The American College of Cardiology (ACC) and the American Heart Association (AHA) developed new guidelines for cardiovascular risk assessment in 2013 to quantitatively predict the 10-year risk for first atherosclerotic cardiovascular disease event. The recent guidelines included risks such as age, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking status, diabetes, and hypertension, which are widely accepted to be major risk factors for cardiovascular disease. These guidelines can be also used to predict stroke event or peripheral artery diseases, apart from cardiovascular disease [1].

Meanwhile, several studies have reported that lower vitamin D levels are correlated with metabolic syndrome, which is an important risk factor for cardiovascular diseases. There is accumulating epidemiological evidence from observational studies suggesting that cardiovascular diseases are associated with vitamin D deficiency [2-4]. Examining the association between serum vitamin D concentration and atherosclerosis cardiovascular disease (ASCVD) score can provide strong evidence for the importance of serum vitamin D concentration for predicting the risk for cardiovascular disease occurrence.

To date, no studies have reported the association of 10-year ASCVD risk score and vitamin D concentration in any country. In this study, we aimed to assess whether there is a correlation between the ASCVD score using the 2013 ACC/AHA guidelines and serum 25-hydroxyvitamin D (25[OH]D) levels in Korean adults.

Finally, 1,134 Koreans (564 men and 570 women) were included after excluding subjects with missing data, known severe cardiovascular disease, and physically inactivity. Participants’ characteristics were summarized in Table 1. The average level of serum vitamin D was 18.42 ng/mL for men and 16.37 ng/mL for women. The average ASCVD risk score was 9.279% for men and 3.52% for women. More men were included in the high-risk group compared to women. The proportion of regular physical activity was almost evenly distributed in both groups. Oral supplementation was more prevalent in women compared to men.

Table 2 presented the coefficients of serum 25(OH)D levels for each metabolic parameter, including ASCVD scoring factors, through Spearman analysis. In both men and women, age was found to be a factor significantly associated with serum 25(OH)D concentration (correlation coefficient [rho]=0.136 for men, rho=0.145 for women, respectively; P=0.001). Additionally, ASCVD risk score, waist circumference, total cholesterol, and HDL cholesterol were also to be significant factors correlating with serum 25(OH)D levels in women.

In Table 3, model 2 displayed a positive association between serum vitamin D level and logarithm-transformed ASCVD score in women after adjusting for central obesity, physical activity, and oral supplements (β=0.015, P=0.022) as confounding variables by linear regression analysis, whereas the association was not statistically significant in men.

We also evaluated the association between serum 25(OH)D and high-risk group participants using logistic regression analysis in Table 4. The ORs and 95% CIs were presented. A significant positive relationship between 25(OH)D and the chance of being in the high-risk group was observed with or without adjustments in women (OR,1.267; 95% CI, 1.039–1.595). No significant association was found in men.

In this study, central obesity, physical activity, and oral supplements were adjusted, as these factors were considered to relate to serum vitamin D level in previous studies. According to Panagiotakos et al. [7], a high degree of physical activity is associated with attenuated circulating levels of vitamin D. Obesity may decrease vitamin D release from the skin and from dietary sources into the circulation by storing fatsoluble vitamin D in subcutaneous fat due to the ‘sequestration theory,’ resulting in an inverse correlation between status of obesity serum 25(OH)D level [8]. Also, waist circumstance was found to be a coefficient for vitamin D level in our research (Table 2). Based on evidence that oral vitamin D supplements increase serum 25(OH)D [9], we also adjusted for oral supplementation as a confounding factor.

We found the presence of a positive association between 25(OH)D level and ASCVD risk score in women after controlling for confounding factors by using linear regression and logistic regression. Women with higher serum 25(OH)D had a higher ASCVD score and women with vitamin D sufficiency had an approximately 1.267-fold increased risk of being in the high-risk group than individuals with vitamin D deficiency, suggesting that vitamin D levels incurred susceptibility for inclusion in the high-risk group. These results were not in accordance with some previous studies on the favorable relationship of high levels of serum vitamin D with cardiovascular diseases. The latest evidence suggested that lower serum concentrations of 25(OH)D were associated with a number of cardiovascular diseases [10,11]. However, in the present study, it appears that age as a variable would play an influential factor for our results in women. As shown in our Table 2, age was a positive coefficient of serum 25(OH)D levels. In women, total cholesterol, another factor for calculating ASCVD score, was also a positive coefficient of serum 25(OH)D. Some studies indicated a positive correlation between vitamin D and total cholesterol [12-14]. Thus, we surmise that age and total cholesterol may have a pivotal effect on the positive correlation between 25(OH)D levels and ASCVD score in women.

Another potential factor influencing the positive relationship could be the frequency of vitamin D supplement intake. Even though we controlled for oral supplements as a confounding variable, data on oral supplements used in our study included all kinds of nutritional supplements such as various types of vitamin supplementations, omega-3 acid, protein-formula, etc. Thus, exact information on whether participants took vitamin D supplements or not was not provided. Elderly women (age is one of important factors to calculate ASCVD score) are more inclined to take vitamin D fortified products or supplements more often with frequent regular hospital visits and to have a higher prevalence of hypochondriasis than men, resulting in the highest serum vitamin D level in individuals over 75 years [15]. More frequent intake of vitamin D supplements in elderly women could affect the positive relationship between vitamin D and ASCVD score in our study. According to Korean research on healthy food in elderly women, 66.8% of elderly women took nutritional supplements and 30.6% of their supplements were composed of vitamin D and mineral supplements, exhibiting a higher rate of oral supplementation than men [16]. Lee et al. [17] found that men were more passive about taking nutritional supplements than women in their research on healthy food intake in Korean men. Therefore, it seems that more frequent intake of vitamin D supplements in elderly women might have strongly influenced our results. Additionally, we adjusted for general nutrient intake, not specific nutrients (Tables 3, 4). Since data on general nutrient intake was not categorized into sections, and detailed data on vitamin D supplements in KNHANES 2014 were not provided, we could not perfectly analyze the variable. Thus, the possibility of oral supplements affecting our results still remains, unfortunately.

The average ASCVD score and the prevalence of being in the high-risk group were higher in men than in women. One possible reason can be due to the different prevalence of cigarette smoking in men and women, as a smoking is thought to exert an influence on predicting the ASCVD scores in our study. The prevalence of tobacco use is 39.3% and 5.5% in men and women, respectively, from 2015 Korean data showing a lower rate of tobacco use in women [18]. However, the smoking rate among women may be underestimated due to inaccuracies in answers to the questionnaire because Korean society places a taboo on women who smoke, resulting in decreased smoking status and lower ASCVD scores in women. According to Park et al. [19] actual female smoking rate is significantly higher than officially reported, showing discrepancies in smoking rate between self-reported surveys and urinary nicotine levels. Furthermore, we observed a higher prevalence of smoking in men in our study, which was oriented towards elderly individuals, and it influenced the ASCVD scores in men. In addition, a higher prevalence of diabetes mellitus would be another explanation for higher ASCVD score in men than in women.

The strength of this study is that it is the first nationwide research to assess interactions between serum 25(OH)D concentration and 10-year ASCVD risk score. We explored the relationship after adjusting for obesity, physical activity, and oral nutritional supplements by using a large, representative, population-based sample of data from Korea.

There were also several limitations. First, the cross-sectional design of the study is a major weakness. Causality cannot be drawn from present study and our results cannot guarantee being part of future guidelines for physicians. Therefore, a longitudinal controlled trial is required to confirm these findings. Second, since it is based predominantly on randomized placebo controlled trials in Western populations, ASCVD score assessment allows for limited interpretation in Korean populations. Asian-specific ASCVD score guidelines are needed in future studies. Third, the optimal cut-off value for vitamin D deficiency level in the Korean population is still controversial. A consensus is required for Asians, including Koreans, in order to identify the optimal cut-off values. Fourth, the production of vitamin D in the skin depends on various sun exposure conditions such as season, latitude, the use of sun block, and skin pigmentation. These variables should be considered for more detailed and accurate research on serum vitamin D levels. In particular, seasonal variations, the strongest factor affecting serum vitamin D level, needs to be addressed in a subsequent study. Furthermore, more intensive identification of causes for the discrepancy of study results between men and women and the positive correlation between serum 25(OH)D and ASCVD score are required. Although age, total cholesterol, and varying frequencies of oral supplement use were considered as influential factors in this study, more evidence is needed. Moreover, ASCVD score is an indirect prognostic factor and we could not determine arterial stiffness or thickness in our sample. Thus, assessing the extent of coronary stenosis or plaque using ultrasonography matched with the ASCVD scores would be necessary to prove the relationship between ASCVD score and arterial-atherosclerotic status. There are also statistical vulnerabilities. A stratified, multistage, probability sampling design would better for statistical analysis for selecting the household units in KNHANES, instead of using simple data sampling analysis. Finally, our study population included only Koreans. Further studies should be conducted with reference to ethnic differences.

In summary, our data demonstrated that a high prevalence of vitamin D deficiency and insufficiency, in otherwise healthy Korean adults, was associated with higher ASCVD score and a higher probability of being in the high-risk group for men compared to women. In addition, there was a significant positive relationship between ASCVD score and serum 25(OH)D concentrations in women after adjusting for confounding variables. These findings in women are the opposite of what we expected based on previous studies that 25(OH)D levels might be negatively associated with the probability of cardiovascular disease occurrence. Age, total cholesterol, and oral supplementation with vitamin D were considered as possible reasons for these findings. In future studies, analyzing exact ingredients such as dietary intake of vitamin D fortified products, oral vitamin D supplements, and cholecalciferol injection status should be conducted to validate our results.

In conclusion, our research indicated women with higher serum 25(OH)D were likely to show higher ASCVD score and also be in a high-risk group based on ASCVD score in Korea. This article was able to assess the relationship between serum 25(OH)D and ASCVD score for the first time.