IJCS | Volume 31, Nº4, July / August 2018

428 Jorge et al. Vitamin D and cardiovascular disease Int J Cardiovasc Sci. 2018;31(4)422-432 Review Article associated with hypotonia, proximal muscle weakness, and nonspecific musculoskeletal pain. 60 Recent studies have reported that vitamin D deficiency is associated with a higher prevalence of myalgia induced by statins. 61 In 2014, Shantha et al. 62 performed a retrospective study with 5,526 patients followed by a prospective analysis in which the patients were followed up for 7 years. The patients with measured serum vitamin D levels who started treatment with statins were considered as the exposure group. The aim was to analyze the association between statin-induced myalgia and vitamin D levels, as well as to establish a cutoff level for vitamin D that would demonstrate a high accuracy for the emergence ofmyalgia. The authors concluded that low levels of vitamin D were associated with myalgia and that a cutoff level of 15 ng/ mL for vitamin D showed a high accuracy in predicting the emergence of myalgia induced by statins. 62 In 2015, Morioka et al. 63 performed a study with 5,907 patients to analyze if the level of vitamin D would modify the association between the use of statin and the emergence of musculoskeletal pain. The authors concluded that the group with vitamin D level below 15 ng/mL and using statins presented an approximately two-fold greater chance of developing musculoskeletal pain than patients who also had vitamin D levels below 15 ng/mL but were not treated with statins. 63 Prospective and randomized studies are needed to confirmthe actual associationbetweenvitaminDdeficiency and the emergence of myalgia induced by statins. In addition, the pathophysiological mechanism that could explain this association still needs to be elucidated. Genetic factors of vitamin D and its implications in cardiovascular disease The increased worldwide prevalence of vitamin D deficiency, or at least of its measurable circulating form, 25-hydroxyvitamin D, can be explained in part by genetic determinants. In 2010, an important multicenter study carried out by Wang et al. pointed out that serum vitamin D levels may be influenced by genetic variations involving its synthesis (7-DHC), hydroxylation (CYP2R1, CYP24A1), and transport protein (VDBP). 64 Most studies analyzing the association between vitamin Ddeficiency andCVDare epidemiological,whichprevents discrimination between association and causality. In this context, Mendelian randomization (MR) is an alternative approach to estimate the causal relationship between modifiable biological exposures and clinical outcomes of interest using genetic variants (single nucleotide polymorphisms, SNPs) as instrumental variables. Thus, MR using summarized data allows the combination of results already published in previous studies, becoming a relevant alternative to investigating causality. 65 Some studies have used MR to investigate a possible causal relationship between vitamin D deficiency and CVD. With respect to hypertension, Vimaleswaran et al. 66 found that increased vitamin D levels could reduce the risk of development of CVD, showing a causal relationship. 66 On the other hand, the results of MR studies have not demonstrated a causal relationship for diabetes mellitus 67 and CAD, 68 in which vitamin D deficiency appears to be a confounding factor. Vitamin D replacement Based on growing evidence of an association between vitamin D deficiency and CVD, many authors have investigated the role of vitamin D supplementation in the prevention and treatment of these pathologies. A randomized study conducted by Hsia et al. 69 with 36,282 postmenopausal women evaluated the supplementation of vitamin D 200 IU plus calcium carbonate twice a day or placebo during a follow-up of 7 years and found that supplementation of vitamin D was unable to reduce cardiovascular risk. 69 This was one of the few randomized studies that evaluated the impact of vitamin D in reducing hard outcomes, namely, incidence of AMI, stroke, and CAD-related death. With regard to hypertension, studies with vitamin D replacement have shown conflicting results. An important systematic review and meta-analysis published by Wu et al. 70 comprising 36,806 patients showed no significant effect of calcium plus vitamin D supplementation in variations in systolic and diastolic BP when compared with lack of supplementation of both. 70 In diabetes mellitus, studies involving vitamin D supplementation have proved disappointing. A study involving 70 children with type 1 diabetes of recent onset, supplementation with calcitriol had a modest effect on the residual function of pancreatic beta cells, but the reduction of glycated hemoglobin after 1 year of treatment was not statistically significant. 71 With respect to type 2 diabetes, study results are conflicting, perhaps due to lack of standardization of the supplemented vitamin D dose or the use of small samples in these studies. A meta-analysis involving 35 controlled studies evaluated the impact of vitamin D supplementation