Original ArticleDeficient serum 25-hydroxyvitamin D is associated with an atherogenic lipid profile: The Very Large Database of Lipids (VLDL-3) study
Graphical abstract
Introduction
Atherosclerotic cardiovascular disease (CVD) is the leading cause of death and disability-adjusted life years lost worldwide.1 Elevated serum concentrations of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and low concentrations of high-density lipoprotein cholesterol (HDL-C) are known to be major risk factors for developing CVD.2, 3, 4, 5 A growing body of cross-sectional evidence indicates that blood levels of vitamin D, a fat-soluble vitamin, are inversely associated with an atherogenic lipid profile.6, 7, 8, 9 These studies have found that individuals with low serum 25-hydroxyvitamin D (25[OH]D) (defined as either <20 ng/mL,6 <30 ng/mL,7 or in the lowest quartile8) have higher LDL-C, higher TG, and lower HDL-C compared with those with higher levels of 25(OH)D (defined as ≥30 ng/mL6, 7 or higher quartiles8). Serum 25(OH)D is considered the best indicator for vitamin D status.10 Lower serum levels of 25(OH)D are also independently associated with CVD events and mortality, even after adjusting for traditional risk factors including hyperlipidemia, diabetes, hypertension, smoking, body mass index (BMI), and prior history of myocardial infarction.11, 12, 13, 14, 15, 16, 17, 18, 19, 20 The impact of vitamin D supplementation on CVD risk reduction remains inconclusive and is a subject of much investigation and debate.21
Past studies examining the association between 25(OH)D and atherogenic lipid profiles used Friedewald-estimated LDL-C (LDL-Cf), which is less accurate than directly measured LDL-C (LDL-Cd), especially in the setting of low LDL-C and high TG.22 LDL also consists of different densities, with small, dense LDL suggested as a more significant CVD risk factor than large, buoyant LDL particles.23 The overall LDL particle density can be determined using the logarithmic LDL density ratio (LLDR), which is the ratio of dense-to-buoyant LDL subclasses (defined as ln[{LDL3-C + LDL4-C}/{LDL1-C + LDL2-C}]).24 Higher values of LLDR indicate denser LDL, which is potentially more atherogenic. No studies have examined associations between 25(OH)D and LDL-Cd or LDL density. Similarly, no studies have evaluated the relationship between 25(OH)D and remnant lipoprotein cholesterol (RLP-C). RLP-Cs are TG-rich lipoproteins consisting of intermediate-density lipoprotein cholesterol (IDL-C) and dense forms of very low–density lipoprotein cholesterol (VLDL-C). RLP-C has been independently associated with the development of CVD.25, 26, 27, 28, 29, 30
Our study set out to examine the association of vitamin D deficiency, as defined by serum 25(OH)D < 20 ng/mL,31 with an extended lipid panel (Vertical Auto Profile [VAP]) including HDL-C, total cholesterol (TC), non–HDL-C, LDL-Cf, LDL-Cd, IDL-C, VLDL-C, RLP-C, TG, and LLDR in a large cohort representative of the general US population. The inability of randomized controlled trials and cross-sectional studies to thus far agree on the associations between 25(OH)D and CVD risk may be due to confounders, such as glycemic status and kidney function that were not accounted for in prior cross-sectional studies. Current literature suggests there is an inverse association between 25(OH)D and incidence of type II diabetes,32 insulin resistance,33, 34 and glycosylated hemoglobin.35, 36, 37 Given the link between diabetes and CVD,38 our study sought to control for glycemic status in our analysis. Previous research has also shown an association between 25(OH)D and kidney function,39, 40, 41 necessitating controlling for kidney function in our study given the link between declining kidney function and increasing risk for CVD.42, 43 Our study also adjusted for age and gender in addition to glycemic status and kidney function. By using this database with directly measured lipid values and adjusting for clinical variables, we can further elucidate the relationship between 25(OH)D and lipids with greater power than prior studies. We hypothesized that 25(OH)D deficiency would be associated with a more atherogenic lipid profile.
Section snippets
Study population
Data in the Very Large Database of Lipids (VLDL) database were collected from 1,340,614 adults (≥18 years of age) in the United States who were clinically referred for VAP (Atherotech, Inc, Birmingham, AL) ultracentrifugation testing for lipid profiles from 2009 to 2011. The distribution of lipid values in this data set matches the distribution in the National Health and Nutrition Examination Survey 2007 to 2008.44 For the primary analysis, we used a cohort of 20,360 individuals from the VLDL
Results
Our final study cohort consisted of 20,360 subjects whose baseline characteristics are listed as median and interquartile range in Table 1. This cohort has similar distributions of age, TC, HDL-C, LDL-Cf, LDL-Cd, and TG compared to all subjects in the VLDL database with a 25(OH)D measurement (n = 70,207) and to all subjects included in the entire VLDL database (n = 1,340,614). There was a greater proportion of women in both our study subset (57.7%) and the entire VLDL subset with 25(OH)D
Discussion
In one of the largest and most detailed studies investigating the association between serum 25(OH)D and lipids, we find that 25(OH)D deficiency is associated with an atherogenic lipid profile across all lipid outcomes examined. Individuals with deficient 25(OH)D have on average 8.4% to 42.2% more of the various atherogenic lipids and 10.4% less HDL-C compared with individuals with optimal serum 25(OH)D. After adjusting for age, gender, glycemic status, and kidney function, 25(OH)D-deficient
Limitations
The study has several limitations. As we do not have access to patient medical records, medication usage, including whether patients were taking vitamin D supplements or not, is unknown. Individuals with favorable health-seeking behavior might be more likely to take vitamin D supplements. Although conversely, older, frailer individuals who are at risk for osteoporosis or osteopenia may also be taking vitamin D supplements. The use of 25(OH)D in our analysis, which integrates sunlight, diet, and
Future directions
The limitations discussed previously do not diminish the role of our study in generating hypotheses for future investigations. Prior observational studies have found links between deficient 25(OH)D and CVD risk, but the mechanism remains unclear.11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Our results indicate that the mechanism by which deficient 25(OH)D increases CVD risk may be mediated through changes in lipids. Our study and others suggest it is likely that only deficient individuals (rather
Conclusions
Despite inconclusive evidence from clinical trials, there remains strong evidence in the literature that 25(OH)D is inversely associated with LDL-Cf and TG and directly associated with HDL-C. Our study not only supports these findings but also shows for the first time, to the best of our knowledge that this inverse association holds true for LDL-Cd, IDL-C, VLDL-C, and RLP-C. Investigators conducting future clinical trials examining the impact of vitamin D supplementation on hyperlipidemia and
Acknowledgment
Atherotech provided the investigators with de-identified data generated from commercial lipid analyses and did not provide payments for the research or article writing and did not participate in data analysis or influence the conclusions. This study was initiated by the investigators and did not receive any specific funding. The authors take responsibility for the accuracy of the statistical analyses and had the sole authority on article preparation and submission for publication.
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