title: 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: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiological Nursing, School of Nursing, University of California, San Francisco (UCSF), #2 Koret Way Box 0610, San Francisco, CA 94143, USA. patricia.weyland@ucsf.edu.
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Weyland
authors.affiliation: Sunlight, Nutrition, and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA. wbgrant@infionline.net.
authors.forename: William B
authors.initials: WB
authors.lastname: Grant
authors.affiliation: Department of Physiological Nursing, School of Nursing, University of California, San Francisco (UCSF), #2 Koret Way Box 0610, San Francisco, CA 94143, USA. jill.howie-esquivel@nursing.ucsf.edu.
authors.forename: Jill
authors.initials: J
authors.lastname: Howie-Esquivel
mesh_terms: D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology*; D006801:Humans; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood; D014808:Vitamin D Deficiency / Q000097:blood / Q000150:complications*
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D