Does Sufficient Evidence Exist to Support a Causal Association between Vitamin D Status and Cardiovascular Disease Risk? An Assessment Using Hill’s Criteria for Causality
Abstract
:1. Introduction
2. Approach and Rationale
Criterion | Defining Question |
---|---|
Strength of the association | Is there a large difference in the outcome between exposed and non-exposed persons? |
Consistency of the observed association | Has the outcome been observed by multiple researchers, in various circumstances, places and at different times? |
Specificity of the association | Are there specific persons or geographic locations associated with specific outcomes? |
Temporality (temporal relationship of the association) | Does the cause always precede the effect? |
Biological gradient | Is there a dose-response curve? |
Plausibility of the biology | Is the suspected causation consistent with current knowledge of biology? |
Coherence | Are there any serious conflicts with the biology or natural history of the disease? |
Experiment (experimental or quasi-experimental evidence) | Has an observed association led to a preventive action that has prevented the outcome? |
Analogy | Is there an analogous exposure and outcome? |
Criterion | Proposed Mechanism | Reference | No Effect | Satisfied? |
---|---|---|---|---|
Strength of association | [6,8,12,50,51,52,53] | Yes | ||
Consistency | [7,15,54,55,56] | Yes | ||
Temporality | [8,18,55,57,58] | Yes | ||
Biological Gradient | [8,55,59,60] | Yes | ||
Plausibility | Blunts renin-angiotensin system | [61,62] | Yes | |
Arterial stiffness (HTN) | [15,62,63,64,65,66] | |||
Reduced risk of DM | [19] | |||
Insulin resistance | [67] | |||
Glucose regulation | [58,67,68] | |||
Seasonal variations in serum 25(OH)D | [4] | |||
Lipids | [69,70] | |||
Metabolic syndrome | [71,72,73,74,75] | |||
DM type 2 and its progression | [19,57,76] | |||
Experiment | RCTs | [77] | [78] | Yes |
Blood pressure reduction | [79] | |||
Blunts renin-angiotensin system | [61] | |||
Arterial stiffness (PWV) | [25] | |||
Insulin resistance | [80,81] | |||
Glucose | [80,81] | |||
Lipids | [82,83,84] | |||
Metabolic syndrome | [85,86] | |||
Analogy | Cancer | [46,87] | Yes | |
DM type 2 | [19] | |||
Confounding Factors | Nitric oxide liberated by solar UV | [88,89,90] | Yes | |
Calcium supplementation | [91] | |||
Reverse causation | [91] | |||
CVD risk factors affect 25(OH)D levels (obesity) | [91] | |||
Physical activity | [92] | |||
Statins | [75,93] | |||
Seasonal variations in temperature | [94,95] | |||
Concerns | ||||
Excess vitamin D | [96] | |||
Hypercalcemia | [97] | |||
DM | Limited effect of vitamin D | [98,99,101] |
3. Findings: Evaluation Using Hill’s Criteria for Causality
3.1. Strength of the Association
3.2. Consistency of the Association
3.3. Temporality
3.4. Biological Gradient (Dose-Response Relation)
3.5. Plausibility
3.5.1. Dyslipidemia
3.5.2. Hypertension
3.5.3. Diabetes Mellitus
3.5.4. Metabolic Syndrome
3.6. Experiment
Mean Serum 25(OH)D (ng/mL) | Vitamin D3 Dose (IU/day) | Increase in 25(OH)D (ng/mL) | Mean Age (year) | Health Outcome of Interest | Findings | Reference |
---|---|---|---|---|---|---|
8.4 | 4000 | 19.6 | 42 | Insulin sensitivity | 5.9 vs. −5.9 (p = 0.003) | [115] |
8.4 | 4000 | 19.6 | 42 | Fasting serum glucose | −3.6 vs. 1.1 (p = 0.02) | [115] |
13 | 400 or 1000 | 13 | 64 | HDL-C, LDL-C, TG, ApoA1, ApoB100, HOMA-IR, hs-CRP, sICAM-1, IL-6 | Not significant | [83] |
<20 | 2000 * | Total cholesterol, HDL-C, LDL-C, TGs | Not significant | [82] | ||
14.7 | 1000 | 15 | 38 | Total cholesterol, LDL-C, ApoA1, ApoA1:ApoB-100 | Significant to p < 0.01 | [108] |
14.7 | 1000 | 15 | 38 | HDL-C, LDL-C:ApoB-100 | Significant to p < 0.04 | [108] |
14.7 | 1000 | 15 | 38 | ApoB-100, lipoprotein(a) | Not significant | [108] |
16.1 | 2857 * | 40 | 52 | Insulin sensitivity | Not significant | [114] |
16.3 | 0 | 51 | Systolic BP | +1.7 mm | [79] | |
16.3 | 1000 | 51 | −0.66 mm | [79] | ||
14.5 | 2000 | 51 | −3.4 mm | [79] | ||
15.6 | 4000 | 51 | −4.0 mm | [79] | ||
19.6 | 4000 | 19.5 | 14.1 | Insulin sensitivity | −1.36 vs. +0.27 (p = 0.03) | [116] |
Fasting insulin | −6.5 vs. +1.2 (p = 0.03) | [116] | ||||
19.6 | 2857 * or 5714 * | 40 | 52 | HDL-C, LDL-C, TGs, ApoA1, ApoB, hs-CRP | Not significant | [84] |
22.9 | 2857 * or 5714 * | 22.8 | 50 | TNF-α, IL-6, HOMA-IR, QUICKI | Not significant | [117] |
23 | 1000 | 21 | 61 | Systolic BP | −1.5 mm vs. +0.4 mm (p = 0.26) | [25] |
30.3 | 2500 | 16 | 64 | Glucose, CRP, FMD, diastolic BP, systolic BP, PWV | Not significant | [118] |
3.7. Analogy
3.8. Confounding Factors
4. Conclusions
Acknowledgements
Author Contributions
Conflicts of Interest
References
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Weyland, P.G.; Grant, W.B.; Howie-Esquivel, J. Does Sufficient Evidence Exist to Support a Causal Association between Vitamin D Status and Cardiovascular Disease Risk? An Assessment Using Hill’s Criteria for Causality. Nutrients 2014, 6, 3403-3430. https://doi.org/10.3390/nu6093403
Weyland PG, Grant WB, Howie-Esquivel J. Does Sufficient Evidence Exist to Support a Causal Association between Vitamin D Status and Cardiovascular Disease Risk? An Assessment Using Hill’s Criteria for Causality. Nutrients. 2014; 6(9):3403-3430. https://doi.org/10.3390/nu6093403
Chicago/Turabian StyleWeyland, Patricia G., William B. Grant, and Jill Howie-Esquivel. 2014. "Does Sufficient Evidence Exist to Support a Causal Association between Vitamin D Status and Cardiovascular Disease Risk? An Assessment Using Hill’s Criteria for Causality" Nutrients 6, no. 9: 3403-3430. https://doi.org/10.3390/nu6093403