Abstract
Context:
Vitamin D binding protein (DBP) is an important determinant of bioavailable vitamin D (BAVD) and may provide clues to racial variation in osteoporosis and atherosclerosis.
Objective:
The objective was to assess relationships between DBP, BAVD, 25-hydroxyvitamin D (25OHD), and 1,25 di-hydroxyvitamin D (1,25OH2D) with kidney, bone, adipose, and atherosclerosis phenotypes in African Americans with type 2 diabetes.
Design:
Cross-sectional (N = 545) and longitudinal (N = 288; mean 5.1 ± 0.9-year follow-up) relationships between vitamin D concentrations with renal phenotypes, vertebral bone mineral density, aorto-iliac, coronary artery, and carotid artery calcified plaque (CP), and adipose tissue volumes were studied.
Setting:
African American-Diabetes Heart Study.
Patients:
Participants were 56.7% female with mean ± standard deviation (sd) age 55.6 ± 9.6 years, diabetes duration 10.3 ± 8.2 years, and eGFR 90.9 ± 22.1 ml/min/1.73 m2.
Interventions:
None.
Main Outcomes and Measures:
Associations tested between vitamin D and the previously mentioned phenotypes adjusting for age, sex, African ancestry proportion, diabetes duration, statins, smoking, changes in estimated glomerular filtration rate, body mass index, hemoglobin A1c, and blood pressure.
Results:
1,25OH2D was inversely associated with change in coronary artery CP (parameter estimate [β] −0.005, standard error [SE] 0.002; P = .037), with a trend for change in carotid artery CP (β −0.007, SE 0.004; P = .074). Further adjustment for renin-aldosterone-system blockade revealed inverse association between 1,25OH2D and change in albuminuria (β −0.004, SE 0.002; P = .037). DBP, BAVD, and 25OHD did not associate significantly with changes in albuminuria, CP, or bone mineral density. BAVD was inversely associated with visceral, subcutaneous, intermuscular, and pericardial adipose volumes.
Conclusions:
In contrast to BAVD and 25OHD, only 1,25OH2D levels were significantly and inversely associated with changes in subclinical atherosclerosis and albuminuria in African Americans, suggesting potential beneficial effects.
Inverse associations are observed between bone mineral density (BMD) and susceptibility to cardiovascular disease (CVD) in many racial and ethnic groups (1–11). In contrast, circulating 25-hydroxyvitamin D (25OHD) concentrations and relationships between 25OHD with bone and subclinical CVD outcomes differ markedly between individuals with recent African and European ancestry (12–14). In African Americans, higher 1,25 di-hydroxyvitamin D (1,25OH2D) levels are paradoxically associated with lower BMD (15). In addition, 25OHD supplementation resulted in greater susceptibility to hip fractures in African American women with osteopenia, opposing results in European American women (16). Despite more severe conventional CVD risk factors, African Americans have markedly lower levels of calcified atherosclerotic plaque (CP) than European Americans and 25OHD concentrations are positively associated with CP in African Americans (15, 17–24). CP is a marker for presence of subclinical CVD. Consistent with racial differences in subclinical CVD, significantly lower rates of myocardial infarction are observed in African Americans compared to European Americans, provided they have equivalent access to health care (25–27).
Powe et al recently demonstrated substantial differences in vitamin D binding protein (DBP) concentrations between European Americans and African Americans, an effect related to ancestrally variable frequencies of two common variants in the DBP gene (28). With genetically mediated differential susceptibility to osteoporosis (bone mineralization) and subclinical atherosclerosis in populations with vs without recent African ancestry and marked differences in concentrations of 25OHD and 1,25OH2D, discovery of DBP led to the recognition that similar concentrations of bioavailable vitamin D (BAVD) were present between races. However, active 1,25OH2D concentrations are significantly higher in African Americans relative to European Americans. Vitamin D is lipid soluble and its concentrations are impacted by adipose tissue volumes and kidney function. The present analyses are the first to test for cross-sectional relationships between visceral, subcutaneous, intermuscular, and pericardial adipose tissue volumes with BAVD in African Americans. Because racial differences in susceptibility to BMD and CP are present and in part genetically mediated, 25OHD, 1,25OH2D, and BAVD concentrations were also analyzed for association with baseline and 5-year change in bone, atherosclerosis, and renal phenotypes in the understudied African American population, specifically African American-Diabetes Heart Study (AA-DHS) participants.
Materials and Methods
Participants
As previously reported, AA-DHS participants are self-identified African Americans with clinically diagnosed type 2 diabetes mellitus (T2D) actively treated with oral hypoglycemic medications and/or insulin (29). Participants have relatively preserved kidney function because they were not recruited if they had prior serum creatinine concentrations > 2.0 mg/dL or end-stage kidney disease. In addition to a medical screening including questionnaires on health status, medications, diet, and physical activity; blood pressure (BP), height, weight, waist and hip circumference, and body mass index (BMI) were measured and an electrocardiogram and fasting laboratory work performed. Laboratory work included assays of glycemic (hemoglobin A1c; HbA1c) and lipid control, electrolytes, 25OHD, 1,25OH2D, intact parathyroid hormone, kidney function, urine albumin:creatinine ratio (UACR), and high sensitivity C-reactive protein. Estimated glomerular filtration rate (eGFR) was computed using the Chronic Kidney Disease Epidemiology Collaboration equation (30). Three hundred AA-DHS participants (150 males, 150 females) returned for a second AA-DHS longitudinal visit; of these, 288 had baseline measures of DBP and BAVD and were included in this longitudinal analysis.
Computed tomography
Computed tomography (CT) scans of the neck, chest, and abdomen were performed to measure CP, volumetric BMD (vBMD) in the thoracic and lumbar vertebrae and visceral, subcutaneous, intermuscular, and pericardial adipose tissue volumes. CP in the coronary arteries (CAC), carotid arteries, and abdominal aortoiliac bed was determined using four- or 16-channel multidetector CT (LightSpeed Qxi and 16 Pro, GE Healthcare, Waukesha, WI, USA) (10, 24, 31). Participants were placed in the supine position on the CT couch over a calibration phantom with verified concentrations of calcium hydroxyl apatite (Image Analysis, Inc., Columbia, KY, USA) for scans of the thorax and abdomen. Unenhanced coronary imaging was performed with electrocardiogram gating in late diastole (75% of the RR interval). Series through the neck for the carotid bifurcation and abdomen for the aortoiliac arteries were performed without electrocardiogram gating using the helical scan mode. CT scans of the coronary, carotid, and aortoiliac vascular territories were analyzed on a GE Advantage Windows Workstation with the SmartScores software package (GE Healthcare) using a modified Agatston scoring method that adjusts for slice thickness and uses the conventional threshold of 130 Hounsfield units (HUs) as well as a calcium mass score using a 90 HU threshold. The calcium mass score was employed to yield stable measures of CP across the three vascular beds and for consistency with vBMD. The CAC mass score was the sum of CP in epicardial coronary arteries (left main, anterior descending, circumflex, right, and posterior descending). The carotid CP mass score was the sum of plaque in the common and internal carotid arteries. The aortoiliac CP mass was the sum of CP present in the abdominal aorta below the renal arteries and in the right and left common iliac arteries.
Quantitative CT for trabecular vBMD (in mg/cm3) in the thoracic spine (T8-T11) and lumbar spine (T12-L3) were measured using quantitative CT 5000 volumetric software and a calcium calibration phantom included in each participant's chest and abdominal CT examination (Image Analysis) (29). Coefficients of variation for these measures were < 1% for thoracic and lumbar vBMD and in sequential studies performed in the same individual the precision error was 2.3%.
Pericardial, visceral, subcutaneous, and intermuscular adipose tissue volumes were measured from volumetric CT acquisitions to reduce variability related to slice location using the Volume Analysis software (Advantage Windows Workstation, GE Healthcare) and a threshold of −190 to −30 Hounsfield units as the definitions of fat-containing tissue, as reported (29).
Vitamin D, vitamin D binding protein, and bioavailable vitamin D
Measures of 25-OHD were performed by Quest Diagnostics Nichols Institute (San Juan Capistrano, CA) (15) and LabCorp using liquid chromatography and mass spectrometry and an immunochemiluminometric assay performed on the DiaSorin LIASON® instrument, respectively, with a high paired sample concordance (n = 14, r2 = 0.92). This automated test measures both vitamin D2 and D3 simultaneously and reports total 25OHD. Major clinical studies, including the Centers for Disease Control, National Health and Nutrition Examination Survey database, and the Women's Health Initiative employed DiaSorin reagents. Measures of 1,25OH2D were performed at Quest (15) or LabCorp® (Burlington, NC) using liquid chromatography mass spectrometry and column chromatography, radioimmunoassay, respectively. Intact parathyroid hormone was measured at LabCorp using an electrochemiluminescence immunoassay.
DBP was measured in ethylenediaminetetraacetate plasma samples that had been continuously stored at −80°C without thawing since collection at the baseline visit. Frozen plasma was thawed in a 37°C water bath for 15 minutes, placed on ice, and then centrifuged at 1700 × g (2800 rpm) for 30 minutes at 4°C. VBDP was determined using a Quantikine® Human Vitamin D BP enzyme-linked immunosorbent assay (catalog number DDBP0; R&D Systems; Minneapolis, MN) according to the manufacturer's instructions. Serum was prediluted 1:2000 or greater in some cases in calibrator diluent before assay. Intra-assay and interassay coefficients of variation were < 10%. All assays were performed using a single lot of reagents and calibrators at Wake Forest School of Medicine. BAVD was computed as described by Powe et al (28) using dissociation constants for the DBP genotype variants as described by Arnaud and Constans (32).
Statistical analyses
Descriptive statistics, including means and standard deviations (sd) and medians for continuous measures and frequencies and proportions for categorical variables, were generated for all reported study measures. Gender differences were tested by independent t tests (continuous variables) and Fisher's exact test (categorical measures). Generalized linear models were fitted to test for associations between BAVD and measures of adipose tissue volume (visceral, pericardial, subcutaneous, intermuscular), parameters of kidney disease (eGFR, UACR), thoracic vertebral and lumbar vertebral vBMD, CAC, carotid artery CP, and aortoiliac CP, and between BAVD and the change in the CP measurements. The Box-Cox method was applied to identify the appropriate transformation best approximating the distributional assumptions of conditional normality and homogeneity of variance of the residuals (33). This method suggested taking the natural logarithm of (CAC+1), (carotid artery CP+1), (aortoiliac CP+1), and (UACR+1) and the square root of lumbar and thoracic vertebral vBMD. For cross-sectional models of adipose tissue volume, an initial unadjusted model was fitted, followed by models adjusting for age, sex, duration of T2D, HbA1c, African ancestry proportion, and BMI. For CP, an initial unadjusted model was followed by models adding adjustments for age, sex, BMI, duration of T2D, smoking, African ancestry proportion, HbA1c, systolic BP, statin use, calcium supplements, CVD, and eGFR. For eGFR, after the initial unadjusted model, covariates included age, sex, BMI, duration of T2D, smoking, African ancestry proportion, HbA1c, systolic BP, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) medications. For UACR, the fully adjusted model also included eGFR. For vBMD, an unadjusted model was followed by a full model adjusting for age, sex, BMI, duration of T2D, African ancestry proportion, HbA1c, systolic BP, smoking, use of hormone replacement therapy, steroids, bisphosphonates, calcium supplements, and eGFR. Before modeling the data, the extremely high values of CAC, carotid artery CP, and aortoiliac CP were winsorized at their observed mean plus 2 sd, respectively. In addition, 52 participants who had undergone coronary artery angioplasty, stent placement, or bypass grafting before the initial visit were removed from cross-sectional analyses for CAC (and analyses assessing change in CAC). To assess longitudinal change in the 288 participants who completed second study visits, models were initially constructed with change in each outcome serving as the dependent variable and time between readings as the predictor; then, a second model adding the level of the predictor observed at the baseline value was fitted. The final model included time between visits, the baseline value, and all the covariates included in the fully adjusted models described previously. In addition, 17 other subjects who had undergone coronary artery angioplasty, stent placement, or bypass grafting between the first and second study visits were excluded from analyses assessing change in CAC. Two laboratories were used to measure 25OHD and 1,25OH2D levels at the baseline visit. To account for potential between laboratory differences, stratified analyses were run for these vitamin D variables by laboratory and the estimates combined using an inverse variance weighted meta-analysis method.
Results
Table 1 displays baseline demographic characteristics of the 545 AA-DHS participants comprising the study sample, stratified by sex. These individuals typically developed T2D in their mid-40s and had slightly greater than 10-year mean diabetes durations, with moderately elevated BMI (females > males), relatively well-controlled BP, and frequent receipt of statins, suggesting reasonable access to medical care. Table 2 displays initial laboratory and imaging results by sex. Although mean HbA1c values were slightly above 8%, the cohort had generally preserved kidney function (mean [sd] eGFR 90.9 [22.1] ml/min/1.73 m2) with a median UACR of 13 mg/g. Mean concentrations of 25 OHD and 1,25OH2D did not differ by sex; however, DBP levels were significantly lower in females without significant differences in BAVD or free vitamin D concentrations. Table 3 displays laboratory and imaging results in 288 AA-DHS longitudinal participants after a mean (sd) 5.1 (0.9) year follow-up.
Table 1.
Demographic Characteristics of AA-DHS Sample at Visit 1
| Variable | Male (n = 236) | Female (n = 309) | All (n = 545) | P Value |
|---|---|---|---|---|
| Age (years) | 56.0 (9.8) | 55.4 (9.5) | 55.6 (9.6) | .46 |
| Age at diabetes onset (years) | 45.5 (10.9) | 45.2 (10.2) | 45.3 (10.5) | .70 |
| Diabetes duration (years) | 10.5 (8.7) | 10.2 (7.8) | 10.3 (8.2) | .71 |
| BMI (kg/m2) | 32.5 (7.4) | 37.4 (8.9) | 35.3 (8.6) | <.0001 |
| Systolic BP (mm Hg) | 132 (18) | 134 (20) | 133 (19) | .36 |
| Diastolic BP (mm Hg) | 79 (11) | 77 (11) | 78 (11) | .017 |
| Hypertension (%) | 52.1 | 50.8 | 51.4 | .76 |
| Lipid medications (%) | 50.4 | 50.5 | 50.5 | .99 |
| Smokers, current/past (%) | 68.3 | 51.0 | 58.5 | .0003 |
| Insulin use (%) | 40.7 | 39.2 | 39.8 | .72 |
| Hormone replacement therapy (%) | NA | 25.7 | NA | NA |
Table 2.
Laboratory and Imaging Results of AA-DHS Sample at Visit 1
| Variable | Male (n = 236) | Female (n = 309) | All (n = 545) | P Value |
|---|---|---|---|---|
| Glucose (mg/dL) | 158 (72) | 145 (62) | 150 (66) | .028 |
| HbA1c (%) | 8.24 (1.95) | 8.02 (2.01) | 8.1 (2.0) | .20 |
| BUN (mg/dL) | 16.2 (15.5) | 14.6 (5.7) | 15.3 (11.1) | .13 |
| Serum creatinine (mg/dL) | 1.09 (0.28) | 0.88 (0.26) | 0.97 (0.28) | <.0001 |
| CKD-EPI eGFR (ml/min/1.73 m2) | 92.0 (20.3) | 90.1 (23.5) | 90.9 (22.1) | .31 |
| UACR (mg/g) | 130 (451) | 168 (675) | 151 (588) | .43 |
| Median UACR (mg/g) | 18.5 | 10.8 | 13 | |
| C-reactive protein (mg/dL) | 0.70 (1.06) | 1.32 (2.13) | 1.04 (1.77) | <.0001 |
| LDL-cholesterol (mg/dL) | 105 (38) | 111 (37) | 108 (38) | .06 |
| HDL-cholesterol (mg/dL) | 44.6 (11.9) | 50.2 (14.1) | 47.8 (13.4) | <.0001 |
| Triglycerides (mg/dL) | 139 (165) | 124 (98) | 130 (131) | .23 |
| Vitamin D binding protein (μg/mL) | 90.1 (77.9) | 75.7 (61.1) | 81.9 (69.2) | .02 |
| Bioavailable vitamin D (ng/mL) | 5.8 (4.3) | 6.3 (4.6) | 6.1 (4.5) | .22 |
| Free vitamin D (pg/mL) | 15.9 (11.9) | 17.7 (13.2) | 16.9 (12.7) | .11 |
| 25-hydroxyvitamin D (ng/mL) | 19.8 (10.3) | 20.8 (12.5) | 20.4 (11.6) | .28 |
| 1,25 dihydroxyvitamin D (pg/mL) | 45.5 (17.0) | 47.1 (18.7) | 46.4 (18.0) | .29 |
| Intact parathyroid hormone (pg/mL) | 49.9 (25.8) | 58.4 (32.0) | 54.7 (29.8) | .001 |
| Calcium (mg/dL) | 9.5 (0.4) | 9.6 (0.4) | 9.5 (0.4) | .007 |
| Phosphorus (mg/dL) | 3.4 (0.6) | 3.7 (0.5) | 3.6 (0.6) | <.0001 |
| Lumbar vBMD (mg/cm3) | 178 (43) | 179 (49) | 179 (46) | .73 |
| Thoracic vBMD (mg/cm3) | 201 (48) | 207 (55) | 204 (52) | 0.15 |
| Pericardial adipose (cm3/45 mm) | 94.5 (46.7) | 85.3 (33.7) | 89.4 (40.0) | .009 |
| Visceral adipose (cm3/15 mm) | 180 (85) | 177 (66) | 178 (74) | .65 |
| Intermuscular adipose (cm3/15 mm) | 8.9 (6.3) | 12.0 (9.1) | 10.7 (8.1) | <.0001 |
| Subcutaneous adipose (cm3/15 mm) | 342 (159) | 512 (169) | 439 (185) | <.0001 |
| Carotid artery CP mass (mg Ca2+) | 221 (633) | 126 (347) | 167 (492) | .039 |
| Coronary artery CP mass (mg Ca2+)a | 659 (1348) | 447 (1379) | 535 (1369) | .093 |
| Aorto-iliac CP mass (mg Ca2+) | 5999 (11 321) | 5123 (9241) | 5498 (10 183) | .34 |
Abbreviations: BUN, blood urea nitrogen; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Excluding 52 participants with prior coronary artery procedures.
Table 3.
Follow-up Laboratory and Imaging Results of AA-DHS Sample After Mean 5.1 Years
| Variable | Male (n = 140) | Female (n = 148) | All (n = 288) | P Value |
|---|---|---|---|---|
| Glucose (mg/dL) | 153 (58) | 149 (59) | 151 (59) | .62 |
| HbA1c (%) | 8.02 (1.78) | 8.16 (1.83) | 8.1 (1.8) | .54 |
| BUN (mg/dL) | 16.9 (7.8) | 16.5 (7.2) | 16.7 (7.5) | .69 |
| Serum creatinine (mg/dL) | 1.19 (0.43) | 0.92 (0.34) | 1.05 (0.41) | <.0001 |
| CKD-EPI eGFR (ml/min/1.73 m2) | 83.4 (22.2) | 84.8 (24.1) | 84.1 (23.2) | .60 |
| UACR (mg/g) | 183 (502) | 190 (637) | 187 (574) | .92 |
| Median UACR (mg/g) | 13.6 | 11.5 | 13 | |
| C-reactive protein (mg/dL) | 0.73 (0.98) | 1.25 (1.67) | 1.00 (1.40) | .002 |
| 25-hydroxyvitamin D (ng/dL) | 21.5 (12.2) | 25.2 (12.0) | 23.4 (12.0) | .011 |
| 1,25 dihydroxyvitamin D (pg/mL) | 54.6 (26.0) | 59.3 (25.2) | 57.0 (25.7) | .12 |
| Intact parathyroid hormone (pg/mL) | 49.3 (27.3) | 53.1 (28.9) | 51.3 (28.2) | .25 |
| Calcium (mg/dL) | 9.5 (0.4) | 9.6 (0.5) | 9.5 (0.5) | .027 |
| Phosphorus (mg/dL) | 3.5 (0.5) | 3.6 (0.5) | 3.6 (0.5) | .029 |
| Lumbar vBMD (mg/cm3) | 165 (42) | 168 (48) | 166 (45) | .65 |
| Thoracic vBMD (mg/cm3) | 179 (47) | 194 (49) | 187 (48) | .009 |
| Carotid artery CP mass (mg Ca2+) | 299 (602) | 216 (468) | 257 (538) | .19 |
| Coronary artery CP mass (mg Ca2+)a | 1488 (2688) | 1100 (2517) | 1288 (2604) | .21 |
| Aorto-iliac CP mass (mg Ca2+) | 8246 (13 698) | 7509 (11 188) | 7867 (12 454) | .62 |
Abbreviations: BUN, blood urea nitrogen; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.
Excluding 17 participants with coronary artery procedures between baseline and follow-up visit
Relationships between BAVD with adipose tissue volumes are displayed in Supplemental Table 1. Significant inverse associations were observed between BAVD and visceral, pericardial, subcutaneous, and intermuscular adipose tissue volumes in models that adjusted for age, sex, T2D duration, HbA1c, and African ancestry proportion. With further adjustment for BMI, significant inverse relationships persisted with visceral and intermuscular adipose tissue volumes (P = .022 and P = .015, respectively; data not shown).
Cross-sectional associations between baseline BAVD, DBP, 25OHD, and 1,25OH2D with subclinical atherosclerosis assessed as calcified atherosclerotic plaque, kidney function, albuminuria, and BMD are displayed in Table 4. BAVD was positively associated with carotid artery CP and aorto-iliac CP, and negatively associated with thoracic vertebral vBMD, lumbar vertebral vBMD, and eGFR in unadjusted models; however, statistical significance was lost after adjustment for relevant covariates (Supplemental Table 2 shows sequential models). A trend toward positive association was seen between 25OHD and carotid artery CP in the fully adjusted model, P = .061. Significant inverse associations were also detected between both 25OHD and BAVD with albuminuria in unadjusted and fully adjusted models. As expected, significant associations were observed between eGFR and 1,25OH2D in all models because the kidneys convert 25OHD to active 1,25OH2D.
Table 4.
Cross-sectional Relationships Between Vitamin D Concentrations With Subclinical Cardiovascular, Bone, and Renal Phenotypes
| Outcome | Adjustment | 25OHD |
1,25OH2D |
DBP |
BAVD |
||||
|---|---|---|---|---|---|---|---|---|---|
| Estimate (se) | P Value | Estimate (se) | P Value | Estimate (se) | P Value | Estimate (se) | P Value | ||
| Coronary artery CP | None | 0.020 (0.011) | .062 | −0.010 (0.007) | .167 | −0.001 (0.002) | .699 | 0.039 (0.028) | .171 |
| Age, sex, BMI, DM duration, smoking, African ancestry, HbA1c, SBP, statins, Ca supplements, eGFR, CVD | <0.001 (0.010) | .928 | −0.004 (0.007) | .593 | −0.001 (0.002) | .495 | 0.011 (0.026) | .668 | |
| Effect size per 0.25 sd change | 0.9 | −31.5 | −36.1 | 22.8 | |||||
| Carotid artery CP | None | 0.033 (0.009) | .0003 | −0.006 (0.006) | .347 | 0.001 (0.002) | .533 | 0.068 (0.024) | .005 |
| Age, sex, BMI, DM duration, smoking, African ancestry, HbA1c, SBP, statins, Ca supplements, eGFR, CVD | 0.017 (0.009) | .061 | 0.003 (0.006) | .639 | 0.001 (0.001) | .351 | 0.037 (0.022) | .102 | |
| Effect size per 0.25 sd change | 14.7 | 0.8 | 6.2 | 10.7 | |||||
| Aorto-iliac CP | None | 0.043 (0.013) | .001 | −0.004 (0.009) | .626 | −0.002 (0.002) | .348 | 0.105 (0.033) | .002 |
| Age, sex, BMI, DM duration, smoking, African ancestry, HbA1c, SBP, statins, Ca supplements, eGFR, CVD | 0.012 (0.011) | .220 | 0.003 (0.007) | .708 | −0.002 (0.002) | .308 | 0.049 (0.027) | .073 | |
| Effect size per 0.25 sd change | 5250 | 1698 | −3529 | 6050 | |||||
| Thoracic vertebral vBMD | None | −0.016 (0.007) | .014 | −0.003 (0.004) | .569 | −0.001 (0.001) | .340 | −0.041 (0.017) | .019 |
| Age, sex, BMI, DM duration, smoking, African ancestry, HbA1c, HRT, steroids, bisphos, Ca supplements, eGFR | −0.003 (0.004) | .513 | −0.002 (0.004) | .694 | −0.001 (0.001) | .393 | −0.004 (0.017) | .826 | |
| Effect size per 0.25 sd change | 0.08 | −0.20 | −0.46 | −0.10 | |||||
| Lumbar vertebral vBMD | None | −0.021 (0.006) | .001 | −0.004 (0.004) | .351 | −0.001 (0.001) | .438 | −0.048 (0.017) | .004 |
| Age, sex, BMI, DM duration, smoking, African ancestry, HbA1c, HRT, steroids, bisphos, Ca supplements, eGFR | <0.001 (0.006) | .929 | −0.003 (0.004) | .491 | −0.001 (0.001) | .313 | −0.005 (0.015) | .740 | |
| Effect size per 0.25 sd change | −0.03 | −0.27 | −0.46 | −0.15 | |||||
| eGFR | None | −0.229 (0.082) | .005 | 0.230 (0.053) | <.0001 | 0.006 (0.014) | .609 | −0.496 (0.210) | .018 |
| Age, sex, BMI, DM duration, smoking, African ancestry, HbA1c, SBP, ACEi/ARBs | −0.061 (0.080) | .448 | 0.256 (0.049) | <.0001 | −0.002 (0.013) | .850 | −0.161 (0.202) | .425 | |
| Effect size per 0.25 sd change | −0.4 | 4.7 | −0.2 | −0.7 | |||||
| UACR | None | −0.027 (0.006) | <.0001 | −0.007 (0.004) | .073 | <0.001 (0.001) | .973 | −0.050 (0.017) | .003 |
| Age, sex, BMI, DM duration, smoking, African ancestry, HbA1c, SBP, ACEi/ARBs, eGFR | −0.020 (0.006) | .002 | −0.006 (0.004) | .137 | −0.001 (0.001) | .644 | −0.032 (0.016) | .049 | |
| Effect size per 0.25 sd change | −5.0 | −1.9 | −0.8 | −3.3 | |||||
Abbreviations: bisphos, bisphosphonates; DM, diabetes mellitus; SBP, systolic blood pressure. Bold numbers indicate P value < .05.
Associations among baseline 25OHD, 1,25OH2D, DBP, and BAVD concentrations were assessed with longitudinal change in CP, eGFR, albuminuria, and BMD in 288 AA-DHS participants after mean (sd) 5.1 (0.9) year follow-up (Table 5 shows unadjusted and fully adjusted models; Supplemental Table S3 shows sequential models). In the fully adjusted models, 25OHD, DBP, and BAVD concentrations were not significantly associated with change in subclinical atherosclerosis, bone mineralization, albuminuria, or kidney function. In contrast, a borderline significant inverse association was detected between 1,25OH2D with change in coronary artery CP after adjustment for initial coronary artery CP score, time between scans, age, sex, BMI, smoking, statins, change in eGFR, HbA1c, BMI, CVD, and systolic BP (β [SE] −0.005[0.002], P = .054); a significant effect was observed with carotid artery CP (β [SE] −0.008[0.004], P = .043) (Supplemental Table 3). Further adjustment for African ancestry proportion reduced the association P value for 1,25OH2D with coronary artery CP (P = .037), but increased it for carotid artery CP (P = .074) (Supplemental Table 3 and Table 5). Significant association was also detected between 1,25OH2D with longitudinal change in albuminuria after full adjustment, including for renin-aldosterone-system blockade. Change in vBMD was not significantly associated with vitamin D concentrations. Adjustment for seasonality was performed in all models where fully adjusted P values for vitamin D and its metabolites were < 0.10. Season was not a significant predictor of outcomes, nor did it change the interpretation of any result (data not shown).
Table 5.
Longitudinal Relationships Between Vitamin D Concentrations With Subclinical Cardiovascular, Bone, and Renal Phenotypes
| Outcome | Adjustment | 25OHD |
1,25OH2D |
DBP |
BAVD |
||||
|---|---|---|---|---|---|---|---|---|---|
| Estimate (se) | P Value | Estimate (se) | P Value | Estimate (se) | P Value | Estimate (se) | P Value | ||
| Δ Coronary artery CP | Time between measures | 0.002 (0.003) | .508 | −0.005 (0.002) | .028 | −0.0001 (0.001) | .559 | 0.006 (0.010) | .570 |
| Log (initial CP score), age, sex, DM duration, statins, smoking; Δ in eGFR, BMI, HbA1c and SBP,CVD, African ancestry | 0.003 (0.003) | .365 | −0.005 (0.002) | .037 | −0.001 (0.001) | .320 | 0.008 (0.010) | .425 | |
| Change per 0.25 sd | 0.02 | −0.05 | −0.03 | 0.02 | |||||
| Δ Carotid artery CP | Time between measures | −0.007 (0.005) | .212 | −0.007 (0.004) | .083 | 0.0001 (0.001) | .823 | −0.025 (0.016) | .115 |
| Log (initial CP score), age, sex, DM duration, statins, smoking; Δ in eGFR, BMI, HbA1c and SBP, CVD, African ancestry | −0.007 (0.006) | .205 | −0.007 (0.004) | .074 | 0.0004 (0.001) | .745 | −0.027 (0.017) | .115 | |
| Change per 0.25 sd | −0.11 | −0.17 | 0.03 | −0.16 | |||||
| Δ Aorto-iliac CP | Time between measures | −0.024 (0.007) | .002 | −0.001 (0.005) | .794 | 0.002 (0.001) | .238 | −0.070 (0.022) | .001 |
| Log (initial CP score), age, sex, DM duration, statins, smoking; Δ in eGFR, BMI, HbA1c, and SBP, CVD, African ancestry | −0.008 (0.004) | .075 | −0.0003 (0.003) | .919 | −0.0002 (0.001) | .812 | −0.019 (0.012) | .136 | |
| Change per 0.25 sd | −0.42 | −0.03 | −0.07 | −0.40 | |||||
| Δ Thoracic vertebral vBMD | Time between measures | 0.113 (0.110) | .303 | −0.014 (0.077) | .850 | −0.019 (0.021) | .374 | 0.388 (0.319) | .225 |
| Initial T-BMD score, age, sex, DM duration, HRT, steroids, bisphos, Ca supplement, smoking, Δ in eGFR, BMI, and HbA1c, African ancestry | 0.066 (0.111) | .549 | −0.028 (0.075) | .708 | −0.033 (0.021) | .116 | 0.303 (0.310) | .329 | |
| Change per 0.25 sd | 0.76 | −0.51 | −2.3 | 1.4 | |||||
| Δ Lumbar vertebral vBMD | Time between measures | 0.023 (0.078) | .765 | −0.079 (0.053) | .140 | −0.028 (0.014) | .052 | 0.111 (0.224) | .620 |
| Initial l-BMD score, age, sex, DM duration, HRT, steroids, bisphos, Ca supplement, smoking, Δ in eGFR, BMI, and HbA1c, African ancestry | −0.004 (0.085) | .966 | −0.066 (0.056) | .237 | −0.031 (0.016) | .051 | 0.028 (0.234) | .907 | |
| Change per 0.25 sd | −0.04 | −1.2 | −2.1 | 0.12 | |||||
| Δ eGFR | Time between measures | 0.112 (0.086) | .155 | −0.090 (0.059) | .128 | −0.012 (0.016) | .474 | 0.383 (0.248) | .125 |
| Initial eGFR, age, sex, DM duration, statins, ACEi/ARB, smoking; Δ in BMI, HbA1c, and SBP, African ancestry | 0.032 (0.079) | .686 | −0.013 (0.056) | .813 | −0.024 (0.015) | .115 | 0.140 (0.228) | .541 | |
| Change per 0.25 sd | 0.37 | −0.24 | −1.7 | 0.63 | |||||
| Δ UACR | Time between measures | 0.002 (0.003) | .472 | −0.004 (0.002) | .025 | 0.0002 (0.000) | .628 | 0.004 (0.007) | .549 |
| Log (initial UACR + 1), age, sex, DM duration, statins, ACEi/ARB, smoking, Δ in BMI, HbA1c, eGFR, and SBP, African ancestry | 0.001 (0.002) | .712 | −0.004 (0.002) | .037 | 0.0004 (0.001) | .444 | −0.002 (0.008) | .831 | |
| Change per 0.25 sd | 13.3 | −81.0 | 32.0 | −8.6 | |||||
Abbreviations: bisphos, bisphosphonates; Ca, calcium; DM, diabetes mellitus; SBP, systolic blood pressure; T-BMD, thoracic vertebral bone mineral density; L-BMD, lumbar vertebral bone mineral density.
Discussion
The AA-DHS longitudinal cohort results constitute the first analysis of cross-sectional and longitudinal relationships among plasma 25OHD, 1,25OH2D, DBP, and BAVD with subclinical cardiovascular, bone, kidney, and adipose tissue phenotypes in African Americans. These analyses are likely to improve our understanding of race-specific variations in vitamin D metabolism (12, 16, 34). Despite genetically mediated differences in DBP between African Americans and European Americans, a finding that results in similar plasma BAVD concentrations in both groups (28), DBP and BAVD were not significantly associated with subclinical CVD measured as CP or BMD in cross-sectional analyses in this carefully phenotyped cohort of African Americans with T2D. BAVD and 25OHD concentrations were significantly and inversely associated with albuminuria in a cross-sectional analysis; 25OHD trended toward positive association with carotid artery CP (P = .061). In longitudinal analyses, only baseline 1,25OH2D concentrations were significantly and inversely associated with change in CAC (P = .037) and with albuminuria (P = .037), with a statistical trend for change in carotid artery CP (P = .074). These results extend our initial report of cross-sectional relationships among 25OHD, 1,25OH2D, and PTH with CP and BMD in AA-DHS; in that report, 25OHD was also associated with carotid artery CP in cross-sectional analyses (15). This is the first report we are aware of with extensive baseline vitamin D phenotype data and BMD and subclinical CVD phenotypes at two time points in a relatively large number of African Americans with T2D.
Considering the effects of DBP, lower plasma 25OHD concentrations in individuals who are of recent African (relative to European) ancestry relate predominantly to biologic (genetically mediated) differences in DBP concentrations and not solely from reduced vitamin D production because of darker skin pigmentation or reduced dietary intake of calcium and vitamin D–containing foods (28, 35). African Americans and European Americans have fairly equivalent BAVD concentrations (28). Detailed AA-DHS phenotypes provided the ability to simultaneously assess relationships among 25OHD, 1,25OH2D, and BAVD with BMD and subclinical CVD. The inverse relationships between BAVD and all adipose tissue volumes, especially visceral and intermuscular adipose, are likely related to the lipophilic nature of vitamin D (15, 36, 37). The negative cross-sectional association between BAVD and 25OHD with albuminuria in this African American cohort with preserved kidney function is novel. Albuminuria, known to be a marker for generalized endothelial dysfunction, is associated with subclinical CVD (increased levels of vascular CP) in this and other studies (38, 39). However, cross-sectional relationships do not prove causation. Longitudinal follow-up in the AA-DHS for the first time demonstrates that active vitamin D or 1,25OH2D is associated with atherosclerosis and albuminuria. In this report of African Americans with T2D, 25OHD, DBP, and BAVD did not associate with change in BMD, CP, or renal parameters after a 5-year follow-up.
Initial AA-DHS visits were conducted between September 2007 and August 2010; second visits were performed between August 2012 and June 2014. Participants received copies of clinical laboratory results (electrolytes, kidney function, albuminuria, fasting blood glucose, HbA1c, lipid profiles, 25OHD, intact parathyroid hormone, 1,25OH2D levels) and CT scans. Medical interventions were not made by study investigators; however, participants were made aware of abnormal test results and asked to discuss them with their physicians. Plasma concentrations of 25OHD and 1,25OH2D rose modestly between visits (Table 2, Table 3). The percentage of participants who reported taking vitamin D supplements was 5.3% (29/545) at visit 1 and 38.5% (111/288) at visit 2. Based on this, we surmise that participants were often told by their physicians to initiate vitamin D supplementation based on the lower levels commonly seen in populations with recent African ancestry (40, 41).
The lack of significant associations between vitamin D concentrations with thoracic or lumbar vertebral vBMD bears discussion. The fully adjusted analysis revealed that 1,25OH2D was not associated with change in thoracic or lumbar vertebral vBMD in individuals of recent African ancestry (Table 5). This lack of association appears to contrast with European populations in which active vitamin D supplementation is protective from osteoporosis (16). Lower BMD in the admixed African American population is known to be associated with a higher frequency of European ancestry, supporting biological effects contributing to low bone mass (35, 42–45).
The AA-DHS longitudinal study has strengths and limitations. The presence of preserved kidney function allowed for carefully performed analyses of vitamin D metabolism without the common complication of diabetic kidney disease in this high-risk for nephropathy African American T2D-affected population. In addition, controlled hypertension and frequent receipt of statins in more than 50% of the sample supports that participants had relatively good access to health care. As such, the AA-DHS appears to provide a reasonable contrast to studies in European Americans and other populations with T2D, without marked differences relating to differential health care access, BP, lipid, or glycemic control. Study limitations include the relatively small sample in the AA-DHS longitudinal cohort (N = 300, 288 with a BAVD measurement); however, AA-DHS contains the most precisely phenotyped sample of African Americans with T2D, with measures of kidney, bone, vascular disease, adiposity, cognitive testing, and brain imaging. Repeat laboratory and CT scans in 300 former participants after a 5-year mean follow-up was a complex undertaking. All AA-DHS participants had T2D; this makes it uncertain to what extent observations would be present in nondiabetic African Americans. We did not adjust for physical activity because questionnaires revealed very low activity levels and the accuracy of data was uncertain. When considering multiple comparisons, findings in this report support strong trends toward significance. For longitudinal association with kidney, bone, and CVD traits, three vitamin D levels were assessed (excluding DBP). Thus, three tests would require a corrected P value < 0.05/3 (P < .017) for significance.
In conclusion, BAVD concentrations were inversely associated with adipose tissue volumes (particularly visceral and intermuscular adipose), but not with subclinical CVD assessed as calcified atherosclerotic plaque or BMD in African Americans with T2D. In cross-sectional analyses, BAVD and 25OHD were inversely associated with albuminuria. Longitudinal analyses demonstrated that only 1,25OH2D or active vitamin D concentrations were associated with slower progression of calcified atherosclerotic plaque and albuminuria; proteinuria is a marker of endothelial dysfunction and subclinical kidney disease. These data provide novel information concerning the roles of DBP and BAVD in African Americans, demonstrating potential links between albuminuria, atherosclerosis, and active forms of vitamin D in this understudied population at high risk for CVD.
Acknowledgments
We thank all study participants and recruiters involved in the Diabetes Heart Study family of studies. This work was supported by National Institutes of Health Grants RO1 DK071891 (B.I.F.) and RO1 HL092301 (D.W.B.) and the General Clinical Research Center of Wake Forest School of Medicine Grant MO1-RR-07122.
Disclosure Summary: The authors have nothing to disclose.
Footnotes
- 1,25OH2D
- 1,25 di-hydroxyvitamin D
- 25OHD
- 25-hydroxyvitamin D
- AA-DHS
- African American-Diabetes Heart Study
- ACEi
- angiotensin-converting enzyme inhibitor
- ARB
- angiotensin receptor blocker
- BAVD
- bioavailable vitamin D
- BMD
- bone mineral density
- BMI
- body mass index
- BP
- blood pressure
- CAC
- coronary artery calcified plaque
- CP
- calcified plaque
- CT
- computed tomography
- CVD
- cardiovascular disease
- DBP
- vitamin D binding protein
- eGFR
- estimated glomerular filtration rate
- SD
- standard deviation
- T2D
- type 2 diabetes
- HBA1c
- hemoglobin A1c
- UACR
- urine albumin:creatinine ratio
- vBMD
- volumetric bone mineral density.
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