma concentrations of 25(OH)D varied substantially by month of blood collection, and, even after adjustment for month of blood collection, concentrations had a log-normal distribution (see Supplementary material online, Figure S2). Median 25(OH)D concentration (standardized for month of blood collection) was 56 nmol/L (interquartile range 45–67 nmol/L) (Table 1). In a sample of 187 men with repeated measurements taken 1.5 years apart, the self-correlation in log 25(OH)D was 0.64. At any given age, men with higher 25(OH)D concentrations were less likely to have a history of vascular disease, cancer, or diabetes, and less likely to have been diagnosed with hypertension or taking treatment for hypertension, than men with lower concentrations. Measured systolic blood pressure at resurvey in 1997 was only weakly related with 25(OH)D concentrations, and blood pressure at the initial examination for the Whitehall study in 1967–70 was unrelated with 25(OH)D concentrations. Men with higher 25(OH)D also had lower mean body mass index than men with lower 25(OH)D and were less likely to have been of manual/clerical grade at retirement. In contrast, men with higher plasma 25(OH)D concentrations had higher mean LDL-C, HDL-C, ApoA1, and albumin concentrations, and lower mean CRP and fibrinogen concentrations, than men with lower 25(OH)D concentrations.
Association of 25-hydroxyvitamin D With Vascular and Non-vascular Mortality
Overall among the 5409 participants, 3215 men died during over 50 000 person years of follow-up (overall death rate: 6.4% per year; mean follow-up among survivors 13 years), including 1358 deaths (2.7% per year) from vascular causes and 1857 deaths (3.7% per year) from non-vascular causes (Table 2). Among the 3568 men without a history of vascular disease, cancer, or diabetes, there were 727 deaths (2.0% per year) from vascular causes and 1124 deaths (3.1% per year) from non-vascular causes. After classifying men into seven groups based on season-adjusted 25(OH)D concentration, higher concentrations of 25(OH)D were inversely and, on the log–log scale, approximately linearly related to the risk of vascular and, at least throughout the range 40–90 nmol/L, of non-vascular mortality in age-adjusted models (Figure 1). The shape of these associations were broadly similar for both vascular and non-vascular mortality [albeit with some attenuation of risk for non-vascular mortality with 25(OH)D concentrations above 80 nmol/L], and, for both outcomes, associations were consistent among men with and without a prior history of vascular disease, cancer, or diabetes.
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Figure 1.
Age-adjusted relevance of measured 25-hydroxyvitamin D for vascular and non-vascular mortality in old age, overall, and separately in men with and without prior disease. Prior disease is defined as cardiovascular disease (recall of a diagnosis of myocardial infarction, angina, or stroke), diabetes, or cancer. In the lower panels, only three risk groups are shown for each disease category to increase the statistical reliability of such subgroup analyses. To convert 25-hydroxyvitamin D from nmol/L to ng/mL, divide by 2.496.
Effect of Adjustment for Potential Confounders
Given age, a doubling in 25(OH)D concentration [corresponding to a ln(2) absolute difference—~2 SDs—on the log-scale] was, on average, associated with a 34% lower risk of vascular mortality (RR 0.66, 95% CI: 0.58–0.75) and a 36% lower risk of non-vascular mortality (RR 0.64, 95% CI: 0.58–0.72; Figure 2). After adjustment for prior diseases (including self-reported measures of health and frailty), established vascular risk factors, markers of inflammation and renal function, this was reduced to a 20% lower risk of vascular mortality (RR 0.80; 95% CI: 0.70–0.91) and a 23% lower risk of non-vascular mortality (RR 0.77; 95% CI: 0.69–0.86). The substantial change in the χ statistics associated with 25(OH)D concentration with these adjustments (from 41.1 to 11.5 for vascular death and 63.3–21.4 for non-vascular death) suggest that a large part of these associations was due to confounding, principally by prior disease. There was no evidence that the RRs associated with a doubling in baseline 25(OH)D concentration varied during follow-up (P values for test of proportionality assumption: P = 0.48 for vascular mortality and P = 0.13 for non-vascular mortality). Associations with particular types of vascular and non-vascular death (e.g. IHD, stroke, cancer, and respiratory death), after adjustment for measured confounders, were broadly similar to the overall RRs seen for vascular and non-vascular mortality (Figure 3). The findings for participants with no prior disease at resurvey were similar to those of the overall study population (see Supplementary material online, Figure S3 and S4). Results were also broadly similar after the exclusion of deaths within the first 5 years of follow-up (to further reduce the possible effect of reverse causality; see Supplementary material online, Figure S5) and were similar when the original 25(OH)D concentrations (i.e. before correction for seasonality) were used in analyses instead of season-adjusted concentrations (see Supplementary material online, Figure S6).
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Figure 2.
Effect of adjustment for known risk factors on the association between measured 25-hydroxyvitamin D and vascular and non-vascular mortality. (A) Recall of a diagnosis of ischaemic heart disease, stroke, cancer, or diabetes, plus self-reported health/frailty; (B) smoking status (current/ex/never); drinking status (current/non); grade of employment; LDL-C, HDL-C, apolipoprotein A1, apolipoprotein B, body mass index, and blood pressure [recall (in 1997) of a diagnosis of hypertension, treatment (in 1997) for hypertension and measured systolic and diastolic blood pressure in both 1997 and in ~1970]; (C) albumin, fibrinogen, and C-reactive protein, and (D) estimated glomerular filtration rate.
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Figure 3.
Association between measured 25-hydroxyvitamin D and cause-specific mortality after adjustment for measured confounders. IHD, ischaemic heart disease. Analyses are adjusted for smoking status (current/ex/never), drinking status (current/non), recall of a diagnosis of ischaemic heart disease, stroke, cancer, or diabetes, self-reported health/frailty, employment grade, LDL-C, HDL-C, apolipoprotein A1, apolipoprotein B, body mass index, markers of inflammation (albumin, fibrinogen, and C-reactive protein), recall (in 1997) of a diagnosis of hypertension, treatment (in 1997) for hypertension and measured systolic and diastolic blood pressure in both 1997 and in ~1970, and estimated glomerular filtration rate.
Meta-analysis of Studies of 25-hydroxyvitamin D and Vascular and All-cause Mortality
The meta-analyses (which included results from the current study) included 12 prospective studies with 4632 vascular deaths and 18 prospective studies with 11 734 deaths from all causes. Participants with a 25(OH)D concentration in the top vs. bottom quarter of distribution had on average, 21% (95% CI: 13–28%) lower vascular mortality (Figure 4) and 28% (95% CI: 24–32%) lower total mortality (Figure 5). Observed RRs varied inversely with the amount of statistical information provided by each study (i.e. study size), with more extreme estimates being seen among smaller studies for both vascular and all-cause mortality.
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Figure 4.
Meta-analysis of the relationship between 25-hydroxyvitamin D concentration and vascular mortality. *Numbers of deaths/people in the whole study are reported for each study, but only half of these deaths would be expected to contribute to analyses of top vs. bottom quarter. This study included both fatal and non-fatal vascular events.
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Figure 5.
Meta-analysis of the relationship between 25-hydroxyvitamin D concentration and all-cause mortality. *Number of deaths/people in the whole study are reported for each study, but only half of these deaths would be expected to contribute to analyses of top vs. bottom quarter.