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Nutrients 2014, 6(9), 3403-3430; doi:10.3390/nu6093403
Review

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

1
,
2,*  and 1
1 Department of Physiological Nursing, School of Nursing, University of California, San Francisco (UCSF), #2 Koret Way Box 0610, San Francisco, CA 94143, USA 2 Sunlight, Nutrition, and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA
* Author to whom correspondence should be addressed.
Received: 22 May 2014 / Revised: 31 July 2014 / Accepted: 18 August 2014 / Published: 2 September 2014
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Abstract

Serum 25-hydroxyvitamin D (25(OH)D) levels have been found to be inversely associated with both prevalent and incident cardiovascular disease (CVD) risk factors; dyslipidemia, hypertension and diabetes mellitus. This review looks for evidence of a causal association between low 25(OH)D levels and increased CVD risk. We evaluated journal articles in light of Hill’s criteria for causality in a biological system. The results of our assessment are as follows. Strength of association: many randomized controlled trials (RCTs), prospective and cross-sectional studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Consistency of observed association: most studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors in various populations, locations and circumstances. Temporality of association: many RCTs and prospective studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Biological gradient (dose-response curve): most studies assessing 25(OH)D levels and CVD risk found an inverse association exhibiting a linear biological gradient. Plausibility of biology: several plausible cellular-level causative mechanisms and biological pathways may lead from a low 25(OH)D level to increased risk for CVD with mediators, such as dyslipidemia, hypertension and diabetes mellitus. Experimental evidence: some well-designed RCTs found increased CVD risk factors with decreasing 25(OH)D levels. Analogy: the association between serum 25(OH)D levels and CVD risk is analogous to that between 25(OH)D levels and the risk of overall cancer, periodontal disease, multiple sclerosis and breast cancer. Conclusion: all relevant Hill criteria for a causal association in a biological system are satisfied to indicate a low 25(OH)D level as a CVD risk factor.
Keywords: association; cardiovascular disease; causation; Hill criteria; vitamin D association; cardiovascular disease; causation; Hill criteria; vitamin D
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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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.

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