Abstract
Background
To analyze the association between serum 25-hydroxyvitamin D level (25(OH)D) and stroke risk based on the National Health and Nutrition Examination Survey (NHANES).
Methods
Between 2007 and 2018, the baseline information of participants from NHNES was collected. Univariate analysis was used to identify the covariates. Multivariate logistic regression model was used to analyze the association between serum 25(OH)D level and the stroke risk.
Results
Of the 8,523 participants, there were 310 participants with stroke and 8,213 participants without stroke. The multivariate logistic analysis showed that serum 25(OH)D deficiency (odds ratio (OR): 1.993, 95% confidence intervals (CI): 1.141-3.481, and P = 0.012) was the significant risk factors for stroke. Subgroup analysis showed that non-Hispanic whites with serum 25(OH)D deficiency (OR: 2.501, 95% CI: 1.094-5.720, and P = 0.001) and insufficiency (OR: 1.853, 95% CI: 1.170-2.934, and P = 0.006) were associated with a higher risk of stroke than those with normal 25(OH)D levels.
Conclusions
Serum 25(OH)D deficiency may be associated with an increased risk of stroke.
1. Introduction
Stroke remains the third most common cause of disability and the second most common cause of death worldwide [1]. In the United States, there were an estimated 795,000 new or recurrent stroke with approximately 130,000 deaths due to stroke each year [2]. The prevalence increases with age in both females and males. By 2030, an additional 3,400,000 adults are estimated to have a stroke in the United States, which increased by 20.5% with 2012 [3]. Stroke is associated with modifiable risk factors (hypertension, hyperglycemia, obesity, hyperlipidemia, and renal dysfunction) and behavioral risk factors (sedentary lifestyle, cigarette smoking, and unhealthy diet) [2, 4]. Interestingly, vitamin D (25-hydroxyvitamin D, 25(OH)D), a hormone mainly regulating calcium homeostasis, is found to be associated with the development of various nonskeletal chronic diseases, including stroke [5], cardiovascular disease [6], cancer [7], metabolic disorder [8], autoimmune disease [9], and infectious diseases [10].
In recent years, several studies have been conducted on the association between 25(OH)D level and stroke risk, but the results are inconsistent. Zhou et al. reported that 25(OH)D levels were associated with ischemic stroke (relative risk: 2.45) [11]. Berghout et al. also found a correlation between 25(OH)D level and prevalent stroke (adjusted odds ratio (OR): 1.31), but only extremely low 25(OH)D level was related to incident stroke (hazard ratio (HR): 1.25), showing that low 25(OH)D level may not increase the risk of stroke [12]. There is another evidence suggesting no association between 25(OH)D levels and incidence of stroke (HR: 1.00) [13]. In view of the inconsistent results, in this study, we used a pooled cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) (2007-2018) to further analyze the association of serum 25(OH)D level with stroke risk.
2. Methods
2.1. Data Sources
NHANES, a nationally representative survey for noninstitutionalized civilians in the United States, is conducted in two-year cycles, with approximately 10,000 persons in each cycle [14]. Participants aged over 18 years who had serum 25(OH)D level measured during the survey were enrolled in this study. Pregnant women and participants who did not respond to the question on stroke history and had missing information (e.g., age, sex, marital status, family income, educational level, and condition of complications) were excluded from the study.
The data used in this study were accessed from NHANES, a continuous program performed by the National Center for Health Statistics. The approval from the Institutional Review Board of Tianjin Medical University was not required because the data from NHANES were freely available.
The baseline characteristics of participants were collected, including age, gender, body mass index (BMI), race (Mexican Americans, non-Hispanic whites, non-Hispanic blacks, other races), marital status (married, widowed/divorced, unmarried, and living with partner), family income (<20,000$ and ≥20,000$), educational level (<high school, high school, and >high school), dietary intake (dietary fiber, total fat, fruits, vegetables, and vitamins A, B, C, and E), total cholesterol (TC), glycated hemoglobin (GHb), high-density lipoprotein (HDL), C-reactive protein (CRP), and 25(OH)D levels (deficiency: <30 nmol/L, insufficiency: 30-50 nmol/L, normal: 50-125 nmol/L, and adequacy: >125 nmol/L), as well as presence or absence of drinking, emphysema, chronic bronchitis, hypertension, high cholesterol, and diabetes mellitus.
The stroke was determined based on the Medical Condition Questionnaire (MCQ). Question MCQ160f “Has a doctor or other health professional ever told you that you had a stroke?” was asked by interviews. The participants answered “yes” were deemed to have stroke.
Diabetes mellitus was identified through the Diabetes Questionnaire (DIQ). Question DIQ010 is “Other than during pregnancy, have you ever been told by a doctor or health professional that you have diabetes or sugar diabetes?” Participants who answered “yes” were considered as diabetic.
The Blood Pressure & Cholesterol Questionnaire (BPQ) question BPQ080 is “Have you ever been told by a doctor or other health professional that your blood cholesterol level was high?” Participants who answered “yes” were considered as with high cholesterol level.
Hypertension was determined according to the question BPQ020, “Have you ever been told by a doctor or other health professional that you had hypertension, also called high blood pressure?” Participants who answered “yes” were considered with hypertension.
Dietary intake was estimated by two 24-hour dietary recall, a validated Automated Multiple-Pass Method jointly completed by the United States Department of Agriculture (USDA) and the United States Department of Health and Human Services (DHHS) [15]. The specific intake of each nutrient was available in the Dietary Interview-Total Nutrients Intakes. Consumptions of dietary fiber, total fat, fruits, vegetables, vitamin A, vitamin B, vitamin C, and vitamin E were retrieved from the dietary data.
2.2. Measurement of Serum 25(OH)D Level
Serum 25(OH)D level (ng/mL) was thought to be the optimal indicator to assess vitamin D status [16]. In the NHANES (2001-2006), the serum 25(OH)D level in approximately 88% of the adult participants was measured using radioimmunoassay kits (DiaSorin Inc., Stillwater, MN). An independent calibration was conducted for radioimmunoassay kits against high-performance liquid chromatography-purified 25(OH)D. Since 2007, the serum 25(OH)D level was measured using ultrahigh performance liquid chromatography-tandem mass spectrometry. Due to the differences in the results of these two measurement methods, this study only analyzed data from 2007 to 2018. The detailed measurement methods and quality assurance for serum 25(OH)D level could be found in the survey laboratory data [17]. The Institute of Medicine (IOM) and United State Preventive Services Task Force define vitamin D sufficiency as a total 25(OH)D level greater than 50 nmol/L [18, 19]. In this study, serum 25(OH)D level < 30 nmol/L is thought as deficiency, 30-50 nmol/L as insufficiency, 50-125 nmol/L as the normal value, and >125 nmol/L as adequacy.
2.3. Statistical Analysis
The SAS software (version 9.4, SAS Institute Inc., NC, USA) was employed to analyze the data. Normally, distributed data were represented as mean ± standard error (SE) and compared using t test, while nonnormal data was presented as median and quartile (M (Q1 and Q3)) and compared using Mann-Whitney U rank-sum test. χ2 test or Fisher's exact test was used to compare the enumeration data which were described as n (%). In the NHANES 2007–2018 study, exam weight was taken into account.
All included data from 2007 to 2018 were not missing. The covariates with significant difference in the univariate analysis were enrolled into the multivariate logistic regression model to analyze the association between serum 25(OH)D levels and the stroke risk. The difference was significant at P < 0.05.
3. Results
3.1. Basic Characteristics of Participants
A total of 10,425 participants with serum 25(OH)D data, stroke information, and age ≥ 18 years were retrieved from the NHANES between 2007 and 2018. After excluding 543 participants without dietary intake data and 1,359 participants with other missing information (BMI, marital status, drinking, emphysema, chronic bronchitis, etc.), 8,523 participants were finally eligible for the study. The process of inclusion and exclusion of participants is shown in Figure 1. Of these 8,523 participants, the mean age was 46.96 ± 0.35 years, 4,201 (48.60%) were males, and 4,322 (51.40%) were females. Among included participants, 1,519 (8.31%) were Mexican Americans, 4,294 (71.57%) were non-Hispanic whites, 1,511 (10.25%) were non-Hispanic blacks, and 1,199 (9.87%) were other races. In addition, there were 749 (6.24%) participants of serum 25(OH)D deficiency, 2,026 (18.71%) participants of serum 25(OH)D insufficiency, 5,585 (72.40%) participants of serum 25(OH)D normal, and 163 (2.65%) participants of serum 25(OH)D adequacy. There were 310 participants of stroke and 8,213 participants of no stroke. More detailed characteristics of participants are shown in Table 1.
Figure 1.
Flow chart of study population inclusion.
Table 1.
Baseline characteristics of participants after multiple imputation.
| Variables | Description (n = 8,523) |
|---|---|
| Age, years, mean ± SE | 46.96 ± 0.35 |
| Gender, n (%) | |
| Male | 4,201 (48.60) |
| Female | 4,322 (51.40) |
| BMI, kg/m2, mean ± SE | 28.79 ± 0.10 |
| Race, n (%) | |
| Mexican Americans | 1,519 (8.31) |
| Other races | 1,199 (9.87) |
| Non-Hispanic whites | 4,294 (71.57) |
| Non-Hispanic blacks | 1,511 (10.25) |
| Marital status, n (%) | |
| Married | 4562 (57.47) |
| Widowed/divorced | 1913 (17.89) |
| Unmarried | 1377 (16.93) |
| Living with partner | 671 (7.71) |
| Educational level, n (%) | |
| <high school | 2408 (18.46) |
| High school | 2010 (23.56) |
| >high school | 4105 (57.98) |
| Family income, n (%) | |
| <20,000$ | 2100 (16.96) |
| ≥20,000$ | 6423 (83.04) |
| Drinking, n (%) | 2337 (23.04) |
| Emphysema, n (%) | 203 (1.91) |
| Chronic bronchitis, n (%) | 474 (5.15) |
| Hypertension, n (%) | 3022 (30.53) |
| High cholesterol, n (%) | 3547 (39.33) |
| Diabetes mellitus, n (%) | 1045 (8.63) |
| Dietary intake, mean ± SE | |
| Dietary fiber | 16.68 ± 0.28 |
| Total fat | 82.96 ± 0.81 |
| Fruits | 1.00 ± 0.02 |
| Vegetables | 1.58 ± 0.03 |
| Vitamin A | 632.18 ± 10.22 |
| Vitamin B | 2.23 ± 0.02 |
| Vitamin C | 84.52 ± 1.96 |
| Vitamin E | 7.90 ± 0.12 |
| TC, nmol/L, mean ± SE | 196.89 ± 0.71 |
| GHb, nmol/L, mean ± SE | 5.60 ± 0.02 |
| HDL, nmol/L, mean ± SE | 52.72 ± 0.37 |
| CRP, nmol/L, mean ± SE | 0.38 ± 0.01 |
| 25(OH)D, nmol/L, n (%) | |
| Deficiency (<30) | 749 (6.24) |
| Insufficiency (30-50) | 2,026 (18.71) |
| Normal (50-125) | 5,585 (72.40) |
| Adequacy (≥125) | 163 (2.65) |
| Stroke, n (%) | |
| Yes | 8,213 (97.20) |
| No | 310 (2.80) |
Notes: BMI: body mass index; TC: total cholesterol; GHb: glycated hemoglobin; HDL: high-density lipoprotein; CRP: C-reactive protein; 25(OH)D: 25-hydroxyvitamin D. Values were presented as mean ± standard error (SE) or median and quartile (M (Q1 and Q3)) for continuous variables and n (%) for categorical variables. In the NHANES 2007–2018 study, exam weight was taken into account.
3.2. Comparison of the Baseline Characteristics between the Stroke and No Stroke Groups
Univariable analyses are shown in Table 2. The results indicated that age (t = −13.62, P < 0.001), BMI (t = −3.60, P < 0.001), GHb (t = −6.67, P < 0.001), CRP (t = −3.55, P < 0.001), and the proportion of drinking (χ2 = 25.510, P < 0.001), emphysema (χ2 = 42.304, P < 0.001), chronic bronchitis (χ2 = 61.132, P < 0.001), hypertension (χ2 = 194.882, P < 0.001), high cholesterol (χ2 = 28.263, P < 0.001), and diabetes mellitus (χ2 = 168.476, P < 0.001) of participants in the stroke group were higher than those in the no stroke group. However, participant's education level (χ2 = 37.712, P < 0.001), HDL (t = 2.97, P = 0.006), serum 25(OH)D (χ2 = 9.357, P = 0.025), the proportion of family income (χ2 = 14.866, P < 0.001), intake of dietary fiber (t = 3.36, P = 0.002), total fat (t = 3.04, P = 0.005), vegetables (t = 3.14, P = 0.004), vitamin B (t = 4.06, P < 0.004), and vitamin E (t = 3.28, P = 0.003) were lower in the stroke group compared with the no stroke group. In addition, there were statistical differences in the race (χ2 = 12.177, P = 0.007) and marital status (χ2 = 25.660, P < 0.001) between the two groups. The serum 25(OH)D level distribution of stroke and no stroke groups is shown in Figure 2, and the results indicated that the proportion of patients with serum 25(OH)D deficiency and insufficiency in the stroke group was higher in the stroke group than that in the no stroke group.
Table 2.
Comparison of the baseline characteristics between stroke and nonstroke groups.
| Variables | Nonstroke group (n = 8,213) | Stroke group (n = 310) | Statistic | P |
|---|---|---|---|---|
| Age, years, mean ± SE | 46.47 ± 0.35 | 63.93 ± 1.28 | t = −13.62 | <0.001 |
| Gender, n (%) | χ 2 = 1.246 | 0.264 | ||
| Male | 4045 (48.74) | 156 (44.01) | ||
| Female | 4168 (51.26) | 154 (55.99) | ||
| BMI, kg/m2, mean ± SE | 28.75 ± 0.10 | 30.16 ± 0.36 | t = −3.60 | 0.001 |
| Race, n (%) | χ 2 = 12.177 | 0.007 | ||
| Mexican Americans | 1492 (8.44) | 27 (3.78) | ||
| Other races | 1172 (9.96) | 27 (6.68) | ||
| Non-Hispanic whites | 4108 (71.44) | 186 (76.23) | ||
| Non-Hispanic blacks | 1441 (10.16) | 70 (13.31) | ||
| Marital status, n (%) | χ 2 = 25.660 | <0.001 | ||
| Married | 4396 (57.59) | 166 (53.30) | ||
| Widowed/divorced | 1804 (17.48) | 109 (32.20) | ||
| Unmarried | 1353 (17.20) | 24 (7.71) | ||
| Living with partner | 660 (7.74) | 11 (6.80) | ||
| Educational level, n (%) | χ 2 = 37.712 | <0.001 | ||
| <high school | 2291 (18.13) | 117 (29.97) | ||
| High school | 1931 (23.40) | 79 (29.04) | ||
| >high school | 3991 (58.47) | 114 (40.99) | ||
| Family income, n (%) | χ 2 = 14.866 | <0.001 | ||
| <20,000$ | 1989 (16.68) | 111 (26.77) | ||
| ≥20,000$ | 6224 (83.32) | 199 (73.23) | ||
| Drinking, n (%) | 2228 (22.66) | 109 (36.32) | χ 2 = 25.510 | <0.001 |
| Emphysema, n (%) | 179 (1.75) | 24 (7.22) | χ 2 = 42.304 | <0.001 |
| Chronic bronchitis, n (%) | 431 (4.79) | 43 (17.71) | χ 2 = 61.132 | <0.001 |
| Hypertension, n (%) | 2773 (29.23) | 249 (75.83) | χ 2 = 194.882 | <0.001 |
| High cholesterol, n (%) | 3364 (38.86) | 183 (55.70) | χ 2 = 28.263 | <0.001 |
| Diabetes mellitus, n (%) | 939 (8.00) | 106 (30.64) | χ 2 = 168.476 | <0.001 |
| Dietary intake, mean ± SE | ||||
| Dietary fiber | 16.74 ± 0.28 | 14.48 ± 0.71 | t = 3.36 | 0.002 |
| Total fat | 83.32 ± 0.76 | 70.44 ± 4.55 | t = 3.04 | 0.005 |
| Fruits | 1.00 ± 0.03 | 0.93 ± 0.08 | t = 0.92 | 0.366 |
| Vegetables | 1.59 ± 0.03 | 1.38 ± 0.07 | t = 3.14 | 0.004 |
| Vitamin A | 633.17 ± 10.04 | 597.84 ± 41.66 | t = 0.89 | 0.381 |
| Vitamin B | 2.24 ± 0.02 | 1.89 ± 0.09 | t = 4.06 | <0.001 |
| Vitamin C | 84.80 ± 1.97 | 74.84 ± 5.03 | t = 2.00 | 0.054 |
| Vitamin E | 7.93 ± 0.11 | 6.71 ± 0.41 | t = 3.28 | 0.003 |
| TC, nmol/L, mean ± SE | 197.05 ± 0.72 | 191.52 ± 3.95 | t = 1.37 | 0.179 |
| GHb, nmol/L, mean ± SE | 5.58 ± 0.01 | 6.09 ± 0.08 | t = −6.67 | <0.001 |
| HDL, nmol/L, mean ± SE | 52.81 ± 0.37 | 49.53 ± 1.05 | t = 2.97 | 0.006 |
| CRP, nmol/L, mean ± SE | 0.37 ± 0.01 | 0.67 ± 0.09 | t = −3.55 | 0.001 |
| 25(OH)D, nmol/L, n (%) | χ 2 = 9.357 | 0.025 | ||
| Deficiency (<30) | 715 (6.11) | 34 (11.01) | ||
| Insufficiency (30-50) | 1957 (18.64) | 69 (21.00) | ||
| Normal (50-125) | 5385 (72.59) | 200 (65.66) | ||
| Adequacy (≥125) | 156 (2.66) | 7 (2.34) |
Notes: BMI: body mass index; TC: total cholesterol; GHb: glycated hemoglobin; HDL: high-density lipoprotein; CRP: C-reactive protein; 25(OH)D: 25-hydroxyvitamin D. Values were presented as mean ± standard error (SE) or median and quartile (M (Q1 and Q3)) for continuous variables and n (%) for categorical variables. In the NHANES 2007–2018 study, exam weight was taken into account.
Figure 2.
The serum 25(OH)D level distribution of stroke and no stroke groups.
3.3. Relationship between Serum 25(OH)D Level and Stroke Risk
Multivariate logistic regression analysis results of the association between serum 25(OH)D levels and the stroke risk are summarized in Figure 3. As is shown, in the univariate serum 25(OH)D logistic regression analysis (model 1), the patients with serum 25(OH)D deficiency (OR: 1.993, 95% confidence interval (95% CI): 1.141-3.481, and P = 0.012) had an increased risk of stroke in contrast to those with normal 25(OH)D levels. After adjustment for covariates of age and gender (model 2), the risk of stroke was increased by 1.369- and 0.523-fold, respectively, in patients with serum 25(OH)D deficiency (OR: 2.369, 95% CI: 1.404-3.995, and P < 0.023) and insufficiency (OR: 1.523, 95% CI: 1.044-2.222, and P = 0.023) when compared with those with normal serum 25(OH)D levels. After the adjustment of all the covariates (model 3), such as age, gender, BMI, educational level, hypertension, vitamin E, and CRP levels, serum 25(OH)D deficiency (OR: 1.770, 95% CI: 1.023-3.065, and P = 0.034) was still the independent risk factors for stroke.
Figure 3.
Multivariate logistic regression forest plot of the association between serum 25(OH)D levels and the stroke risk.
3.4. Further Analysis of the Relationship between Serum 25(OH)D Level and Stroke Risk Based on Race
Further analysis results of the relationship between serum 25(OH)D levels and stroke risk based on race are shown in Table 3. Except for non-Hispanic whites, the association between serum 25(OH)D level and stroke risk was not statistically significant among Mexican Americans, non-Hispanic blacks, and other races (all P > 0.05). In the univariate serum 25(OH)D logistic regression analysis, the non-Hispanic whites with serum 25(OH)D deficiency (OR: 4.651, 95% CI: 1.908-11.338, and P < 0.001) and insufficiency (OR: 1.957, 95% CI: 1.257-3.047, and P = 0.002) had a higher risk of stroke than those with normal 25(OH)D levels. After adjustment for part covariates, the risk of stroke was increased by 2.087- and 0.982-fold, respectively, in patients with serum 25(OH)D deficiency (OR: 3.087, 95% CI: 1.390-6.856, and P = 0.004) and insufficiency (OR: 1.982, 95% CI: 95% CI: 1.246-3.153, and P = 0.003) as compared with participants with normal serum 25(OH)D levels. After adjustment for all the covariates, the risk of stroke in patients with serum 25(OH)D deficiency (OR: 2.501, 95% CI: 1.094-5.720, and P = 0.001) and insufficiency (OR: 1.853, 95% CI: 1.170-2.934, and P = 0.006) was 2.501 times and 1.853 times that of patients with normal serum 25(OH)D levels, respectively.
Table 3.
Subgroup analysis of the association between serum 25(OH)D levels and the stroke risk based on race.
| Race | N (%) | Model 1 OR (95% CI) |
P | Model 2 OR (95% CI) |
P | Model 3 OR (95% CI) |
P |
|---|---|---|---|---|---|---|---|
| Mexican Americans | |||||||
| 25(OH)D, nmol/L | |||||||
| Deficiency (<30) | 115 (7.75) | 0.762 (0.230-2.524) | 0.643 | 1.015 (0.310-3.320) | 0.979 | 0.868 (0.282-2.671) | 0.798 |
| Insufficiency (30-50) | 524 (34.98) | 0.676 (0.308-1.484) | 0.309 | 0.786 (0.364-1.697) | 0.522 | 0.778 (0.351-1.727) | 0.520 |
| Normal (50-125) | 878 (57.17) | Ref | Ref | Ref | |||
| Adequacy (≥125) | 2 (0.10) | - | - | - | |||
| Non-Hispanic whites | |||||||
| 25(OH)D, nmol/L | |||||||
| Deficiency (<30) | 108 (10.62) | 4.651 (1.908-11.338) | <0.001 | 3.087 (1.390-6.856) | 0.004 | 2.501 (1.094-5.720) | 0.024 |
| Insufficiency (30-50) | 353 (29.13) | 1.957 (1.257-3.047) | 0.002 | 1.982 (1.246-3.153) | 0.003 | 1.853 (1.170-2.934) | 0.006 |
| Normal (50-125) | 731 (59.69) | Ref | Ref | Ref | |||
| Adequacy (≥125) | 7 (0.56) | 0.954 (0.456-1.995) | 0.897 | 0.922 (0.481-1.767) | 0.800 | 1.011 (0.574-1.781) | 0.969 |
| Non-Hispanic blacks | |||||||
| 25(OH)D, nmol/L | |||||||
| Deficiency (<30) | 123 (2.40) | 0.746 (0.437-1.273) | 0.262 | 1.009 (0.550-1.851) | 0.976 | 0.837 (0.470-1.492) | 0.528 |
| Insufficiency (30-50) | 567 (12.43) | 0.555 (0.209-1.473) | 0.218 | 0.739 (0.276-1.977) | 0.529 | 0.702 (0.264-1.864) | 0.459 |
| Normal (50-125) | 3461 (81.65) | Ref | Ref | Ref | |||
| Adequacy (≥125) | 143 (3.53) | 1.739 (0.185-16.329) | 0.613 | 0.819 (0.097-6.899) | 0.848 | 1.298 (0.145-11.605) | 0.808 |
| Other races | |||||||
| 25(OH)D, nmol/L | |||||||
| Deficiency (<30) | 403 (27.69) | 0.615 (0.135-2.798) | 0.513 | 1.050 (0.298-3.695) | 0.937 | 0.828 (0.267-2.571) | 0.734 |
| Insufficiency (30-50) | 582 (39.36) | 0.334 (0.089-1.261) | 0.092 | 0.408 (0.107-1.555) | 0.172 | 0.379 (0.095-1.502) | 0.151 |
| Normal (50-125) | 515 (32.36) | Ref | Ref | Ref | |||
| Adequacy (≥125) | 11 (0.60) | - | - | - |
Notes: model 1 is the univariate logistic regression analysis for 25(OH)D levels; model 2 is the multivariate logistic regression analysis after adjustments for age and gender; model 3 is the multivariate logistic regression analysis after adjustment for the covariates including age, gender, BMI, educational level, hypertension, vitamin B, and CRP levels.
4. Discussion
A total of 8,523 eligible participants were involved into the present study, among whom 310 participants were subjected to stroke, while 8,213 participants were not. The multivariate logistic analysis showed that serum 25(OH)D deficiency was the significant risk factor for stroke. All these findings suggested that the patients with serum 25(OH)D deficiency (<30 nmol/L) might have an increased risk of stroke. Subgroup analysis showed that non-Hispanic whites with serum 25(OH)D deficiency and insufficiency were associated with a high risk of stroke.
As a fat-soluble vitamin, vitamin D, can affect cardiomyocytes, endothelial cells, vascular smooth muscle cells, and inflammatory cells by binding vitamin D receptors (VDR) and exert the effects of inhibiting myocardial hypertrophy, protecting vascular endothelium, and regulating inflammatory responses, consequently decreasing the onset risk of cardiovascular and cerebrovascular diseases and improving patients' prognosis [20–22]. 25(OH)D, a major circulation form of vitamin D in the body, can better reflect vitamin D status. Several studies reported vitamin D deficiency, whether in serum or in intake, may be associated with an increased risk of ischemic stroke [11, 23]. In the present study, a pooled cross-sectional data from NHANES were used to identify the association of serum 25(OH)D level with the stroke risk. The risk of stroke was found to significantly increase in patients with serum 25(OH)D deficiency and insufficiency. However, vitamin D status is under the influence of various factors including age, living areas, exposure to sunlight, and vitamin D daily dietary intake [24, 25]. After adjustment for multiple covariates, our results still showed that serum 25(OH)D deficiency is related to an increased risk of stroke.
The impact of serum 25(OH)D level-related stroke risk between different races is controversial. The study of Judd et al. indicated that lower 25(OH)D level is a significant risk factor for incident stroke, and no statistically significant difference was observed between blacks and whites [26]. However, Michos et al. found that serum 25(OH)D deficiency was associated with a higher risk of stroke in whites but not in blacks (hazard ratios 2.13 vs. 0.93) [27]. Our results showed that a lower serum 25(OH)D level was related to an increased risk of stroke in non-Hispanic whites. Robinson-Cohen et al. also demonstrated that lower serum 25(OH)D level was related to an increased risk of incident coronary heart disease among participants who were Hispanic [28]. In addition, several studies indicated that both low and high serum 25(OH)D levels have increased the risk of stroke [29, 30]. However, the relationship between high 25(OH)D levels and stroke risk was not observed in this study. The possible explanation was that the sample size of participants with higher high 25(OH)D levels is not large, and no statistically significant results can be obtained.
At present, the effect of 25(OH)D level on the stroke risk can be explained by several mechanisms below. Inappropriate activation of the renin-angiotensin system (RAS) may be a major risk factor for stroke [31]. 25(OH)D, a negative endocrine regulator of the renin-angiotensin system (RAS), may influence the stroke risk through RAS regulation [31, 32]. A previous experiment showed that by regulating cholesterol efflux and macrophage polarization through elevated CYP27A1 activation, vitamin D played a protective role against atherosclerosis in hypercholesterolemic swine [33]. Activated vitamin D may defer atherosclerosis by inhibiting the formation of foam cells and the process of macrophage cholesterol absorption, consequently reducing the risk of developing stroke [34]. There is another study showing that vitamin D deficiency contributes to facilitating secondary hyperparathyroidism, while the increased levels of parathyroid hormone may accelerate the inflammatory response in atherosclerosis [35, 36]. In addition, activated vitamin D plays a crucial role in preventing thrombosis, which may explain why the low vitamin D level is associated with an increased risk of ischemic stroke [37, 38].
The strength of the present study was that it was a large-scale, population-based study, providing strong evidence for assessing the relationship between vitamin D status and stroke risk. Compared with the single-center studies, our research results may be more generalizable. Furthermore, we conducted a further analysis of the relationship between serum 25(OH)D level and stroke risk based on race. However, there existed some limitations. First, the data in our study were accessed from the NHNES database, which may be lack of some important variables, such as vitamin D supplementation, exposure to sunlight, living areas, and seasons of vitamin D measurement. Second, the stroke history was confirmed through self-reported data. Despite lack of verification for self-reporting stroke in NHANES, the stroke history from questionnaire was checked. In several studies, the self-reported data from NHANES were used to identify the risk factors for cardiovascular diseases [39–41].
5. Conclusions
The results suggested that serum 25(OH)D deficiency (<30 nmol/L) might be related to an increased risk of stroke. In addition, non-Hispanic whites with serum 25(OH)D deficiency (<30 nmol/L) and insufficiency (30-50 nmol/L) were associated with a high risk of stroke than those with normal 25(OH)D levels.
Acknowledgments
This study was funded by the Natural Science Foundation of Tianjin (Project number: 18JCQNJC11500).
Data Availability
The data utilized to support the findings are available from the corresponding authors upon request.
Conflicts of Interest
The authors declare that they have no competing interests in this study.
Authors' Contributions
Lan Wang and Shu Li contributed equally to this work.
References
- 1.Feigin V. L., Forouzanfar M. H., Krishnamurthi R., et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study. Lancet . 2014;383(9913):245–255. doi: 10.1016/S0140-6736(13)61953-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Benjamin E. J., Muntner P., Alonso A., et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation . 2019;139(10):e56–e528. doi: 10.1161/CIR.0000000000000659. [DOI] [PubMed] [Google Scholar]
- 3.Heidenreich P. A., Albert N. M., Allen L. A., et al. Forecasting the impact of heart failure in the United States. Circulation Heart Failure . 2013;6(3):606–619. doi: 10.1161/HHF.0b013e318291329a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Feigin V. L., Roth G. A., Naghavi M., et al. Global burden of stroke and risk factors in 188 countries, during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet Neurology . 2016;15(9):913–924. doi: 10.1016/S1474-4422(16)30073-4. [DOI] [PubMed] [Google Scholar]
- 5.Pilz S., Dobnig H., Fischer J. E., et al. Low vitamin d levels predict stroke in patients referred to coronary angiography. Stroke . 2008;39(9):2611–2613. doi: 10.1161/STROKEAHA.107.513655. [DOI] [PubMed] [Google Scholar]
- 6.Zittermann A., Pilz S. Vitamin D and cardiovascular disease: an update. Anticancer Research . 2019;39(9):4627–4635. doi: 10.21873/anticanres.13643. [DOI] [PubMed] [Google Scholar]
- 7.Jeon S. M., Shin E. A. Exploring vitamin D metabolism and function in cancer. Experimental & Molecular Medicine . 2018;50(4):1–14. doi: 10.1038/s12276-018-0038-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Grammatiki M., Rapti E., Karras S., Ajjan R. A., Kotsa K. Vitamin D and diabetes mellitus: causal or casual association? Reviews in Endocrine & Metabolic Disorders . 2017;18(2):227–241. doi: 10.1007/s11154-016-9403-y. [DOI] [PubMed] [Google Scholar]
- 9.Wang J., Lv S., Chen G., et al. Meta-analysis of the association between vitamin D and autoimmune thyroid disease. Nutrients . 2015;7(4):2485–2498. doi: 10.3390/nu7042485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Watkins R. R., Lemonovich T. L., Salata R. A. An update on the association of vitamin D deficiency with common infectious diseases. Canadian Journal of Physiology and Pharmacology . 2015;93(5):363–368. doi: 10.1139/cjpp-2014-0352. [DOI] [PubMed] [Google Scholar]
- 11.Zhou R., Wang M., Huang H., Li W., Hu Y., Wu T. Lower vitamin D status is associated with an increased risk of ischemic stroke: a systematic review and meta-analysis. Nutrients . 2018;10(3):p. 277. doi: 10.3390/nu10030277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Berghout B. P., Fani L., Heshmatollah A., et al. Vitamin D status and risk of Stroke. Stroke . 2019;50(9):2293–2298. doi: 10.1161/STROKEAHA.119.025449. [DOI] [PubMed] [Google Scholar]
- 13.Skaaby T., Husemoen L. L., Pisinger C., et al. Vitamin D status and incident cardiovascular disease and all-cause mortality: a general population study. Endocrine . 2013;43(3):618–625. doi: 10.1007/s12020-012-9805-x. [DOI] [PubMed] [Google Scholar]
- 14.Fain J. A. Nhanes. Diabetes Educ . 2017;43(2):p. 151. doi: 10.1177/0145721717698651. [DOI] [PubMed] [Google Scholar]
- 15.Blanton C. A., Moshfegh A. J., Baer D. J., Kretsch M. J. The USDA Automated Multiple-Pass Method accurately estimates group total energy and nutrient intake. 2006. June 2021, https://pubag.nal.usda.gov/catalog/10039. [DOI] [PubMed]
- 16.Deng X., Song Y., Manson J. E., et al. Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. BMC Medicine . 2013;11:p. 187. doi: 10.1186/1741-7015-11-187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.National Center for Health Statistics: Analytical note for 25-hydroxyvitamin D data analysis using NHANES III (1988-1994), NHANES 2001-2006, and NHANES 2007-2010. June 2021, https://wwwn.cdc.gov/nchs/nhanes/vitamind/analyticalnote.aspx?h=/nchs/data/nhanes/2007-2008/labmethods/VID_E_met_Vitamin_D.pdf&t=2007-2008%20Vitamin%20D%20Lab%20Method.
- 18.Ross A. C., Manson J. E., Abrams S. A., et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. Journal of Clinical Endocrinology and Metabolism . 2011;96(1):53–58. doi: 10.1210/jc.2010-2704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.LeFevre M. L., on behalf of the US Preventive Services Task Force Screening for vitamin D deficiency in adults: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine . 2015;162(2):133–140. doi: 10.7326/M14-2450. [DOI] [PubMed] [Google Scholar]
- 20.Schleithoff S. S., Zittermann A., Tenderich G., Berthold H. K., Stehle P., Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. The American Journal of Clinical Nutrition . 2006;83(4):754–759. doi: 10.1093/ajcn/83.4.754. [DOI] [PubMed] [Google Scholar]
- 21.Saponaro F., Marcocci C., Zucchi R. Vitamin D status and cardiovascular outcome. Journal of Endocrinological Investigation . 2019;42(11):1285–1290. doi: 10.1007/s40618-019-01057-y. [DOI] [PubMed] [Google Scholar]
- 22.Wimalawansa S. J. Vitamin D and cardiovascular diseases: causality. The Journal of Steroid Biochemistry and Molecular Biology . 2018;175:29–43. doi: 10.1016/j.jsbmb.2016.12.016. [DOI] [PubMed] [Google Scholar]
- 23.Brøndum-Jacobsen P., Nordestgaard B. G., Schnohr P., Benn M. 25-hydroxyvitamin D and symptomatic ischemic stroke: an original study and meta-analysis. Annals of Neurology . 2013;73(1):38–47. doi: 10.1002/ana.23738. [DOI] [PubMed] [Google Scholar]
- 24.Pilz S., Tomaschitz A., Drechsler C., Zittermann A., Dekker J. M., Marz W. Vitamin D supplementation: a promising approach for the prevention and treatment of strokes. Current Drug Targets . 2011;12(1):88–96. doi: 10.2174/138945011793591563. [DOI] [PubMed] [Google Scholar]
- 25.Sheerah H. A., Eshak E. S., Cui R., Imano H., Iso H., Tamakoshi A. Relationship between dietary vitamin D and deaths from stroke and coronary heart Disease. Stroke . 2018;49(2):454–457. doi: 10.1161/STROKEAHA.117.019417. [DOI] [PubMed] [Google Scholar]
- 26.Judd S. E., Morgan C. J., Panwar B., et al. Vitamin D deficiency and incident stroke risk in community-living black and white adults. International Journal of Stroke: official journal of the International Stroke Society . 2016;11(1):93–102. doi: 10.1177/1747493015607515. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Michos E. D., Reis J. P., Post W. S., et al. 25-Hydroxyvitamin D deficiency is associated with fatal stroke among whites but not blacks: the NHANES-III linked mortality files. Nutrition . 2012;28(4):367–371. doi: 10.1016/j.nut.2011.10.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Robinson-Cohen C., Hoofnagle A. N., Ix J. H., et al. Racial differences in the association of serum 25-hydroxyvitamin D concentration with coronary heart disease events. JAMA . 2013;310(2):179–188. doi: 10.1001/jama.2013.7228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Leung R. Y., Han Y., Sing C. W., et al. Serum 25-hydroxyvitamin D and the risk of stroke in Hong Kong Chinese. Thrombosis and Haemostasis . 2017;117(1):158–163. doi: 10.1160/TH16-07-0551. [DOI] [PubMed] [Google Scholar]
- 30.Durup D., Jørgensen H. L., Christensen J., et al. A reverse J-shaped association between serum 25-hydroxyvitamin D and cardiovascular disease mortality: the CopD study. The Journal of Clinical Endocrinology and Metabolism . 2015;100(6):2339–2346. doi: 10.1210/jc.2014-4551. [DOI] [PubMed] [Google Scholar]
- 31.McMullan C. J., Borgi L., Curhan G. C., Fisher N., Forman J. P. The effect of vitamin D on renin-angiotensin system activation and blood pressure. Journal of Hypertension . 2017;35(4):822–829. doi: 10.1097/HJH.0000000000001220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Forman J. P., Williams J. S., Fisher N. D. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension . 2010;55(5):1283–1288. doi: 10.1161/HYPERTENSIONAHA.109.148619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Yin K., You Y., Swier V., et al. Vitamin D protects against atherosclerosis via regulation of cholesterol efflux and macrophage polarization in hypercholesterolemic swine. Arteriosclerosis, Thrombosis, and Vascular Biology . 2015;35(11):2432–2442. doi: 10.1161/ATVBAHA.115.306132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.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]
- 35.Tomaschitz A., Ritz E., Pieske B., et al. Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease. Metabolism: clinical and experimental . 2014;63(1):20–31. doi: 10.1016/j.metabol.2013.08.016. [DOI] [PubMed] [Google Scholar]
- 36.Martín-Ventura J́. L., Ortego M., Esbrit P., Hernández-Presa M. A., Ortega L., Egido J. Possible role of parathyroid hormone-related protein as a proinflammatory cytokine in atherosclerosis. Stroke . 2003;34(7):1783–1789. doi: 10.1161/01.STR.0000078371.00577.76. [DOI] [PubMed] [Google Scholar]
- 37.Moscarelli L., Zanazzi M., Bertoni E., et al. Renin angiotensin system blockade and activated vitamin D as a means of preventing deep vein thrombosis in renal transplant recipients. Clinical Nephrology . 2011;75(5):440–450. doi: 10.5414/CNP75440. [DOI] [PubMed] [Google Scholar]
- 38.Wu W. X., He D. R. Low vitamin D levels are associated with the development of deep venous thromboembolic events in patients with ischemic stroke. Clinical and Applied Thrombosis/Hemostasis: official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis . 2018;24(9_suppl):69s–75s. doi: 10.1177/1076029618786574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Kim D. H., Sabour S., Sagar U. N., Adams S., Whellan D. J. Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination Survey 2001 to 2004) The American Journal of Cardiology . 2008;102(11):1540–1544. doi: 10.1016/j.amjcard.2008.06.067. [DOI] [PubMed] [Google Scholar]
- 40.Kendrick J., Targher G., Smits G., Chonchol M. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis . 2009;205(1):255–260. doi: 10.1016/j.atherosclerosis.2008.10.033. [DOI] [PubMed] [Google Scholar]
- 41.Yoon S. S., Dillon C. F., Illoh K., Carroll M. Trends in the prevalence of coronary heart disease in the U.S.: National Health and Nutrition Examination Survey, 2001-2012. American Journal of Preventive Medicine . 2016;51(4):437–445. doi: 10.1016/j.amepre.2016.02.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data utilized to support the findings are available from the corresponding authors upon request.