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. Author manuscript; available in PMC: 2014 Nov 6.
Published in final edited form as: Pediatrics. 2009 Aug 3;124(3):e371–e379. doi: 10.1542/peds.2009-0213

Vitamin D Status and Cardiometabolic Risk Factors in the US Adolescent Population

Jared P Reis a, Denise von Mühlen b, Edgar R Miller III a, Erin D Michos c, Lawrence J Appel a
PMCID: PMC4222068  NIHMSID: NIHMS639173  PMID: 19661053

Abstract

OBJECTIVE

Evidence on the association of vitamin D with cardiovascular risk factors in youth is very limited. We examined whether low serum vitamin D levels [25(OH)D] are associated with cardiovascular risk factors in US adolescents aged 12–19 years.

METHODS

Cross-sectional analysis of 3,577 fasting, nonpregnant adolescents without diagnosed diabetes who participated in the 2001–2004 National Health and Nutrition Examination Survey (NHANES). Risk factors for cardiovascular disease measured using standard methods and defined according to age-modified Adult Treatment Panel-III definitions.

RESULTS

Mean 25(OH)D in US adolescents was 24.8 ng/mL; lowest in black (15.5 ng/mL), intermediate in Mexican American (21.5 ng/mL), and highest in white (28.0 ng/mL) adolescents (p<0.001, for each pair-wise comparison). Low 25(OH)D levels were strongly associated with overweight status and abdominal obesity (ptrend<0.001, for both). Following adjustment for age, sex, race/ethnicity, body mass index, socioeconomic status, and physical activity, 25(OH)D levels were inversely associated with systolic blood pressure (p=0.02) and plasma glucose concentrations (p=0.01). The adjusted odds ratio (95% CI) for those in the lowest (<15 ng/mL) compared to the highest quartile (>26 ng/mL) of 25(OH)D for hypertension was 2.36 (1.33, 4.19); for fasting hyperglycemia 2.54 (1.01, 6.40); for low HDL-cholesterol 1.54 (0.99, 2.39); for hypertriglyceridemia 1.00 (0.49, 2.04); and for metabolic syndrome 3.88 (1.57, 9.58).

CONCLUSIONS

Low serum vitamin D in US adolescents is strongly associated with an increased prevalence of hypertension, hyperglycemia, and metabolic syndrome, independent of adiposity. Whether the low concentrations of vitamin D among adolescents predicts future adverse health events remains to be determined.

Keywords: cardiovascular, children, dietary supplements

At the end of the 19th century, there was an epidemic of vitamin D-deficient rickets in US children that resulted in growth retardation, muscle weakness, skeletal deformities, and tetany.1 With the fortification of milk and other foods with vitamin D and the encouragement of moderate sunlight exposure, rickets was almost completely eradicated by the middle of the 20th century.2 While rickets in children and osteomalacia in adults may represent the extreme consequences of severe vitamin D deficiency, lesser degrees of deficiency or insufficiency may have important health effects. Indeed, increased parathyroid hormone levels during childhood and adolescence, secondary to vitamin D deficiency or insufficiency results in calcium resorption from the skeleton, which may lower peak bone mass and increase the risk of developing osteoporosis during adulthood.3–5

Although a great deal of attention has been justifiably placed on understanding the consequences of vitamin D deficiency or insufficiency on bone health, a growing body of evidence from several lines of scientific inquiry indicates hypovitaminosis D may influence the development of cardiovascular disease.6 Low 25-hydroxyvitamin D [25(OH)D] levels, an indicator of vitamin D status incorporating both cutaneous production from sunlight exposure and dietary intake,7 have been observed in cerebrovascular,8,9 heart failure,10 and coronary heart disease patients.8,11 Furthermore, low vitamin D has been linked with higher rates of metabolic syndrome,12 hypertension,13 diabetes,14 myocardial infarction,15 peripheral arterial disease,16 and cardiovascular disease.17

While cardiovascular disease events occur most frequently during or after the fifth decade of life, pathological evidence suggests precursors of cardiovascular disease originate in childhood.18,19 Longitudinal studies have shown risk factor levels in young adulthood track into and predict the occurrence of cardiovascular disease in adulthood.20,21 A significant association between vitamin D and cardiovascular risk factors in youth would suggest that the successful repletion of vitamin D has the potential to improve the cardiovascular risk profile during childhood and adolescence, and lower the risk of developing cardiovascular disease in adulthood. Compared to adults, however, very little is known about the association between vitamin D and risk factors for cardiovascular disease in youth. The present study sought to examine the association of serum vitamin D levels with select cardiovascular disease risk factors and the prevalence of metabolic syndrome among a nationally representative population-based sample of US adolescents aged 12–19 years.

METHODS

Study population

The present study was based on data from the 2001–2004 National Health and Nutrition Examination Survey (NHANES) conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. Since 1999, NHANES has been a continuous series of cross-sectional surveys which employ a complex, multistage, stratified probability sampling design to select participants representative of the civilian, noninstitutionalized US population. Data collection occurs during a home interview and a health examination conducted within a mobile examination center. The Institutional Review Board at the Centers for Disease Control and Prevention annually reviews the overall design of NHANES. Written informed consent is obtained for all subjects ≥18 years of age or from the parent or guardian of those <18 years. Written assent is also obtained from participants <18 years.

A total of 4,666 adolescents aged 12–19 years completed a health examination as part of NHANES 2001–2004. For our purposes, we excluded girls who were pregnant (n = 105), those who had fasted for less than 6 hours or greater than 24 hours prior to the health examination and blood draw (n = 796), those who did not have a valid 25(OH)D measurement (n = 228), and those with diagnosed diabetes (based upon a physician diagnosed history or use of medication; n = 9). The remaining 3,528 adolescents formed the sample population for the current analysis.

Data collection

Information regarding age, race/ethnicity, family income, and physical activity was obtained by a family member who was most knowledgeable about the child (usually a mother or father) or self-report. Race/ethnicity was categorized as non-Hispanic white, non-Hispanic black, Mexican American, or “other,” including those who identified as multiracial or of other Hispanic origin. Socioeconomic status was estimated with the poverty-to-income ratio, which divides family (defined as 2 or more related people who live together) income by the poverty threshold. Poverty thresholds are updated annually and are adjusted for inflation. In 2002, for example, the average poverty threshold was $19,307 for a family of 4 and $22,831 for a family of 5. A poverty-to-income ratio less than 1 indicates that the family is below the poverty threshold (range, 0–5). Information on physical activity was obtained during the household interview for subjects 12–15 years of age and during the health examination interview for those 16–19 years. The frequency and duration of walking/bicycling for transportation, home or yard work, and moderate to vigorous intensity leisure-time physical activities during the past month was requested. Responses to these questions were incorporated into a single summary variable expressed in metabolic equivalent-minutes/day (MET-min/day) using intensity values recommended by the National Center for Health Statistics.22 Use of dietary supplements containing vitamin D during the previous month was ascertained.

A certified technician measured blood pressure a maximum of 4 times in seated subjects after a 5 minute rest with a mercury-gravity sphygmomanometer. Child, adult, and large arm cuff sizes were available. The average of all available measurements was used for analysis. Body weight to the nearest 0.1 kilogram and standing height to the nearest 0.1 centimeter were measured once using a Toledo electronic scale and Seca stadiometer. Body mass index was calculated as weight in kilograms divided by the square of height in meters. Waist circumference was measured to the nearest 0.1 centimeter using a steel measuring tape placed level with the iliac crest at the end of a normal expiration.

Laboratory measures

During the health examination blood samples were obtained by venipuncture and immediately centrifuged, aliquoted, and frozen to −20°C. The frozen serum and plasma samples were then shipped on dry ice to central laboratories and stored at −70°C until analysis. Serum 25(OH)D [25(OH)D2 + 25(OH)D3] levels were measured by radioimmunoassay (Diasorin Inc., Stillwater, MN). Total (intra-assay and inter-assay) coefficients of variation ranged from 6.3–13.2%, the limit of detection was 3 ng/mL, and the reference range was 10–55 ng/mL. We categorized 25(OH)D into quartiles using cutting points based upon the weighted population distribution of vitamin D in the current study sample.

Plasma glucose was measured using standard hexokinase enzymatic assays. Glycosolated hemoglobin (HbA1c) was determined with boronate affinity high performance liquid chromatography (Primus Corporation, Kansas City, MO) and standardized to the reference method used in the Diabetes Complications and Control Trial.23 Lipid measurements were performed at the Johns Hopkins University Lipoprotein Analytical Laboratory. HDL-cholesterol was measured on a Hitachi model 704 analyzer (Roche Diagnostics, Indianapolis, IN) after precipitation of the other lipoproteins with a heparin-manganese chloride mixture. Triglyceride levels were determined by using a series of enzymatic reactions producing glycerol and then hydrogen peroxide.

Definitions

For this analysis, the majority of cardiovascular risk factors were defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) definition modified for age.24,25 These risk factors were defined as follows: waist circumference ≥90th percentile for age and sex;26,27 HDL cholesterol ≤40 mg/dL; triglycerides ≥110 mg/dL; systolic or diastolic blood pressure ≥90th percentile for age, sex, and height,28 or use of blood pressure medications; and fasting glucose ≥100 mg/dL.29 Thresholds for the oldest age group were applied to subjects older than the highest age category for the blood pressure (≥17 years) criteria. The presence of the metabolic syndrome phenotype was defined as ≥3 of these 5 characteristics. A body mass index ≥95th percentile for age and sex was used to define “obese” on the basis of growth charts published by the Centers for Disease Control and Prevention in 2000.30

Statistical analysis

All analyses were weighted to the US population to provide nationally representative estimates. SAS-callable SUDAAN statistical software, version 9.0 (Research Triangle Institute, Research Triangle Park, NC) was used to account for the complex sampling design and weighting of the NHANES sample. Participant characteristics were described using means and proportions and their 95% confidence intervals. Mean 25(OH)D concentrations according to sub-groups were compared by independent sample t-tests. We calculated multivariable-adjusted mean metabolic cardiovascular risk factor levels according to quartiles of serum 25(OH)D and examined these associations with a test for linear trend. Multivariable logistic regression models were used to estimate odds ratios and 95% confidence intervals for cardiovascular risk factors according to quartiles of 25(OH)D. Models for body mass index and waist circumference were adjusted for age, sex, race/ethnicity, poverty-to-income ratio, and physical activity. Subsequent risk factor models adjusted additionally for body mass index. Tests for a linear trend were determined by entering the continuous 25(OH)D variable into the model as an ordinal term. A similar pattern of results was obtained by entering either the median of the quartile categories of 25(OH)D as a continuous variable or the quartile categories as an ordinal variable to the multivariable logistic regression models. Statistical significance was defined at the p<0.05 level using two-sided tests.

RESULTS

The sociodemographic and clinical characteristics of the US adolescent population included in the current study are presented in Table 1. During 2001–2004, the prevalence of obesity was 17.6%, abdominal obesity 16.4%, high blood pressure 6.4%, elevated fasting glucose 2.5%, low HDL-cholesterol 20.7%, and elevated triglycerides 21.9%. The prevalence of metabolic syndrome was 5.9%. Only 3.3% of adolescents reported using supplements which contained vitamin D during the previous month, with an average (95% CI) dose of 509.4 (427.0, 591.8) IU/day.

Table 1.

Characteristics of US adolescents aged 12–19 years, NHANES, 2001–2004

Characteristic Mean or Percent (95% CI)
Unweighted n 3,528
Age, years 15.4 (15.3, 15.6)
Sex, %
  Boys 51.5 (49.5, 53.5)
  Girls 48.5 (46.5, 50.5)
Race/ethnicity, %
  White 64.7 (59.3, 70.1)
  Black 13.5 (10.5, 16.5)
  Mexican American 11.0 (7.9, 14.1)
Poverty-to-income ratio 2.56 (2.43, 2.69)
Physical activity, MET-min/day 486.9 (458.5, 515.2)
Supplemental vitamin D user, % 3.3 (2.7, 3.9)
Anthropometrics
  Body mass index ≥ 95th percentile, % 17.6 (15.5, 19.7)
  Waist circumference ≥ 90th percentile, % 16.4 (14.5, 18.5)
Blood pressure
  Systolic blood pressure, mmHg 108.5 (107.8, 109.2)
  Diastolic blood pressure, mmHg 61.5 (60.8, 62.3)
  High blood pressure, %* 6.4 (5.3, 7.5)
Diabetes-related measures
  Fasting glucose, mg/dL 86.1 (85.5, 86.6)
  HbA1c (mean percent) 5.2 (5.1, 5.2)
  Fasting glucose ≥100 mg/dL, % 2.5 (1.9, 3.1)
Lipids
  HDL cholesterol ≤ 40 mg/dL, % 20.7 (18.4, 23.4)
  Triglycerides ≥ 110 mg/dL, % 21.9 (19.4, 24.7)
Metabolic syndrome, %† 5.9 (4.8, 7.0)
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NHANES denotes National Health and Nutrition Examination Survey; CI, confidence interval.

*

Defined as systolic or diastolic blood pressure ≥90th percentile for age, sex, and height,28 or medication use.

†

Defined according to the method of Cook et al24,25

Table 2 displays the mean 25(OH)D level according to demographic and clinical characteristics of the cohort. Mean 25(OH)D levels were highest in white, intermediate in Mexican Americans, and lowest in black adolescents (p<0.001, for each pair-wise comparison). Mean 25(OH)D levels were higher among adolescents who reported the use of vitamin D supplements and lower in those defined as obese or abdominally obese. Vitamin D levels were also lower in adolescents with high blood pressure, low HDL cholesterol, and those with metabolic syndrome. Although not statistically significant, there was a trend toward a lower mean 25(OH)D level in girls and those with elevated fasting glucose. No differences were observed in vitamin D status by age or level of triglycerides.

Table 2.

Mean 25-hydroxyvitamin D [25(OH)D] levels among US adolescents aged 12–19 years and according to sub-groups, NHANES, 2001–2004

Unweighted n Mean
25(OH)D level
(95% CI), ng/mL		 pvalue
Overall 3,528 24.8 (23.8, 25.9) --
Age, years
  12–15 1,786 24.7 (23.9, 25.6) 0.730
  16–19 1,742 24.9 (23.5, 26.3)
Sex
  Boys 1,811 25.2 (24.3, 26.1) 0.082
  Girls 1,717 24.4 (23.5, 25.3)
Race/ethnicity
  Non-Hispanic white 1,054 28.0 (27.0, 29.0) < 0.001, for each
  Non-Hispanic black 1,117 15.5 (14.6, 16.4) pair-wise
  Mexican American 1,119 21.5 (20.6, 22.4) comparison
Vitamin D supplement user
  Yes 91 29.6 (26.6, 32.7) 0.001
  No 3,437 24.7 (23.6, 25.7)
Body mass index ≥ 95th percentile*
  Yes 650 21.4 (20.3, 22.5) < 0.001
  No 2,834 25.6 (24.5, 26.8)
Waist circumference ≥ 90th percentile*
  Yes 573 22.1 (20.9, 23.3) < 0.001
  No 2,893 25.5 (24.3, 26.6)
High blood pressure†
  Yes 213 22.7 (21.1, 24.3) 0.003
  No 3,217 25.0 (24.2, 25.8)
Fasting glucose ≥ 100 mg/dL
  Yes 109 22.8 (20.3, 25.3) 0.063
  No 3,400 24.9 (24.1, 25.7)
HDL cholesterol ≤ 40 mg/dL
  Yes 649 22.6 (21.7, 23.5) < 0.001
  No 2,867 25.4 (24.6, 26.2)
Triglycerides ≥ 110 mg/dL
  Yes 653 23.8 (22.4, 25.2) 0.114
  No 2,855 25.0 (24.2, 25.8)
Metabolic syndrome‡
  Yes 192 20.8 (19.3, 22.3) < 0.001
  No 3,336 25.1 (24.0, 26.1)
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NHANES denotes National Health and Nutrition Examination Survey; CI, confidence interval.

*

According to age and sex.26,27

†

Defined as systolic or diastolic blood pressure ≥90th percentile for age, sex, and height,28 or use of blood pressure medications.

‡

Defined according to the method of Cook et al24,25

Table 3 shows the adjusted mean cardiovascular disease risk factor levels according to quartiles of serum 25(OH)D. After adjusting for age, sex, race/ethnicity, poverty-to-income ratio, and physical activity, significant trends for a lower body mass index and waist circumference were observed in adolescents with higher vitamin D levels. Mean systolic blood pressure and fasting glucose were also lower in those with higher levels of vitamin D, even after additional adjustment for adiposity. No association was observed between vitamin D and diastolic blood pressure, HbA1c, HDL-cholesterol, or triglyceride concentrations.

Table 3.

Adjusted mean (95% confidence interval) cardiovascular disease risk factors according to quartiles of 25-hydroxyvitamin D [25(OH)D] among US adolescents aged 12–19 years, NHANES, 2001–2004

Quartile of serum 25(OH)D, ng/mL
I (< 15.0) II (15.0–21.0) III (21.1–26.0) IV (> 26.0) ptrend
Body mass index, kg/m2* 26.0 (25.2, 26.8) 24.3 (23.7, 24.9) 23.5 (23.1, 24.0) 22.1 (21.7, 22.5) < 0.001
Waist circumference, cm* 87.5 (85.3, 89.7) 83.9 (82.5, 85.3) 81.3 (80.1, 82.5) 77.8 (76.6, 79.0) < 0.001
Blood pressure, mmHg
  Systolic† 109.7 (108.4, 111.0) 108.5 (107.5, 109.5) 108.1 (107.0, 109.2) 108.1 (107.3, 108.9) 0.020
  Diastolic† 61.7 (60.3, 63.1) 62.1 (60.8, 63.4) 61.2 (60.2, 62.2) 61.2 (60.0, 62.4) 0.082
Diabetes measures
  Fasting glucose, mg/dL† 88.3 (86.9, 89.7) 86.2 (85.3, 87.1) 85.3 (84.7, 85.9) 85.6 (85.0, 86.2) 0.010
  HbA1c(%)† 5.17 (5.09, 5.25) 5.18 (5.14, 5.22) 5.14 (5.10, 5.18) 5.16 (5.14, 5.18) 0.673
Lipids, mg/dL
  HDL-cholesterol† 52.0 (49.9, 53.1) 51.4 (49.9, 54.1) 51.3 (50.1, 52.5) 53.7 (52.3, 55.1) 0.112
  Triglycerides† 95.7 (78.1, 113.3) 84.8 (78.5, 91.1) 88.1 (81.3, 94.9) 83.4 (79.2, 87.6) 0.695
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NHANES denotes National Health and Nutrition Examination Survey.

*

Adjusted for age (years), sex, race/ethnicity (non-Hispanic white, non-Hispanic Black, Mexican American, other), poverty-to-income ratio (continuous), and physical activity (MET-min/day).

†

Adjusted for variables listed above in addition to body mass index (kg/m2).

The multivariable-adjusted association between 25(OH)D and obesity, abdominal obesity, high blood pressure, elevated fasting glucose, low HDL-cholesterol, elevated triglycerides, and metabolic syndrome are shown in Table 4. Adjusted odds ratios for obesity, abdominal obesity, high blood pressure, and metabolic syndrome increased significantly with decreasing quartile of vitamin D. Compared to adolescents with the highest serum 25(OH)D levels, the adjusted odds ratio for elevated fasting glucose was 2.54 (95% CI: 1.01, 6.40) for those in the lowest 25(OH)D quartile. The associations between low vitamin D status and high blood pressure, elevated fasting glucose, and metabolic syndrome were independent of the potential confounding effects of age, sex, race/ethnicity, poverty-to-income ratio, physical activity, and body mass index. A similar pattern of association between vitamin D, high blood pressure, and elevated fasting glucose was observed when models were adjusted for abdominal adiposity as reflected by waist circumference as opposed to body mass index (data not shown). No association was observed between 25(OH)D and low HDL-cholesterol or increased triglyceride concentration.

Table 4.

Age-, sex-, and race/ethnicity-adjusted prevalence, adjusted odds ratios (OR), and 95% confidence intervals (CI) of select cardiovascular disease risk factors according to serum 25-hydroxyvitamin D [25(OH)D] level among US adolescents 12–19 years, NHANES, 2001–2004

Quartile of Serum 25(OH)D, ng/mL
I (< 15.0) II (15.0–21.0) III (21.1–26.0) IV (> 26.0) ptrend
Body mass index ≥ 95th percentile*
  Prevalence, % 30.7 (25.8, 36.1) 22.6 (19.6, 25.9) 16.5 (13.9, 19.4) 10.4 (7.9, 13.6) < 0.001
  Adjusted OR (95% CI)† 5.24 (3.47, 7.91) 2.99 (1.98, 4.53) 2.02 (1.34, 3.06) 1.00 (referent) < 0.001
Waist circumference ≥ 90th percentile*
  Prevalence, % 26.9 (22.1, 32.4) 20.8 (18.1, 23.8) 16.1 (13.7, 18.8) 9.7 (7.7, 12.1) < 0.001
  Adjusted OR (95% CI)† 7.21 (4.36, 11.94) 3.64 (2.14, 6.20) 2.19 (1.25, 3.83) 1.00 (referent) < 0.001
High blood pressure‡
  Prevalence, % 11.2 (7.6, 16.2) 6.7 (5.1, 8.7) 4.4 (3.1, 6.3) 3.7 (2.6, 5.3) 0.013
  Adjusted OR (95% CI)§ 2.36 (1.33, 4.19) 1.26 (0.65, 2.44) 1.04 (0.55, 1.97) 1.00 (referent) 0.046
Fasting glucose ≥ 100 mg/dL
  Prevalence, % 6.4 (3.8, 10.7) 2.9 (2.0, 4.4) 3.0 (1.9, 4.8) 1.3 (0.7, 2.3) 0.144
  Adjusted OR (95% CI)§ 2.54 (1.01, 6.40) 1.18 (0.50, 2.79) 0.85 (0.39, 1.88) 1.00 (referent) 0.101
HDL cholesterol ≤ 40 mg/dL
  Prevalence, % 29.9 (25.8, 34.3) 20.9 (17.9, 24.4) 18.8 (15.7, 22.3) 12.5 (10.2, 15.2) < 0.001
  Adjusted OR (95% CI)§ 1.54 (0.99, 2.39) 1.33 (0.89, 1.99) 1.10 (0.72, 1.70) 1.00 (referent) 0.084
Triglycerides ≥ 110 mg/dL
  Prevalence, % 23.0 (18.1, 28.8) 20.7 (17.4, 24.5) 17.6 (15.1, 20.4) 17.0 (14.6, 19.7) 0.119
  Adjusted OR (95% CI)§ 1.00 (0.49, 2.04) 1.03 (0.59, 1.80) 0.91 (0.66, 1.26) 1.00 (referent) 0.371
Metabolic syndrome‖
  Prevalence, % 14.6 (10.4, 20.1) 6.9 (5.2, 9.2) 5.2 (3.6, 7.5) 2.2 (1.5, 3.2) < 0.001
  Adjusted OR (95% CI)§ 3.88 (1.57, 9.58) 2.35 (1.09, 5.07) 2.05 (0.89, 4.70) 1.00 (referent) 0.003
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NHANES denotes National Health and Nutrition Examination Survey.

*

According to age and sex.26,27

†

Adjusted for age, sex, race/ethnicity, poverty-to-income ratio, and physical activity.

‡

Defined as systolic or diastolic blood pressure ≥90th percentile for age, sex, and height,28 or medication use.

§

Adjusted for age, sex, race/ethnicity, poverty-to-income ratio, physical activity, and body mass index.

‖

Defined according to the method of Cook et al24,25

DISCUSSION

In this nationally representative population-based sample of US adolescents, low serum concentrations of vitamin D were significantly associated with obesity status, abdominal obesity, high blood pressure, fasting hyperglycemia, and metabolic syndrome. These results are consistent with the limited data in adult populations showing vitamin D levels are associated with major cardiometabolic risk factors. Associations with high blood pressure, fasting hyperglycemia, and metabolic syndrome were independent of several potential confounding factors, including adiposity, physical activity, and race/ethnicity. To the best of our knowledge, this is the first nationally representative study to examine the prevalence of cardiovascular risk factors according to different concentrations of vitamin D in youth.

Our results are consistent with previous studies which have suggested that low vitamin D levels in adulthood may influence the risk of developing hypertension,13,31 diabetes,14 and metabolic syndrome.32,33 Hypovitaminosis D has also been strongly associated with a higher frequency of myocardial infarction,15 cardiovascular disease,17 and related mortality.34 Few other studies have examined the relations between vitamin D and cardiovascular disease risk factors in youth. For example, in a small study of 127 overweight children and adolescents attending an endocrine clinic, Alemzadeh et al35 showed vitamin D levels were positively associated with insulin sensitivity and inversely correlated with HbA1c levels, suggesting a possible role for vitamin D in the pathogenesis of diabetes and cardiovascular disease originating in childhood. Future studies are necessary to determine the long-term consequences of vitamin D deficiency, including whether low vitamin D levels during childhood significantly predict the occurrence of type 2 diabetes and cardiovascular disease in adulthood.

The associations of vitamin D with high blood pressure, elevated fasting glucose, and metabolic syndrome were independent of overall obesity and abdominal adiposity. These findings are in agreement with the results of previous studies suggesting these associations cannot be completely accounted for by the low vitamin D levels of those with excess adiposity.12,33,36,37 Although increased parathyroid hormone levels secondary to vitamin D deficiency may increase intracellular calcium in adipocytes leading to increased lipogenesis and weight gain,38 the inverse association observed between serum vitamin D levels and adiposity is likely to be at least partly due to the sequestering of vitamin D within adipose tissue.39,40 In a small randomized, placebo-controlled trial of vitamin D supplementation up to 40,000 IU per week for 12 months, no change in body weight or other indicators of adiposity in adults aged 21–70 years was observed.41 Decreased skin exposure to UV-light as a result of clothing preferences and reduced outdoor activities may also contribute to the low vitamin D levels of adolescents with higher amounts of adiposity.

In the current study we observed an independent cross-sectional association between vitamin D, systolic blood pressure, and hypertension. Some,13,31 but not all,42 prospective observational studies of middle-aged men and women support an association between low vitamin D levels or dietary intake and incident hypertension. In addition, two small, short-term intervention studies, one which assigned patients with mild hypertension to receive UVB for 6 weeks43 and the other 800 IU/day of oral vitamin D for 8 weeks,44 resulted in significant reductions in blood pressure. There is increasing evidence that vitamin D may be a negative endocrine regulator of the renin-angiotensin system. The activated metabolite of 25(OH)D, 1,25-dihydroxyvitamin D [1, 25(OH)2D], has been shown to inhibit renin gene expression.45 Furthermore, vitamin D receptor null mice exhibit increased renin levels, systemic hypertension, and ultimately develop cardiac hypertrophy.46 In addition, the 1α-hydroxylase enzyme that converts 25(OH)D to 1,25(OH)2D is expressed in a variety of tissues, including human endothelial cells and vascular smooth muscle cells,47,48 which suggests another mechanism by which vitamin D may influence the systemic control of blood pressure.

In the current study, a doubling of the odds ratio for elevated fasting glucose was observed among adolescents in the first quartile of serum vitamin D compared with the fourth quartile, independent of adiposity. While the exact mechanisms linking vitamin D insufficiency with hyperglycemia and subsequent diabetes risk are not completely understood, there is accumulating evidence that vitamin D may directly influence pancreatic beta cell secretory function through their nuclear vitamin D receptors as well as influence insulin sensitivity through insulin receptor expression regulation of intracellular calcium.49 In animal models, the administration of high doses of 1,25(OH)2D has been shown to prevent the development of type 1 diabetes, primarily through immune regulation.50 Indirect mechanisms may include effects on inflammatory pathways and increased parathyroid hormone concentrations, secondary to vitamin D deficiency, which have been shown to be inversely associated with insulin sensitivity in healthy adults.51,52 The effects of vitamin D on insulin sensitivity may also explain, at least in part, the independent association with metabolic syndrome observed in the current study.53

This study had a number of strengths, including its nationally representative population-based sample of US adolescents, standardized data collection protocols, and rigorous quality control procedures. However, the cross-sectional nature of this study limits a causal inference among low vitamin D status and cardiometabolic risk factors. Future studies with a long-term longitudinal design are warranted to identify the temporal sequence among these variables. Additional limitations include the lack of information regarding residential geographic location, the season during which blood samples were obtained, and the measurement of parathyroid hormone levels. However, even if the results of the current study are due to secondary hyperparathyroidism, the appropriate treatment would include the repletion of vitamin D, which justifies our focus on vitamin D levels.

In conclusion, we found low vitamin D levels in US adolescents were strongly associated with several important risk factors for cardiovascular disease, including high blood pressure, fasting hyperglycemia, and metabolic syndrome, independent of adiposity and several other potential confounding factors. Additional research is necessary to determine whether low vitamin D status during childhood and adolescence may impact the subsequent development of cardiovascular disease during adulthood. Evidence from randomized clinical trials is required before vitamin D supplementation can be recommended in the primary prevention of metabolic cardiovascular risk factors in youth.

ACKNOWLEDGEMENTS

Dr. Reis was supported by a grant from the National Heart, Lung, and Blood Institute (T32 HL07024).

Glossary

25(OH)D

25-hydroxyvitamin D

NHANES

National Health and Nutrition Examination Survey

NCEP ATP III

National Cholesterol Education Program Adult Treatment III

1,25(OH)2D

1,25-dihydroxyvitamin D

Footnotes

No disclosures to report.

REFERENCES

  • 1.Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest. 2006;116(8):2062–2072. doi: 10.1172/JCI29449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Welch TR, Bergstrom WH, Tsang RC. Vitamin D-deficient rickets: the reemergence of a once-conquered disease. J Pediatr. 2000;137(2):143–145. doi: 10.1067/mpd.2000.109008. [DOI] [PubMed] [Google Scholar]
  • 3.Docio S, Riancho JA, Perez A, Olmos JM, Amado JA, Gonzalez-Macias J. Seasonal deficiency of vitamin D in children: a potential target for osteoporosis-preventing strategies? J Bone Miner Res. 1998;13(4):544–548. doi: 10.1359/jbmr.1998.13.4.544. [DOI] [PubMed] [Google Scholar]
  • 4.Harkness L, Cromer B. Low levels of 25-hydroxy vitamin D are associated with elevated parathyroid hormone in healthy adolescent females. Osteoporos Int. 2005;16(1):109–113. doi: 10.1007/s00198-004-1656-8. [DOI] [PubMed] [Google Scholar]
  • 5.Outila TA, Karkkainen MU, Lamberg-Allardt CJ. Vitamin D status affects serum parathyroid hormone concentrations during winter in female adolescents: associations with forearm bone mineral density. Am J Clin Nutr. 2001;74(2):206–210. doi: 10.1093/ajcn/74.2.206. [DOI] [PubMed] [Google Scholar]
  • 6.Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr. 2005;94(4):483–492. doi: 10.1079/bjn20051544. [DOI] [PubMed] [Google Scholar]
  • 7.Zerwekh JE. Blood biomarkers of vitamin D status. Am J Clin Nutr. 2008;87(4):1087S–1091S. doi: 10.1093/ajcn/87.4.1087S. [DOI] [PubMed] [Google Scholar]
  • 8.Cigolini M, Iagulli MP, Miconi V, Galiotto M, Lombardi S, Targher G. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2006;29(3):722–724. doi: 10.2337/diacare.29.03.06.dc05-2148. [DOI] [PubMed] [Google Scholar]
  • 9.Poole KE, Loveridge N, Barker PJ, et al. Reduced vitamin D in acute stroke. Stroke. 2006;37(1):243–245. doi: 10.1161/01.STR.0000195184.24297.c1. [DOI] [PubMed] [Google Scholar]
  • 10.Zittermann A, Schleithoff SS, Tenderich G, Berthold HK, Korfer R, Stehle P. Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol. 2003;41(1):105–112. doi: 10.1016/s0735-1097(02)02624-4. [DOI] [PubMed] [Google Scholar]
  • 11.Scragg R, Jackson R, Holdaway IM, Lim T, Beaglehole R. Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol. 1990;19(3):559–563. doi: 10.1093/ije/19.3.559. [DOI] [PubMed] [Google Scholar]
  • 12.Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care. 2005;28(5):1228–1230. doi: 10.2337/diacare.28.5.1228. [DOI] [PubMed] [Google Scholar]
  • 13.Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension. 2007;49(5):1063–1069. doi: 10.1161/HYPERTENSIONAHA.107.087288. [DOI] [PubMed] [Google Scholar]
  • 14.Knekt P, Laaksonen M, Mattila C, et al. Serum vitamin D and subsequent occurrence of type 2 diabetes. Epidemiology. 2008;19(5):666–671. doi: 10.1097/EDE.0b013e318176b8ad. [DOI] [PubMed] [Google Scholar]
  • 15.Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168(11):1174–1180. doi: 10.1001/archinte.168.11.1174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Reis JP, Michos ED, von Muhlen D, Miller ER., 3rd Differences in vitamin D status as a possible contributor to the racial disparity in peripheral arterial disease. Am J Clin Nutr. 2008;88(6):1469–1477. doi: 10.3945/ajcn.2008.26447. [DOI] [PubMed] [Google Scholar]
  • 17.Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D Deficiency and Risk of Cardiovascular Disease. Circulation. 2008 doi: 10.1161/CIRCULATIONAHA.107.706127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. A preliminary report from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Jama. 1990;264(23):3018–3024. doi: 10.1001/jama.1990.03450230054029. [DOI] [PubMed] [Google Scholar]
  • 19.Berenson GS, Srinivasan SR, Bao W, Newman WP, 3rd, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med. 1998;338(23):1650–1656. doi: 10.1056/NEJM199806043382302. [DOI] [PubMed] [Google Scholar]
  • 20.Klag MJ, Ford DE, Mead LA, et al. Serum cholesterol in young men and subsequent cardiovascular disease. N Engl J Med. 1993;328(5):313–318. doi: 10.1056/NEJM199302043280504. [DOI] [PubMed] [Google Scholar]
  • 21.Porkka KV, Viikari JS, Taimela S, Dahl M, Akerblom HK. Tracking and predictiveness of serum lipid and lipoprotein measurements in childhood: a 12-year follow-up. The Cardiovascular Risk in Young Finns study. Am J Epidemiol. 1994;140(12):1096–1110. doi: 10.1093/oxfordjournals.aje.a117210. [DOI] [PubMed] [Google Scholar]
  • 22.Ainsworth BE, Haskell WL, Whitt MC, et al. Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc. 2000;32(9 Suppl):S498–S504. doi: 10.1097/00005768-200009001-00009. [DOI] [PubMed] [Google Scholar]
  • 23.The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes. 1995;44(8):968–983. [PubMed] [Google Scholar]
  • 24.Cook S, Auinger P, Li C, Ford ES. Metabolic syndrome rates in United States adolescents, from the National Health and Nutrition Examination Survey, 1999–2002. J Pediatr. 2008;152(2):165–170. doi: 10.1016/j.jpeds.2007.06.004. [DOI] [PubMed] [Google Scholar]
  • 25.Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988–1994. Arch Pediatr Adolesc Med. 2003;157(8):821–827. doi: 10.1001/archpedi.157.8.821. [DOI] [PubMed] [Google Scholar]
  • 26.Fernandez JR, Redden DT, Pietrobelli A, Allison DB. Waist circumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents. J Pediatr. 2004;145(4):439–444. doi: 10.1016/j.jpeds.2004.06.044. [DOI] [PubMed] [Google Scholar]
  • 27.Li C, Ford ES, Mokdad AH, Cook S. Recent trends in waist circumference and waist-height ratio among US children and adolescents. Pediatrics. 2006;118(5):e1390–e1398. doi: 10.1542/peds.2006-1062. [DOI] [PubMed] [Google Scholar]
  • 28.The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114:555–576. (2 Suppl 4th Report) [PubMed] [Google Scholar]
  • 29.Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(Suppl 1):S5–S20. doi: 10.2337/diacare.26.2007.s5. [DOI] [PubMed] [Google Scholar]
  • 30.Kuczmarski RJ, Ogden CL, Guo SS, et al. CDC Growth Charts for the United States: Methods and Development. In: Statistics NCfH, editor. Vital Health Stat. 2002. [PubMed] [Google Scholar]
  • 31.Forman JP, Curhan GC, Taylor EN. Plasma 25-hydroxyvitamin d levels and risk of incident hypertension among young women. Hypertension. 2008;52(5):828–832. doi: 10.1161/HYPERTENSIONAHA.108.117630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2007;167(11):1159–1165. doi: 10.1001/archinte.167.11.1159. [DOI] [PubMed] [Google Scholar]
  • 33.Reis JP, von Muhlen D, Miller ER., 3rd Relation of 25-hydroxyvitamin D and parathyroid hormone levels with metabolic syndrome among US adults. Eur J Endocrinol. 2008;159(1):41–48. doi: 10.1530/EJE-08-0072. [DOI] [PubMed] [Google Scholar]
  • 34.Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168(12):1340–1349. doi: 10.1001/archinte.168.12.1340. [DOI] [PubMed] [Google Scholar]
  • 35.Alemzadeh R, Kichler J, Babar G, Calhoun M. Hypovitaminosis D in obese children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism. 2008;57(2):183–191. doi: 10.1016/j.metabol.2007.08.023. [DOI] [PubMed] [Google Scholar]
  • 36.Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care. 2004;27(12):2813–2818. doi: 10.2337/diacare.27.12.2813. [DOI] [PubMed] [Google Scholar]
  • 37.Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am J Hypertens. 2007;20(7):713–719. doi: 10.1016/j.amjhyper.2007.01.017. [DOI] [PubMed] [Google Scholar]
  • 38.McCarty MF, Thomas CA. PTH excess may promote weight gain by impeding catecholamine-induced lipolysis-implications for the impact of calcium, vitamin D, and alcohol on body weight. Med Hypotheses. 2003;61(5–6):535–542. doi: 10.1016/s0306-9877(03)00227-5. [DOI] [PubMed] [Google Scholar]
  • 39.Liel Y, Ulmer E, Shary J, Hollis BW, Bell NH. Low circulating vitamin D in obesity. Calcif Tissue Int. 1988;43(4):199–201. doi: 10.1007/BF02555135. [DOI] [PubMed] [Google Scholar]
  • 40.Reinehr T, de Sousa G, Alexy U, Kersting M, Andler W. Vitamin D status and parathyroid hormone in obese children before and after weight loss. Eur J Endocrinol. 2007;157(2):225–232. doi: 10.1530/EJE-07-0188. [DOI] [PubMed] [Google Scholar]
  • 41.Sneve M, Figenschau Y, Jorde R. Supplementation with cholecalciferol does not result in weight reduction in overweight and obese subjects. Eur J Endocrinol. 2008;159(6):675–684. doi: 10.1530/EJE-08-0339. [DOI] [PubMed] [Google Scholar]
  • 42.Forman JP, Bischoff-Ferrari HA, Willett WC, Stampfer MJ, Curhan GC. Vitamin D intake and risk of incident hypertension: results from three large prospective cohort studies. Hypertension. 2005;46(4):676–682. doi: 10.1161/01.HYP.0000182662.82666.37. [DOI] [PubMed] [Google Scholar]
  • 43.Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet. 1998;352(9129):709–710. doi: 10.1016/S0140-6736(05)60827-6. [DOI] [PubMed] [Google Scholar]
  • 44.Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab. 2001;86(4):1633–1637. doi: 10.1210/jcem.86.4.7393. [DOI] [PubMed] [Google Scholar]
  • 45.Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110(2):229–238. doi: 10.1172/JCI15219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Xiang W, Kong J, Chen S, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab. 2005;288(1):E125–E132. doi: 10.1152/ajpendo.00224.2004. [DOI] [PubMed] [Google Scholar]
  • 47.Merke J, Milde P, Lewicka S, et al. Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. J Clin Invest. 1989;83(6):1903–1915. doi: 10.1172/JCI114097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Somjen D, Weisman Y, Kohen F, et al. 25-hydroxyvitamin D3-1alpha-hydroxylase is expressed in human vascular smooth muscle cells and is upregulated by parathyroid hormone and estrogenic compounds. Circulation. 2005;111(13):1666–1671. doi: 10.1161/01.CIR.0000160353.27927.70. [DOI] [PubMed] [Google Scholar]
  • 49.Tai K, Need AG, Horowitz M, Chapman IM. Vitamin D, glucose, insulin, and insulin sensitivity. Nutrition. 2008;24(3):279–285. doi: 10.1016/j.nut.2007.11.006. [DOI] [PubMed] [Google Scholar]
  • 50.Mathieu C, Waer M, Laureys J, Rutgeerts O, Bouillon R. Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3. Diabetologia. 1994;37(6):552–558. doi: 10.1007/BF00403372. [DOI] [PubMed] [Google Scholar]
  • 51.Chiu KC, Chuang LM, Lee NP, et al. Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level. Metabolism. 2000;49(11):1501–1505. doi: 10.1053/meta.2000.17708. [DOI] [PubMed] [Google Scholar]
  • 52.Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? Qjm. 2002;95(12):787–796. doi: 10.1093/qjmed/95.12.787. [DOI] [PubMed] [Google Scholar]
  • 53.Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415–1428. doi: 10.1016/S0140-6736(05)66378-7. [DOI] [PubMed] [Google Scholar]

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