European Journal of Clinical Nutrition (2014), 1–7 © 2014 Macmillan Publishers Limited All rights reserved 0954-3007/14 www.nature.com/ejcn
ORIGINAL ARTICLE
Association of vitamin D with respiratory outcomes in Canadian children SJ Niruban1, K Alagiakrishnan2, J Beach2 and A Senthilselvan1 BACKGROUND/OBJECTIVES: Vitamin D modifies airway inflammation and appears to be important in building immunity against respiratory infections, and so is potentially beneficial in asthma. However, to date results from studies investigating the relationship of vitamin D with respiratory outcomes are inconsistent. The objective of this study was to determine the association of vitamin D with current wheeze, ever asthma and lung function. SUBJECTS/METHODS: Data on 1213 children aged 6–12 years, from the Canadian Health Measures Survey, were considered for the study. Serum 25-hydroxy vitamin D (25(OH)D) levels were categorized into three categories: ⩽ 49 nmol/l (low); 50–74 nmol/l (moderate); and ⩾ 75 nmol/l (high). RESULTS: Children in the low and high 25(OH)D categories were more likely to report current wheeze in comparison to those in the moderate category (odds ratio (OR): 3.26, 95% confidence interval (CI): 1.16–9.17 and OR: 2.14, 95% CI: 1.07–4.28, respectively). The results for the association between 25(OH)D levels and ever asthma were similar to those observed for current wheeze, except that a significant association was observed only in the lower category. The rate of increase in forced expiratory volume in one second and forced vital capacity with age was greater in the moderate category. CONCLUSIONS: Children in both low and high 25(OH)D categories had increased risk of current wheeze and reduced rate of change in lung function with age in comparison to the moderate category, raising the possibility of a U-shaped association between vitamin D levels and respiratory health. Clearer guidelines for optimal vitamin D levels are required to improve respiratory health in children. European Journal of Clinical Nutrition advance online publication, 2 July 2014; doi:10.1038/ejcn.2014.121
INTRODUCTION Asthma is the most common chronic condition affecting children in developed countries.1,2 Asthma prevalence has been increasing during recent decades in many parts of the world.3–6 It is likely that this increase in asthma prevalence is influenced by many environmental 4 and behavioral factors. 7–9 Vitamin D has been recognized to play an important role in innate and adaptive immune responses for some years.10 It has been shown to be a potent stimulator of the mechanisms associated with pathogen elimination.11 Recent animal studies have raised the possibility of vitamin D exerting some of its effect on inflammation and autoimmune diseases through the regulation of Th17 cells (a T-cell lineage distinct from T-helper 1 (Th1) or Th2 cells).10 Initially, Bäck et al.8 demonstrated a significant association of vitamin D with asthma-related parameters, including lung function, in a representative adult population from the US. However, despite ongoing research, the evidence remains conflicting, with studies reporting protective effects,12–14 adverse effects,8,15,16 as well as an absence of any effect17,18 of vitamin D on asthma. There are also suggestions that maternal vitamin D status19–23 and early infant supplementation8,15 may influence the early programming of the immune system and so the development of asthma and allergic diseases in offspring. A committee appointed by the Institute of Medicine reported that a serum vitamin D level of ⩾ 50 nmol/l for skeletal health, and
higher values were not consistently associated with increased health benefit.24 For extraskeletal outcomes such as cancer, cardiovascular disease, diabetes and autoimmune disorders, no recommendations were made by the committee due to the inconsistent and inconclusive evidence.24 In the conclusion of their manuscript the authors reported that ‘serum concentrations of 25(OH)D above 30 ng/ml (75 nmol/l) are not consistently associated with increased benefit, and risks have been identified for some outcomes at 25OHD levels above 50 ng/ml (125 nmol/l).’ Interestingly, the relationship between 25-hydroxy vitamin D (25 (OH)D) levels and some of the extraskeletal outcomes has been reported to be U-shaped, with increased risk at both low and high levels of 25(OH)D.25 In our study, we used the data from the Canadian Health Measures Survey to further examine whether there might be a non-linear relationship between serum 25[OH]D concentration and current wheeze, ever asthma and lung function parameters in children. MATERIALS AND METHODS The Canadian Health Measures Survey was developed by Statistics Canada in partnership with Health Canada and the Public Health Agency of Canada.26 The survey included two main components: an in-home interview and a clinic visit.27 Upon completion of the household interview, participants were asked to attend a mobile examination centre.28 (More details of the methods are given in online Supplementary Methods.)
1 School of Public Health, University of Alberta, Edmonton, Alberta, Canada and 2Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Correspondence: Dr A Senthilselvan, School of Public Health, University of Alberta, 3-276 Edmonton Clinic Health Academy, 11405–87 Avenue, Edmonton, Alberta, Canada T6G 2T4. E-mail: [email protected] Received 5 December 2013; revised 14 April 2014; accepted 16 May 2014
Association of vitamin D with respiratory outcomes SJ Niruban et al
2 After excluding adolescents and adults, 1213 children aged 6–12 years were included in the study. Of these 1030 had vitamin D measurements, and 951 of the 1030 children had valid lung function measurements. In the Canadian Health Measures Survey, the presence of current wheeze was established from the question ‘Has your child had wheezing or whistling in the chest in the last 12 months?’ from the clinic questionnaire. The presence of ever asthma was determined from the question ‘We are interested in long-term conditions which are expected to last or have already lasted 6 months or more and that have been diagnosed by a health professional: Do you have asthma?’ Spirometric measurements comprised forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced expiratory flow between 25 and 75% of the FVC (FEF25–75%). The calendar months of data collection were grouped into four seasons, with winter spanning over 4 months reflecting the long Canadian winter (spring: April and May; summer: June–August; fall: September–November; winter: December–March).
Statistical analysis The 25(OH)D levels were divided into three categories: 13.7–o50 nmol/l (low), 50– o75 nmol/l (moderate) and 75–195.1 nmol/l (high), where 13.7 and 195.1 nmol/l are the minimum and maximum values of the 25(OH)D levels. Four categories based on the quartiles of 25(OH)D levels (13.7–57.9, 58.0–72.5, 72.6–86.8, 86.9–195.1 nmol/l) were also considered for comparison with results obtained with three categories. Multiple logistic regression analysis was used to test the association between 25(OH)D levels, and current wheeze and ever asthma after controlling for other factors. Multiple linear regression was used to determine the relationship between the 25(OH)D levels and lung function after controlling for other factors. We used the package mgcv in R (R Core Team, 2013) to conduct logistic regression analysis using the generalized additive model procedure29 to explore the non-linear relationship between 25(OH) levels and current wheeze.
RESULTS The mean age of the children was 9.1 years. The prevalence of current wheeze and ever asthma was 7.4% and 10.3%, respectively. Among the children with ever asthma, 53.4% children had current wheeze. Among the children reporting current wheeze, 65.9% reported less than four episodes of wheeze while 34.1% reported four or more episodes of wheeze in the last 12 months. Although there was variation in the mean 25(OH)D levels between the four seasons (Supplementary Table 1), the overall differences between the mean values were not statistically significant (P = 0.43). As shown in Table 1, the proportion of children in the low, moderate and high 25(OH)D categories was 15.6%, 37.5% and 46.9%, respectively. The prevalence of current wheeze was 11.4%, 4.1% and 7.7% in the low, moderate and high 25(OH)D categories, respectively. Children in the low and high 25(OH)D categories were more likely to report current wheeze in comparison to those in the moderate category. Children with a family history of asthma had a significantly greater prevalence of current wheeze (16.0%) than those without a family history of asthma (5.0%). As shown in Table 2, the prevalence of ever asthma was 14.5%, 8.2% and 10.2% in the low, moderate and high 25(OH)D categories, respectively. Children in the low and high 25(OH)D categories were more likely to have a report of ever asthma in comparison to those children in the moderate category. Children with a family history of asthma had a significantly greater prevalence of ever asthma (25.9%) than those without a family history of asthma (5.6%). The factors included in Tables 1 and 2 were initially considered for the multiple logistic regression analysis of current wheeze and ever asthma, respectively. The results from the final multiple logistic regression of current wheeze or ever asthma are shown in Table 3. After controlling for confounders including season, children in both the low and high 25(OH)D categories had an increased odds of reporting current wheeze in comparison to those in the moderate category (odds ratio (OR): 3.26; 95% European Journal of Clinical Nutrition (2014) 1 – 7
confidence interval (CI): 1.16–9.17 for low vs moderate, and OR: 2.14; 95% CI: 1.07–4.28 for high vs moderate). Children in the low 25(OH)D category had an increased odds of ever asthma in comparison to those in the moderate category (OR: 1.86, 95% CI: 1.15, 3.01). Children in the high 25(OH)D category had a nonsignificant increased risk of ever asthma in comparison to the moderate category (OR: 1.46, 95% CI: 0.76, 2.80). When we considered four categories using the 25(OH)D quartiles, relative to the second quartile, ORs of current wheeze were 2.75 (95% CI: 1.20, 6.31; P = 0.02) in the first quartile, 3.02 (95% CI: 1.26, 7.25; P = 0.018) in the third quartile and 1.59 (95% CI: 0.85, 2.98; P = 0.13) in the fourth quartile after controlling for the factors considered in Table 3. The adjusted ORs for three and four 25(OH)D categories are further illustrated in Supplementary Table 2. The mean values of age, height, weight and lung function outcomes were significantly different between the three 25(OH)D categories (Table 4). The mean percent predicted FEV1, FVC, FEV1/ FVC ratio and FEF25–75% were the greatest in the moderate 25(OH) D category in comparison to the low and high 25(OH)D categories, but the differences between categories were not statistically significant. Table 5 displays the relationship between 25(OH)D levels, and FEV1, FVC, FEV1/FVC ratio and FEF25–75% after adjusting for age, sex, race (Caucasian or not), height, height-squared (for FEV1 and FVC) and weight. The interaction effect between 25(OH)D levels and children’s age was significant in the relationship of 25(OH)D levels with FVC (P = 0.02) and FEV1 (P = 0.02). To elucidate the interaction effects, the estimated mean FEV1 and FVC values were plotted against the children’s age, for male Caucasian children with height and weight adjusted to the mean values in Supplementary Figures 1 and 2, respectively. Supplementary Figure 1 shows that the increase in FEV1 with children’s age, indicated by the slopes of the fitted lines, was greater in the moderate 25(OH)D category than in the low and high 25(OH)D categories. The relationship between FEV1 and age for females and for other race categories was similar to Supplementary Figure 1 except for a shift in the intercepts. As shown in Supplementary Figure 2, the results for FVC were similar to those observed for FEV1, with the slopes greater in the moderate 25(OH)D category than in the low and high 25(OH)D categories. After controlling for the factors in Table 5, mean FEV1/FVC ratio was greater for the low and high 25(OH)D categories than for the moderate category, with the difference being statistically significant only between moderate and high 25(OH)D categories. As shown in Table 5, there was a significant interaction between weight and 25(OH)D categories in the regression model for FEF25–75%, with the increase in FEF25–75% with children’s weight being greater in the moderate 25(OH)D category than in the low and high 25(OH)D categories. The relationship between 25(OH)D levels and lung function measurements remained significant after including the variable for season with four categories in a multiple regression model that also included age, sex, race (Caucasian or not), height, height-squared (for FEV1 and FVC) and weight (data not shown). In the generalized additive model analysis, the 25(OH)D level was considered as a continuous variable and its relationship with current wheeze was examined. To characterize the interpretation of the results from generalized additive model procedure, the predicted risk of current wheeze was plotted in Figure 1 against the 25(OH)D levels for a male child of 9 years with a positive family history of asthma and absence of electric heating at home. After controlling for the factors considered previously in Table 3, there was an increased risk of current wheeze for 25(OH)D levels from 13.7 to about 50 nmol/l, followed by a minimal risk of current wheeze until about 75 nmol/l and then an increase in the risk of current wheeze until from 75 to ~ 100 nmol/l. As indicated by the wide 95% confidence intervals in Figure 1, the risk estimates were not stable above 100 nmol/l due to the small number of observations. © 2014 Macmillan Publishers Limited
Association of vitamin D with respiratory outcomes SJ Niruban et al
3 Table 1.
Characteristics of the study sample, proportion of current wheeze by factors and odds ratio for the relationship of factors with current
wheeze Factors
Distribution of characteristics in the sample (%)
Proportion of current wheeze within factor (%)
Unadjusted OR (95% CI)
Vitamin D level (nmol/l) o 50 50 too 75 ⩾ 75
15.6 37.5 46.9
11.4 4.1 7.7
3.02 (1.04, 8.78) 1.0 1.96 (0.91, 4.22)
Sex Female Male
47.5 52.5
6.7 8.1
1.00 1.21 (0.75, 1.98)
Body mass index Underweight or normal weight Overweight or Obese
67.8 32.2
7.9 5.8
1.00 0.72 (0.32, 1.63)
Caucasian Yes No
77.9 22.1
7.5 7.4
1.00 0.99 (0.19, 5.21)
No. of children412 years ⩽1 ⩾2
86.6 13.4
6.2 15.5
1.00 2.79 (1.38, 5.64)
Family history of asthma No Yes
76.3 23.7
4.9 15.9
1.00 3.64 (1.67, 7.95)
Household income Middle Low High
27.2 26.9 45.9
6.8 7.1 8.0
1.00 1.05 (0.31, 3.64) 1.21 (0.35, 4.11)
Smoking inside home No Yes
88.6 11.4
6.9 11.3
1.00 1.71 (0.41, 7.17)
Use of gas furnace No Yes
39.0 61.0
4.3 9.3
1.00 2.28 (1.11, 4.67)
Use of electric heating No Yes
71.8 28.2
9.3 2.5
1.00 0.25 (0.15, 0.43)
Region Ontario Quebec, New Brunswick British Columbia, Alberta
41.4 28.4 30.2
8.7 4.5 8.4
1.00 0.49 (0.25, 0.97) 0.96 (0.51, 1.84)
Season Winter Spring Summer Fall
27.3 22.8 25.7 24.1
9.2 6.8 4.7 7.0
1.00 0.80 (0.25, 2.58) 0.53 (0.13, 2.15) 0.84 (0.27, 2.60)
Daily sun exposure 1–3 h o1 h 43 h
36.3 11.4 52.3
7.8 10.5 6.5
1.00 1.39 (0.22, 8.62) 0.82 (0.39, 1.70)
Use of sunscreen Always/often Sometimes Rarely/never
66.3 16.7 17.0
6.4 5.9 11.8
1.00 0.92 (0.38, 2.23) 1.96 (1.05, 3.66)
Daily consumption of milk At least once Less than once More than twice
58.2 10.6 31.2
5.8 13.4 8.5
1.00 2.52 (0.77, 8.23) 1.52 (0.92, 2.51)
Daily sedentary activities 0–2 h 3–4 h ⩾5h
64.9 23.9 11.1
5.9 6.9 9.9
1.00 1.18 (0.66, 2.10) 1.74 (0.88, 3.44)
P-valuea 0.08
0.38
0.37
0.99
0.004
0.002
0.83
0.25
0.02
o0.001
0.08
0.78
0.58
0.07
0.12
0.17
Abbreviations: CI, confidence interval; OR, odds ratio. aP-value from chi-squared test indicating significant difference in the characteristics between children with and without current wheeze.
© 2014 Macmillan Publishers Limited
European Journal of Clinical Nutrition (2014) 1 – 7
Association of vitamin D with respiratory outcomes SJ Niruban et al
4 Table 2. Proportion of ever asthma by factors and odds ratio for the relationship of factors with ever asthma Factor
Proportion of ever asthma within factor
Unadjusted OR (95% CI)
Factors
Current wheeze
Ever asthma
OR (95% CI)
P-value
OR (95% CI)
P-value
Age (years)
1.10 (0.88, 1.37)
0.36
1.15 (0.96, 1.37)
0.12
Sex Female Male
1.00 1.12 (0.69, 1.82)
0.61
1.00 0.91 (0.46, 1.79)
0.76
Family history of asthma No 1.00 Yes 4.22 (1.58, 11.23)
0.008
1.00 6.14 (3.71, 0.14)
o0.001
Number of children412 years ⩽1 1.00 ⩾2 2.19 (1.02, 4.72)
0.046
– –
Use of electric heating No 1.00 Yes 0.29 (0.11, 0.75)
0.016
– –
0.13
Vitamin D level (nmol/l) o50 50– o75 ⩾ 75
14.5 8.2 10.2
1.9 (1.27, 2.84) 1.00 1.28 (0.65, 2.50)
Sex Female Male
10.2 10.5
1.00 1.03 (0.6, 1.78)
BMI Underweight or normal weight Overweight/obese
P-valuea
Table 3. Results from the multiple logistic regression of current wheeze and ever asthma with vitamin D levels
0.89
0.09 12.6 8.6
1.00 0.65 (0.39, 1.10) 0.01
Caucasian Yes No
9.2 14.4
1.00 1.67 (1.11, 2.50)
No. of children412 years ⩽1 ⩾2
9.7 14.0
1.00 1.51 (0.43, 5.37)
Family history of asthma No Yes
5.6 25.9
1.00 5.94 (3.55, 9.95)
Household income Middle Low High
8.9 14.3 9.2
1.00 1.7 (0.78, 3.72) 1.03 (0.48, 2.18)
0.38
o 0.001
0.14
0.05
Smoking inside home No Yes
9.2 18.7
1.00 2.26 (0.77, 6.66)
Use of gas furnace No Yes
11.0 9.7
1.00 0.88 (0.48, 1.59)
0.61
0.81
Use of electric heating No Yes
10.0 10.6
1.00 1.07 (0.57, 2.02)
Region Ontario Quebec, New Brunswick British Columbia, Alberta
11.1 9.8 9.7
1.00 0.87 (0.46, 1.66) 0.87 (0.30, 2.48)
Season Winter Spring Summer Fall
10.1 11.1 6.4 8.7
1.00 1.01 (0.46, 2.24) 0.56 (0,29, 1.06) 1.19 (0.46, 3.11)
Daily sun exposure 1–3 h o1 h 43 h
7.9 16.2 10.7
1.00 2.27 (1.35, 3.84) 1.41 (0.79, 2.53)
Use of sunscreen Always / often Sometimes Rarely / never
9.3 9.8 13.3
1.00 1.06 (0.54, 2.08) 1.51 (0.69, 3.3)
Daily consumption of milk At least once Less than once More than twice
9.9 12.6 10.2
1.00 1.31 (0.42, 4.05) 1.03 (0.70, 1.53)
Daily sedentary hours 0–2 h 3–4 h ⩾5h
9.3 8.6 11.7
1.00 0.91 (0.57, 1.47) 1.29 (0.36, 4.57)
Season Winter Spring Summer Fall
— — —
1.00 0.55 (0.16, 1.92) 0.75 (0.18, 3.03) 0.79 (0.22, 2.80)
Vitamin D level (nmol/L) o50 3.40 (1.06, 10.89) 50–o75 1.00 ⩾ 75 2.26 (1.18, 4.33)
4.09 (2.29, 7.30) 1.00 1.62 (0.91, 2.88)
0.32 0.66 0.69 0.041 0.019
1.00 0.71 (0.32, 1.58) 0.52 (0.23, 1.19) 0.98 (0.37, 2.62) 1.86 (1.16, 3.01) 1.00 1.54 (0.77, 3.08)
o0.001 0.091
0.36 0.11 0.97 0.015 0.20
Abbreviations: CI, confidence interval; OR, odds ratio. 0.87
0.12
0.068
0.33
0.69
0.66
Abbreviations: CI, confidence interval; OR, odds ratio. aP-values indicate the significant difference in the characteristics between children with and without ever asthma.
European Journal of Clinical Nutrition (2014) 1 – 7
Daily sun exposure o1 h 1–3 h 43 h
DISCUSSION In this study of children of ages 6–12 years, we found a U-shaped relationship between 25(OH)D levels and current wheeze and lung function, indicators of current respiratory health. The U-shaped relationship was also observed between 25(OH)D levels and ever asthma, but the OR for the high 25(OH)D category was not statistically significant. As the report of ever asthma was determined from the diagnosis of asthma by a health professional during the participant’s entire lifetime, children with ever asthma might not have had asthma-related symptoms at the time of collection of blood used in 25(OH)D measurements. One of the conclusions in the Institute of Medicine report was that 25(OH)D levels 475 nmol/l were not consistently associated with increased benefit and the risks have been identified for some outcomes at 25(OH)D levels 4125 nmol/l.23 Based on this report, we chose three categories, 13.7–49 nmol/l (low), 50–74 nmol/l (moderate) and 75–195.1 nmol/L (high) in our study and found an increased risk for adverse respiratory health outcomes in low and high categories in comparison to the moderate category. This U-shaped non-linear relationship between 25(OH)D levels and current wheeze was further examined in two independent analyses by considering 25(OH)D levels as a continuous variable and a four-level categorical variable based on quartiles, respectively. Although there was some evidence for the U-shaped relationship in these analyses, the increased risk observed between 25(OH)D levels and current wheeze in the fourth 25 (OH)D quartile (86.9–195.1 nmol/l) was not statistically significant, © 2014 Macmillan Publishers Limited
Association of vitamin D with respiratory outcomes SJ Niruban et al
5 of gastrointestinal inflammatory disease (colitis) in which treatment with 1,25(OH)D3 was shown to reduce interleukin-17 expression.31 A recent review article proposed asthma as ‘a chronic disease of the innate and adaptive immune systems responding to viruses and allergens,32 providing the relevance for examining the relationship between vitamin D and respiratory outcomes in our study. Several studies have previously investigated the relationship between vitamin D levels in mothers during pregnancy,19–23,33 cord blood at birth 16 and children at different ages,12–14,34,35 and respiratory outcomes including indictors of wheezing, asthma or lung function in children at various ages. Except for two studies,16,33 all other studies considered vitamin D level as a continuous or binary variable in investigating the relationship between vitamin D levels and respiratory outcomes. In addition, the two studies that investigated the non-linear relationship did not find a significant U-shaped relationship between vitamin D levels and wheezing and/or asthma.16,33 In the first study, from Tucson, AZ, cord blood 25(OH)D levels were measured at birth and relative to the reference category (50–74.9 nmol/l), 25(OH)D levelso 50 nmol/l and ⩾ 100 nmol/l were associated with increased total IgE and inhalant allergen-specific IgE measured at ages 1 to 5 years in a longitudinal analysis, but no association was observed with asthma prevalence at 5 years.16 In the second study, from Spain, circulating maternal vitamin D [25(OH)D3] levels were measured, and relative to the first quartile (o 54.8nmol/l), there was a significant decreasing trend in the ORs for lower respiratory tract infections in the second (54.8–72.3 nmol/l), third (73–92.5 nmol/l) and fourth quartiles (492.5 nmol); however, none of the ORs were statistically significant.33 In this study, there was no significant association between circulating vitamin D (25 (OH)D3) levels and wheezing at age 1 year or asthma at age 4–6 years. In our study, we considered the serum 25(OH)D levels in children and found a non-linear U-shaped relationship with current wheeze and lung function, indicators of current respiratory health. There is evidence from previous studies for the association of low and high levels vitamin D with increased risk of wheezing or asthma in children. In a large birth cohort study of infants from
which was not entirely consistent with the significant increased risk observed in the high 25(OH)D category (75–195.1 nmol/l) in our other analyses. Vitamin D plays an active role in regulating specific phases of human immunity and has been shown to be associated with innate and adaptive immunity. The vitamin D receptor gene and the gene for 1α-hydroxylase (CYP27B1) have been shown to be induced following activation of Toll-like receptor 2/1 gene, the principal pathogen recognition receptor for Mycobacterium tuberculosis.11 However, the role of CYP27B1 gene in the expression of the vitamin D receptor gene following activation of the Toll-like receptor 2/1 gene is not very clear.10 The possibility of Vitamin D acting as a regulator of Th17 cells, which have the capacity to synthesize the pro-inflammatory cytokine interleukin-17,30 has been suggested from animal models
Table 4. Distribution of demographic factors and lung function by vitamin D categories Factor
Vitamin D categories o50 nmol/l 50–o75 nmol/l ⩾ 75 (nmol/L) Mean (s.d.)
Age (years) Height (cm) Weight (kg) FVC (l) FEV1 (l) FEV1/FVC FEF25–75% (l/s) % Predicted FVC % Predicted FEV1 % Predicted FEV1/FVC
9.9 144.7 43.6 2.59 2.17 0.85 2.31 101.9 98.86 96.84
Mean (s.d.)
Mean (s.d.)
(2.9) 9.3 (3.2) (20.4) 139.4 (22.0) (24.9) 36.4 (18.7) (1.11) 2.43 (1.14) (0.86) 2.05 (0.95) (0.1) 0.85 (0.1) (1.07) 2.22 (1.25) (18.14) 103.09 (20.22) (18.56) 100.89 (20.67) (11.71) 97.8 (11.26)
9.0 137.8 34.2 2.33 1.94 0.84 2.01 102.3 98.73 96.49
(3.1) (20.3) (17.6) (0.96) (0.77) (0.09) (1.05) (17.61) (17.99) (10.69)
P-valuea 0.002 0.002 0.004 0.03 0.005 0.06 0.001 0.45 0.06 0.06
Abbreviations: FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity. aP-values are from analysis of variance for comparison between vitamin D categories.
Table 5.
Results from the multiple linear regression analysis of lung function outcomes FVC (ml)
FEV1 (ml)
FEV1/FVC (%)
FEF25–75% (ml/s)
β (s.e.)
β (s.e.)
β (s.e.)
β (s.e.)a
(14.4)¶ (15.85) (38.6)‡ (2.94)** (0.07)¶ (1.94)‡
− 0.197 (0.198) 2.198 (0.485)§ — 0.08 (0.062) — − 0.156 (0.061)‡
57.62 (14.2)¶ 103.49 (36.73)‡ — 23.74 (4.22)** 0.41 (0.14)‡ 7.69 (5.98)
− 59.61 (25.57)‡ — − 47.12 (12.79)¶
0.436 (0.793) — − 1.46 (0.398)¶
− 52.27 (57.91) — − 142.48 (48.86)‡
Age and vitamin D level interaction o50 − 26.65 (22.79) 50–o75 (ref ) — ⩾ 75 − 36 (10.32)¶
− 25.28 (15.35) — − 29.5 (8.08)¶
— — —
— — —
Weight and vitamin D level interaction o50 — 50–o75 (ref ) — ⩾ 75 — Intercept 2376.73 (25.66)**
— — — 1972.11 (16.58)**
— — — 83.974 (0.397)**
− 10.26 (3.31)¶ — − 8.58 (3.42)‡ 2039.94 (44.59)**
Factor
a
Ageb Sex (ref—male) Caucasian (ref—yes) Heightb Height2 b Weightb
68.93 − 109.49 − 143.35 27.48 0.29 12.91
Vitamin D level (nmol/l) o50 50 too 75 (ref) ⩾ 75
(15.88)§ (16.06)** (53.05)‡ (3.35)** (0.06)§ (1.62)**
− 73.88 (32.19)‡ — − 17.88 (21.49)
a
52.49 − 33.05 − 102.25 26.21 0.28 5.83
a
‡
P-value ⩽ 0.05. ¶P-value ⩽ 0.01. §P-value ⩽ 0.001. **P-value ⩽0.0001. aβ (s.e.), regression coefficient (s.e.). bVariables were centralized.
© 2014 Macmillan Publishers Limited
European Journal of Clinical Nutrition (2014) 1 – 7
Association of vitamin D with respiratory outcomes SJ Niruban et al
6 is required from randomized control trials in determining safer 25 (OH)D levels in the management of asthma in children. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS The research and analysis are based on the data from Statistics Canada and opinions expressed herein do not represent the views of Statistics Canada.
REFERENCES
Figure 1. Relationship between predicted risk of current wheeze and serum vitamin D level from the generalized additive model. The predicted risk is plotted for a male child at age 9 years with positive family history of asthma and absence of electric heating at home.
New Zealand, lower cord-blood 25(OH)D levels were associated with increased risk of wheezing at 15 months, 3 years and 5 years of age.36 In contrast, a Swedish birth cohort study reported that a higher intake of vitamin D during infancy was associated with an increased cumulative incidence of atopic dermatitis, allergic rhinitis and asthma from infancy to 6 years.8 Similar to the finding of this study, a birth cohort study from the United States also reported that early infant vitamin D supplementation was associated with an increased risk of asthma by 3 years of age among black children.15 The biological mechanism for the U-shaped relationship suggested is unknown, but might be related to the potential of vitamin D to modify the immune response as has been previously reported in a number of experimental studies. Based on a review of these experimental studies,37 the authors suggested that vitamin D helped blunt Th2 responses by having inhibitory effects on the production of a number of cytokines, providing a possible explanation for the increased risk of respiratory outcomes associated with lower vitamin D levels in our study. In contrast, excess supplementation of vitamin D in mice was associated with an increase in the production of Th2 cytokines and serum IgE,38 a marker of allergic diseases including asthma, providing a possible explanation for the increased risk of respiratory outcomes with higher levels of vitamin D levels in our study. It may be that the timing of vitamin D exposure during the immune response and the baseline level of vitamin D are both important contributors to any effect. Measured serum 25(OH)D level includes contributions from both cutaneous production and dietary intake (for example, fortified milk).2,13 The half-life of vitamin D is ~ 3 weeks and is affected by serum calcium levels.39–41 Cutaneous synthesis of vitamin D is dependent on skin pigmentation, age, behavioral and lifestyle factors.42,43 Our study was conducted in Canada, which is located in the northern hemisphere (43N latitude, and above),44 with children living in some of the data collection sites receiving sun light only for a short duration, as little as 3 h per day during the winter months.45 Consequently very limited cutaneous vitamin D synthesis occurs during this period.46 In addition, season, skin pigmentation, use of sunscreen and duration of daily sun exposure were not significant factors in our study. As reported in other studies, the confounding effect of these variables may be minimal among children.47,48 In summary, the observed association in these data between vitamin D levels with current wheeze and lung function appear to support a U-shaped dose–response relationship. Further evidence European Journal of Clinical Nutrition (2014) 1 – 7
1 WHO. Asthma Fact sheet N307. World Health Organization: Geneva, 2011. Available at www.who.int/mediacentre/factsheets/fs307/en/index.html (accessed 16 October 2013). 2 Litonjua AA. Fat-soluble vitamins and atopic disease: what is the evidence? Proc Nutr Soc 2012; 71: 67–74. 3 Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK et al. ISAAC Phase Three Study Group. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006; 368: 733–743. 4 Gergen PJ, Weiss KB. The increasing problem of asthma in the United States. Am Rev Respir Dis 1992; 146: 823–824. 5 The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC). Eur Respir J 1998; 12, 315–335. 6 Kay AB. Allergy and allergic diseases. First of two parts. N Engl J Med 2001; 344: 30–37. 7 Maziak W. The asthma epidemic and our artificial habitats. BMC Pulm Med 2005; 5: 5. 8 Bäck O, Blomquist HK, Hernell O, Stenberg B. Does vitamin D intake during infancy promote the development of atopic allergy? Acta Derm Venereol 2009; 89: 28–32. 9 Torres-Borrego J, Moreno-Solís G, Molina-Terán AB. Diet for the prevention of asthma and allergies in early childhood: much ado about something? Allergol Immunopathol 2012; 4: 244–252. 10 Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Rheum Dis Clin North Am 2012; 381: 125–139. 11 Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311: 1770–1773. 12 Brehm JM, Celedón JC, Soto-Quiros ME, Avila L, Hunninghake GM, Forno E et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med 2009; 179: 765–771. 13 van Oeffelen AA, Bekkers MB, Smit HA, Kerkhof M, Koppelman GH, Haveman-Nies A et al. Serum micronutrient concentrations and childhood asthma: the PIAMA birth cohort study. Pediatr Allergy Immunol 2011; 22: 784–793. 14 Bener A, Ehlayel MS, Tulic MK, Hamid Q. Vitamin D deficiency as a strong predictor of asthma in children. Int Arch Allergy Immunol 2012; 157: 168–175. 15 Milner JD, Stein DM, McCarter R, Moon RY. Early infant multivitamin supplementation is associated with increased risk for food allergy and asthma. Pediatrics 2004; 114: 27–32. 16 Rothers J, Wright AL, Stern DA, Halonen M, Camargo CA Jr. Cord blood 25-hydroxyvitamin D levels are associated with aeroallergen sensitization in children from Tucson, Arizona. J Allergy Clin Immunol 2011; 128: 1093–1099. 17 Oren E, Banerji A, Camargo CA Jr. Vitamin D and atopic disorders in an obese population screened for vitamin D deficiency. J Allergy Clin Immunol 2008; 121: 533–534. 18 Lewis E, Fernandez C, Nella A, Hopp R, Gallagher JC, Casale TB. Relationship of 25-hydroxyvitamin D and asthma control in children. Ann Allergy Asthma Immunol 2012; 108: 281–282. 19 Erkkola M, Kaila M, Nwaru BI, Kronberg-Kippilä C, Ahonen S, Nevalainen J et al. Maternal vitamin D intake during pregnancy is inversely associated with asthma and allergic rhinitis in 5-year-old children. Clin Exp Allergy 2009; 39: 875–882. 20 Devereux G, Litonjua AA, Turner SW, Craig LC, McNeill G, Martindale S et al. Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr 2007; 85: 853–859. 21 Gale CR, Robinson SM, Harvey N, Javaid MK, Jiang B, Martyn CN et al. Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr 2008; 62: 68–77.
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7 22 Camargo CA Jr, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR et al. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr 2007; 85: 788–795. 23 Pike KC, Inskip HM, Robinson S, Lucas JS, Cooper C, Harvey NC et al. Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes. Thorax 2012; 67: 950–956. 24 Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011; 96: 53–58. 25 IOM (Institute of Medicine). Dietary Reference Intakes for Calcium and Vitamin D. The National Academies Press: Washington, DC, 2011. 26 Tremblay M, Wolfson M, Gorber SC. Canadian Health Measures Survey: rationale, background and overview. Health Rep 2007; 18(Suppl): 7–20. 27 Statistics Canada. Canadian Health Measures Survey (CHMS) Data User Guide: Cycle 1. Statistics Canada: Ottawa (ON), 2011. www23.statcan.gc.ca/imdb-bmdi/pub/ document/5071_D2_T1_V1-eng.htm (accessed 4 November 2013). 28 Bryan S, St-Denis M, Wojtas D. Canadian Health Measures Survey: clinic operations and logistics. Health Rep 2007; 18(Suppl): 53–70. 29 Wood SN.Generalized Additive Models: An Introduction With R. Chapman & Hall/ CRC: New York, NY, 2006. 30 Harrington LE, Mangan PR, Weaver CT. Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 2006; 18: 349–356. 31 Daniel C, Sartory NA, Zahn N, Radeke HH, Stein JM. Immune modulatory treatment of TNBS colitis with calcitriol is associated with a change of a Th1/Th17 to a Th2 and regulatory T cell profile. J Pharmacol Exp Ther 2008; 324: 23–33. 32 Holtzman MJ. Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens. J Clin Invest 2012; 122: 2741–2748. 33 Morales E, Romieu I, Guerra S, Ballester F, Rebagliato M, Vioque J et al. INMAProject. Maternal vitamin D status in pregnancy and risk of lower respiratory tract infections, wheezing, and asthma in offspring. Epidemiology 2012; 23: 64–71. 34 Alyasin S, Momen T, Kashef S, Alipour A, Amin R. The relationship between serum 25 hydroxy vitamin D levels and asthma in children. Allergy Asthma Immunol Res 2011; 3: 251–255. 35 Gupta A, Sjoukes A, Richards D, Banya W, Hawrylowicz C, Bush A et al. Relationship between serum vitamin D, disease severity, and airway remodeling in children with asthma. Am J Respir Crit Care Med 2011; 184: 1342–1349.
36 Camargo CA Jr, Ingham T, Wickens K, Thadhani R, Silvers KM, Epton MJ et al. New Zealand Asthma and Allergy Cohort Study Group. Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics 2011; 127: e180–e187. 37 Searing DA, Leung DY. Vitamin D in atopic dermatitis, asthma and allergic diseases. Immunol Allergy Clin North Am 2010; 30: 397–409. 38 Matheu V, Bäck O, Mondoc E, Issazadeh-Navikas S. Dual effects of vitaminDinduced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease. J Allergy Clin Immunol 2003; 112: 585–592. 39 Radlović N, Mladenović M, Simić D, Radlović P. Vitamin D in the light of current knowledge. Srp Arh Celok Lek 2012; 140: 110–114. 40 Lips P. Interaction between vitamin D and calcium. Scand J Clin Lab Invest Suppl 2012; 243: 60–64. 41 Bouillon R. Why modest but widespread improvement of the vitamin D status is the best strategy? Best Pract Res Clin Endocrinol Metab 2011; 25: 693–702. 42 Cranney A, Horsley T, O'Donnell S, Weiler H, Puil L, Ooi D et al. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep) 2007; 158: 1–235. 43 Langlois K, Greene-Finestone L, Little J, Hidiroglou N, Whiting S. Vitamin D status of Canadians as measured in the 2007 to 2009 Canadian Health Measures Survey. Health Rep 2010; 21: 47–55. 44 Infinite Gravity. Canadian City and Town Geographic Coordinates. Infinite Gravity: Maple Ridge (BC), 2004. Available at www.infinitegravity.ca/mapdata/canada.asp (accessed 16 October 2013). 45 Climate & Temperature: Canada, 2012. climatemps.com. Available at http://www. climatetemp.info/canada/ (accessed 16 October 2013). 46 Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 1988; 67: 373–378. 47 Brehm JM, Acosta-Pérez E, Klei L, Roeder K, Barmada M, Boutaoui N et al. Vitamin D insufficiency and severe asthma exacerbations in Puerto Rican children. Am J Respir Crit Care Med 2012; 186: 140–146. 48 Searing DA, Zhang Y, Murphy JR, Hauk PJ, Goleva E, Leung DY. Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol 2010; 125: 995–1000.
Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website (http://www.nature.com/ejcn)
© 2014 Macmillan Publishers Limited
European Journal of Clinical Nutrition (2014) 1 – 7
ORIGINAL ARTICLE
Association of vitamin D with respiratory outcomes in Canadian children SJ Niruban1, K Alagiakrishnan2, J Beach2 and A Senthilselvan1 BACKGROUND/OBJECTIVES: Vitamin D modifies airway inflammation and appears to be important in building immunity against respiratory infections, and so is potentially beneficial in asthma. However, to date results from studies investigating the relationship of vitamin D with respiratory outcomes are inconsistent. The objective of this study was to determine the association of vitamin D with current wheeze, ever asthma and lung function. SUBJECTS/METHODS: Data on 1213 children aged 6–12 years, from the Canadian Health Measures Survey, were considered for the study. Serum 25-hydroxy vitamin D (25(OH)D) levels were categorized into three categories: ⩽ 49 nmol/l (low); 50–74 nmol/l (moderate); and ⩾ 75 nmol/l (high). RESULTS: Children in the low and high 25(OH)D categories were more likely to report current wheeze in comparison to those in the moderate category (odds ratio (OR): 3.26, 95% confidence interval (CI): 1.16–9.17 and OR: 2.14, 95% CI: 1.07–4.28, respectively). The results for the association between 25(OH)D levels and ever asthma were similar to those observed for current wheeze, except that a significant association was observed only in the lower category. The rate of increase in forced expiratory volume in one second and forced vital capacity with age was greater in the moderate category. CONCLUSIONS: Children in both low and high 25(OH)D categories had increased risk of current wheeze and reduced rate of change in lung function with age in comparison to the moderate category, raising the possibility of a U-shaped association between vitamin D levels and respiratory health. Clearer guidelines for optimal vitamin D levels are required to improve respiratory health in children. European Journal of Clinical Nutrition advance online publication, 2 July 2014; doi:10.1038/ejcn.2014.121
INTRODUCTION Asthma is the most common chronic condition affecting children in developed countries.1,2 Asthma prevalence has been increasing during recent decades in many parts of the world.3–6 It is likely that this increase in asthma prevalence is influenced by many environmental 4 and behavioral factors. 7–9 Vitamin D has been recognized to play an important role in innate and adaptive immune responses for some years.10 It has been shown to be a potent stimulator of the mechanisms associated with pathogen elimination.11 Recent animal studies have raised the possibility of vitamin D exerting some of its effect on inflammation and autoimmune diseases through the regulation of Th17 cells (a T-cell lineage distinct from T-helper 1 (Th1) or Th2 cells).10 Initially, Bäck et al.8 demonstrated a significant association of vitamin D with asthma-related parameters, including lung function, in a representative adult population from the US. However, despite ongoing research, the evidence remains conflicting, with studies reporting protective effects,12–14 adverse effects,8,15,16 as well as an absence of any effect17,18 of vitamin D on asthma. There are also suggestions that maternal vitamin D status19–23 and early infant supplementation8,15 may influence the early programming of the immune system and so the development of asthma and allergic diseases in offspring. A committee appointed by the Institute of Medicine reported that a serum vitamin D level of ⩾ 50 nmol/l for skeletal health, and
higher values were not consistently associated with increased health benefit.24 For extraskeletal outcomes such as cancer, cardiovascular disease, diabetes and autoimmune disorders, no recommendations were made by the committee due to the inconsistent and inconclusive evidence.24 In the conclusion of their manuscript the authors reported that ‘serum concentrations of 25(OH)D above 30 ng/ml (75 nmol/l) are not consistently associated with increased benefit, and risks have been identified for some outcomes at 25OHD levels above 50 ng/ml (125 nmol/l).’ Interestingly, the relationship between 25-hydroxy vitamin D (25 (OH)D) levels and some of the extraskeletal outcomes has been reported to be U-shaped, with increased risk at both low and high levels of 25(OH)D.25 In our study, we used the data from the Canadian Health Measures Survey to further examine whether there might be a non-linear relationship between serum 25[OH]D concentration and current wheeze, ever asthma and lung function parameters in children. MATERIALS AND METHODS The Canadian Health Measures Survey was developed by Statistics Canada in partnership with Health Canada and the Public Health Agency of Canada.26 The survey included two main components: an in-home interview and a clinic visit.27 Upon completion of the household interview, participants were asked to attend a mobile examination centre.28 (More details of the methods are given in online Supplementary Methods.)
1 School of Public Health, University of Alberta, Edmonton, Alberta, Canada and 2Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Correspondence: Dr A Senthilselvan, School of Public Health, University of Alberta, 3-276 Edmonton Clinic Health Academy, 11405–87 Avenue, Edmonton, Alberta, Canada T6G 2T4. E-mail: [email protected] Received 5 December 2013; revised 14 April 2014; accepted 16 May 2014
Association of vitamin D with respiratory outcomes SJ Niruban et al
2 After excluding adolescents and adults, 1213 children aged 6–12 years were included in the study. Of these 1030 had vitamin D measurements, and 951 of the 1030 children had valid lung function measurements. In the Canadian Health Measures Survey, the presence of current wheeze was established from the question ‘Has your child had wheezing or whistling in the chest in the last 12 months?’ from the clinic questionnaire. The presence of ever asthma was determined from the question ‘We are interested in long-term conditions which are expected to last or have already lasted 6 months or more and that have been diagnosed by a health professional: Do you have asthma?’ Spirometric measurements comprised forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced expiratory flow between 25 and 75% of the FVC (FEF25–75%). The calendar months of data collection were grouped into four seasons, with winter spanning over 4 months reflecting the long Canadian winter (spring: April and May; summer: June–August; fall: September–November; winter: December–March).
Statistical analysis The 25(OH)D levels were divided into three categories: 13.7–o50 nmol/l (low), 50– o75 nmol/l (moderate) and 75–195.1 nmol/l (high), where 13.7 and 195.1 nmol/l are the minimum and maximum values of the 25(OH)D levels. Four categories based on the quartiles of 25(OH)D levels (13.7–57.9, 58.0–72.5, 72.6–86.8, 86.9–195.1 nmol/l) were also considered for comparison with results obtained with three categories. Multiple logistic regression analysis was used to test the association between 25(OH)D levels, and current wheeze and ever asthma after controlling for other factors. Multiple linear regression was used to determine the relationship between the 25(OH)D levels and lung function after controlling for other factors. We used the package mgcv in R (R Core Team, 2013) to conduct logistic regression analysis using the generalized additive model procedure29 to explore the non-linear relationship between 25(OH) levels and current wheeze.
RESULTS The mean age of the children was 9.1 years. The prevalence of current wheeze and ever asthma was 7.4% and 10.3%, respectively. Among the children with ever asthma, 53.4% children had current wheeze. Among the children reporting current wheeze, 65.9% reported less than four episodes of wheeze while 34.1% reported four or more episodes of wheeze in the last 12 months. Although there was variation in the mean 25(OH)D levels between the four seasons (Supplementary Table 1), the overall differences between the mean values were not statistically significant (P = 0.43). As shown in Table 1, the proportion of children in the low, moderate and high 25(OH)D categories was 15.6%, 37.5% and 46.9%, respectively. The prevalence of current wheeze was 11.4%, 4.1% and 7.7% in the low, moderate and high 25(OH)D categories, respectively. Children in the low and high 25(OH)D categories were more likely to report current wheeze in comparison to those in the moderate category. Children with a family history of asthma had a significantly greater prevalence of current wheeze (16.0%) than those without a family history of asthma (5.0%). As shown in Table 2, the prevalence of ever asthma was 14.5%, 8.2% and 10.2% in the low, moderate and high 25(OH)D categories, respectively. Children in the low and high 25(OH)D categories were more likely to have a report of ever asthma in comparison to those children in the moderate category. Children with a family history of asthma had a significantly greater prevalence of ever asthma (25.9%) than those without a family history of asthma (5.6%). The factors included in Tables 1 and 2 were initially considered for the multiple logistic regression analysis of current wheeze and ever asthma, respectively. The results from the final multiple logistic regression of current wheeze or ever asthma are shown in Table 3. After controlling for confounders including season, children in both the low and high 25(OH)D categories had an increased odds of reporting current wheeze in comparison to those in the moderate category (odds ratio (OR): 3.26; 95% European Journal of Clinical Nutrition (2014) 1 – 7
confidence interval (CI): 1.16–9.17 for low vs moderate, and OR: 2.14; 95% CI: 1.07–4.28 for high vs moderate). Children in the low 25(OH)D category had an increased odds of ever asthma in comparison to those in the moderate category (OR: 1.86, 95% CI: 1.15, 3.01). Children in the high 25(OH)D category had a nonsignificant increased risk of ever asthma in comparison to the moderate category (OR: 1.46, 95% CI: 0.76, 2.80). When we considered four categories using the 25(OH)D quartiles, relative to the second quartile, ORs of current wheeze were 2.75 (95% CI: 1.20, 6.31; P = 0.02) in the first quartile, 3.02 (95% CI: 1.26, 7.25; P = 0.018) in the third quartile and 1.59 (95% CI: 0.85, 2.98; P = 0.13) in the fourth quartile after controlling for the factors considered in Table 3. The adjusted ORs for three and four 25(OH)D categories are further illustrated in Supplementary Table 2. The mean values of age, height, weight and lung function outcomes were significantly different between the three 25(OH)D categories (Table 4). The mean percent predicted FEV1, FVC, FEV1/ FVC ratio and FEF25–75% were the greatest in the moderate 25(OH) D category in comparison to the low and high 25(OH)D categories, but the differences between categories were not statistically significant. Table 5 displays the relationship between 25(OH)D levels, and FEV1, FVC, FEV1/FVC ratio and FEF25–75% after adjusting for age, sex, race (Caucasian or not), height, height-squared (for FEV1 and FVC) and weight. The interaction effect between 25(OH)D levels and children’s age was significant in the relationship of 25(OH)D levels with FVC (P = 0.02) and FEV1 (P = 0.02). To elucidate the interaction effects, the estimated mean FEV1 and FVC values were plotted against the children’s age, for male Caucasian children with height and weight adjusted to the mean values in Supplementary Figures 1 and 2, respectively. Supplementary Figure 1 shows that the increase in FEV1 with children’s age, indicated by the slopes of the fitted lines, was greater in the moderate 25(OH)D category than in the low and high 25(OH)D categories. The relationship between FEV1 and age for females and for other race categories was similar to Supplementary Figure 1 except for a shift in the intercepts. As shown in Supplementary Figure 2, the results for FVC were similar to those observed for FEV1, with the slopes greater in the moderate 25(OH)D category than in the low and high 25(OH)D categories. After controlling for the factors in Table 5, mean FEV1/FVC ratio was greater for the low and high 25(OH)D categories than for the moderate category, with the difference being statistically significant only between moderate and high 25(OH)D categories. As shown in Table 5, there was a significant interaction between weight and 25(OH)D categories in the regression model for FEF25–75%, with the increase in FEF25–75% with children’s weight being greater in the moderate 25(OH)D category than in the low and high 25(OH)D categories. The relationship between 25(OH)D levels and lung function measurements remained significant after including the variable for season with four categories in a multiple regression model that also included age, sex, race (Caucasian or not), height, height-squared (for FEV1 and FVC) and weight (data not shown). In the generalized additive model analysis, the 25(OH)D level was considered as a continuous variable and its relationship with current wheeze was examined. To characterize the interpretation of the results from generalized additive model procedure, the predicted risk of current wheeze was plotted in Figure 1 against the 25(OH)D levels for a male child of 9 years with a positive family history of asthma and absence of electric heating at home. After controlling for the factors considered previously in Table 3, there was an increased risk of current wheeze for 25(OH)D levels from 13.7 to about 50 nmol/l, followed by a minimal risk of current wheeze until about 75 nmol/l and then an increase in the risk of current wheeze until from 75 to ~ 100 nmol/l. As indicated by the wide 95% confidence intervals in Figure 1, the risk estimates were not stable above 100 nmol/l due to the small number of observations. © 2014 Macmillan Publishers Limited
Association of vitamin D with respiratory outcomes SJ Niruban et al
3 Table 1.
Characteristics of the study sample, proportion of current wheeze by factors and odds ratio for the relationship of factors with current
wheeze Factors
Distribution of characteristics in the sample (%)
Proportion of current wheeze within factor (%)
Unadjusted OR (95% CI)
Vitamin D level (nmol/l) o 50 50 too 75 ⩾ 75
15.6 37.5 46.9
11.4 4.1 7.7
3.02 (1.04, 8.78) 1.0 1.96 (0.91, 4.22)
Sex Female Male
47.5 52.5
6.7 8.1
1.00 1.21 (0.75, 1.98)
Body mass index Underweight or normal weight Overweight or Obese
67.8 32.2
7.9 5.8
1.00 0.72 (0.32, 1.63)
Caucasian Yes No
77.9 22.1
7.5 7.4
1.00 0.99 (0.19, 5.21)
No. of children412 years ⩽1 ⩾2
86.6 13.4
6.2 15.5
1.00 2.79 (1.38, 5.64)
Family history of asthma No Yes
76.3 23.7
4.9 15.9
1.00 3.64 (1.67, 7.95)
Household income Middle Low High
27.2 26.9 45.9
6.8 7.1 8.0
1.00 1.05 (0.31, 3.64) 1.21 (0.35, 4.11)
Smoking inside home No Yes
88.6 11.4
6.9 11.3
1.00 1.71 (0.41, 7.17)
Use of gas furnace No Yes
39.0 61.0
4.3 9.3
1.00 2.28 (1.11, 4.67)
Use of electric heating No Yes
71.8 28.2
9.3 2.5
1.00 0.25 (0.15, 0.43)
Region Ontario Quebec, New Brunswick British Columbia, Alberta
41.4 28.4 30.2
8.7 4.5 8.4
1.00 0.49 (0.25, 0.97) 0.96 (0.51, 1.84)
Season Winter Spring Summer Fall
27.3 22.8 25.7 24.1
9.2 6.8 4.7 7.0
1.00 0.80 (0.25, 2.58) 0.53 (0.13, 2.15) 0.84 (0.27, 2.60)
Daily sun exposure 1–3 h o1 h 43 h
36.3 11.4 52.3
7.8 10.5 6.5
1.00 1.39 (0.22, 8.62) 0.82 (0.39, 1.70)
Use of sunscreen Always/often Sometimes Rarely/never
66.3 16.7 17.0
6.4 5.9 11.8
1.00 0.92 (0.38, 2.23) 1.96 (1.05, 3.66)
Daily consumption of milk At least once Less than once More than twice
58.2 10.6 31.2
5.8 13.4 8.5
1.00 2.52 (0.77, 8.23) 1.52 (0.92, 2.51)
Daily sedentary activities 0–2 h 3–4 h ⩾5h
64.9 23.9 11.1
5.9 6.9 9.9
1.00 1.18 (0.66, 2.10) 1.74 (0.88, 3.44)
P-valuea 0.08
0.38
0.37
0.99
0.004
0.002
0.83
0.25
0.02
o0.001
0.08
0.78
0.58
0.07
0.12
0.17
Abbreviations: CI, confidence interval; OR, odds ratio. aP-value from chi-squared test indicating significant difference in the characteristics between children with and without current wheeze.
© 2014 Macmillan Publishers Limited
European Journal of Clinical Nutrition (2014) 1 – 7
Association of vitamin D with respiratory outcomes SJ Niruban et al
4 Table 2. Proportion of ever asthma by factors and odds ratio for the relationship of factors with ever asthma Factor
Proportion of ever asthma within factor
Unadjusted OR (95% CI)
Factors
Current wheeze
Ever asthma
OR (95% CI)
P-value
OR (95% CI)
P-value
Age (years)
1.10 (0.88, 1.37)
0.36
1.15 (0.96, 1.37)
0.12
Sex Female Male
1.00 1.12 (0.69, 1.82)
0.61
1.00 0.91 (0.46, 1.79)
0.76
Family history of asthma No 1.00 Yes 4.22 (1.58, 11.23)
0.008
1.00 6.14 (3.71, 0.14)
o0.001
Number of children412 years ⩽1 1.00 ⩾2 2.19 (1.02, 4.72)
0.046
– –
Use of electric heating No 1.00 Yes 0.29 (0.11, 0.75)
0.016
– –
0.13
Vitamin D level (nmol/l) o50 50– o75 ⩾ 75
14.5 8.2 10.2
1.9 (1.27, 2.84) 1.00 1.28 (0.65, 2.50)
Sex Female Male
10.2 10.5
1.00 1.03 (0.6, 1.78)
BMI Underweight or normal weight Overweight/obese
P-valuea
Table 3. Results from the multiple logistic regression of current wheeze and ever asthma with vitamin D levels
0.89
0.09 12.6 8.6
1.00 0.65 (0.39, 1.10) 0.01
Caucasian Yes No
9.2 14.4
1.00 1.67 (1.11, 2.50)
No. of children412 years ⩽1 ⩾2
9.7 14.0
1.00 1.51 (0.43, 5.37)
Family history of asthma No Yes
5.6 25.9
1.00 5.94 (3.55, 9.95)
Household income Middle Low High
8.9 14.3 9.2
1.00 1.7 (0.78, 3.72) 1.03 (0.48, 2.18)
0.38
o 0.001
0.14
0.05
Smoking inside home No Yes
9.2 18.7
1.00 2.26 (0.77, 6.66)
Use of gas furnace No Yes
11.0 9.7
1.00 0.88 (0.48, 1.59)
0.61
0.81
Use of electric heating No Yes
10.0 10.6
1.00 1.07 (0.57, 2.02)
Region Ontario Quebec, New Brunswick British Columbia, Alberta
11.1 9.8 9.7
1.00 0.87 (0.46, 1.66) 0.87 (0.30, 2.48)
Season Winter Spring Summer Fall
10.1 11.1 6.4 8.7
1.00 1.01 (0.46, 2.24) 0.56 (0,29, 1.06) 1.19 (0.46, 3.11)
Daily sun exposure 1–3 h o1 h 43 h
7.9 16.2 10.7
1.00 2.27 (1.35, 3.84) 1.41 (0.79, 2.53)
Use of sunscreen Always / often Sometimes Rarely / never
9.3 9.8 13.3
1.00 1.06 (0.54, 2.08) 1.51 (0.69, 3.3)
Daily consumption of milk At least once Less than once More than twice
9.9 12.6 10.2
1.00 1.31 (0.42, 4.05) 1.03 (0.70, 1.53)
Daily sedentary hours 0–2 h 3–4 h ⩾5h
9.3 8.6 11.7
1.00 0.91 (0.57, 1.47) 1.29 (0.36, 4.57)
Season Winter Spring Summer Fall
— — —
1.00 0.55 (0.16, 1.92) 0.75 (0.18, 3.03) 0.79 (0.22, 2.80)
Vitamin D level (nmol/L) o50 3.40 (1.06, 10.89) 50–o75 1.00 ⩾ 75 2.26 (1.18, 4.33)
4.09 (2.29, 7.30) 1.00 1.62 (0.91, 2.88)
0.32 0.66 0.69 0.041 0.019
1.00 0.71 (0.32, 1.58) 0.52 (0.23, 1.19) 0.98 (0.37, 2.62) 1.86 (1.16, 3.01) 1.00 1.54 (0.77, 3.08)
o0.001 0.091
0.36 0.11 0.97 0.015 0.20
Abbreviations: CI, confidence interval; OR, odds ratio. 0.87
0.12
0.068
0.33
0.69
0.66
Abbreviations: CI, confidence interval; OR, odds ratio. aP-values indicate the significant difference in the characteristics between children with and without ever asthma.
European Journal of Clinical Nutrition (2014) 1 – 7
Daily sun exposure o1 h 1–3 h 43 h
DISCUSSION In this study of children of ages 6–12 years, we found a U-shaped relationship between 25(OH)D levels and current wheeze and lung function, indicators of current respiratory health. The U-shaped relationship was also observed between 25(OH)D levels and ever asthma, but the OR for the high 25(OH)D category was not statistically significant. As the report of ever asthma was determined from the diagnosis of asthma by a health professional during the participant’s entire lifetime, children with ever asthma might not have had asthma-related symptoms at the time of collection of blood used in 25(OH)D measurements. One of the conclusions in the Institute of Medicine report was that 25(OH)D levels 475 nmol/l were not consistently associated with increased benefit and the risks have been identified for some outcomes at 25(OH)D levels 4125 nmol/l.23 Based on this report, we chose three categories, 13.7–49 nmol/l (low), 50–74 nmol/l (moderate) and 75–195.1 nmol/L (high) in our study and found an increased risk for adverse respiratory health outcomes in low and high categories in comparison to the moderate category. This U-shaped non-linear relationship between 25(OH)D levels and current wheeze was further examined in two independent analyses by considering 25(OH)D levels as a continuous variable and a four-level categorical variable based on quartiles, respectively. Although there was some evidence for the U-shaped relationship in these analyses, the increased risk observed between 25(OH)D levels and current wheeze in the fourth 25 (OH)D quartile (86.9–195.1 nmol/l) was not statistically significant, © 2014 Macmillan Publishers Limited
Association of vitamin D with respiratory outcomes SJ Niruban et al
5 of gastrointestinal inflammatory disease (colitis) in which treatment with 1,25(OH)D3 was shown to reduce interleukin-17 expression.31 A recent review article proposed asthma as ‘a chronic disease of the innate and adaptive immune systems responding to viruses and allergens,32 providing the relevance for examining the relationship between vitamin D and respiratory outcomes in our study. Several studies have previously investigated the relationship between vitamin D levels in mothers during pregnancy,19–23,33 cord blood at birth 16 and children at different ages,12–14,34,35 and respiratory outcomes including indictors of wheezing, asthma or lung function in children at various ages. Except for two studies,16,33 all other studies considered vitamin D level as a continuous or binary variable in investigating the relationship between vitamin D levels and respiratory outcomes. In addition, the two studies that investigated the non-linear relationship did not find a significant U-shaped relationship between vitamin D levels and wheezing and/or asthma.16,33 In the first study, from Tucson, AZ, cord blood 25(OH)D levels were measured at birth and relative to the reference category (50–74.9 nmol/l), 25(OH)D levelso 50 nmol/l and ⩾ 100 nmol/l were associated with increased total IgE and inhalant allergen-specific IgE measured at ages 1 to 5 years in a longitudinal analysis, but no association was observed with asthma prevalence at 5 years.16 In the second study, from Spain, circulating maternal vitamin D [25(OH)D3] levels were measured, and relative to the first quartile (o 54.8nmol/l), there was a significant decreasing trend in the ORs for lower respiratory tract infections in the second (54.8–72.3 nmol/l), third (73–92.5 nmol/l) and fourth quartiles (492.5 nmol); however, none of the ORs were statistically significant.33 In this study, there was no significant association between circulating vitamin D (25 (OH)D3) levels and wheezing at age 1 year or asthma at age 4–6 years. In our study, we considered the serum 25(OH)D levels in children and found a non-linear U-shaped relationship with current wheeze and lung function, indicators of current respiratory health. There is evidence from previous studies for the association of low and high levels vitamin D with increased risk of wheezing or asthma in children. In a large birth cohort study of infants from
which was not entirely consistent with the significant increased risk observed in the high 25(OH)D category (75–195.1 nmol/l) in our other analyses. Vitamin D plays an active role in regulating specific phases of human immunity and has been shown to be associated with innate and adaptive immunity. The vitamin D receptor gene and the gene for 1α-hydroxylase (CYP27B1) have been shown to be induced following activation of Toll-like receptor 2/1 gene, the principal pathogen recognition receptor for Mycobacterium tuberculosis.11 However, the role of CYP27B1 gene in the expression of the vitamin D receptor gene following activation of the Toll-like receptor 2/1 gene is not very clear.10 The possibility of Vitamin D acting as a regulator of Th17 cells, which have the capacity to synthesize the pro-inflammatory cytokine interleukin-17,30 has been suggested from animal models
Table 4. Distribution of demographic factors and lung function by vitamin D categories Factor
Vitamin D categories o50 nmol/l 50–o75 nmol/l ⩾ 75 (nmol/L) Mean (s.d.)
Age (years) Height (cm) Weight (kg) FVC (l) FEV1 (l) FEV1/FVC FEF25–75% (l/s) % Predicted FVC % Predicted FEV1 % Predicted FEV1/FVC
9.9 144.7 43.6 2.59 2.17 0.85 2.31 101.9 98.86 96.84
Mean (s.d.)
Mean (s.d.)
(2.9) 9.3 (3.2) (20.4) 139.4 (22.0) (24.9) 36.4 (18.7) (1.11) 2.43 (1.14) (0.86) 2.05 (0.95) (0.1) 0.85 (0.1) (1.07) 2.22 (1.25) (18.14) 103.09 (20.22) (18.56) 100.89 (20.67) (11.71) 97.8 (11.26)
9.0 137.8 34.2 2.33 1.94 0.84 2.01 102.3 98.73 96.49
(3.1) (20.3) (17.6) (0.96) (0.77) (0.09) (1.05) (17.61) (17.99) (10.69)
P-valuea 0.002 0.002 0.004 0.03 0.005 0.06 0.001 0.45 0.06 0.06
Abbreviations: FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity. aP-values are from analysis of variance for comparison between vitamin D categories.
Table 5.
Results from the multiple linear regression analysis of lung function outcomes FVC (ml)
FEV1 (ml)
FEV1/FVC (%)
FEF25–75% (ml/s)
β (s.e.)
β (s.e.)
β (s.e.)
β (s.e.)a
(14.4)¶ (15.85) (38.6)‡ (2.94)** (0.07)¶ (1.94)‡
− 0.197 (0.198) 2.198 (0.485)§ — 0.08 (0.062) — − 0.156 (0.061)‡
57.62 (14.2)¶ 103.49 (36.73)‡ — 23.74 (4.22)** 0.41 (0.14)‡ 7.69 (5.98)
− 59.61 (25.57)‡ — − 47.12 (12.79)¶
0.436 (0.793) — − 1.46 (0.398)¶
− 52.27 (57.91) — − 142.48 (48.86)‡
Age and vitamin D level interaction o50 − 26.65 (22.79) 50–o75 (ref ) — ⩾ 75 − 36 (10.32)¶
− 25.28 (15.35) — − 29.5 (8.08)¶
— — —
— — —
Weight and vitamin D level interaction o50 — 50–o75 (ref ) — ⩾ 75 — Intercept 2376.73 (25.66)**
— — — 1972.11 (16.58)**
— — — 83.974 (0.397)**
− 10.26 (3.31)¶ — − 8.58 (3.42)‡ 2039.94 (44.59)**
Factor
a
Ageb Sex (ref—male) Caucasian (ref—yes) Heightb Height2 b Weightb
68.93 − 109.49 − 143.35 27.48 0.29 12.91
Vitamin D level (nmol/l) o50 50 too 75 (ref) ⩾ 75
(15.88)§ (16.06)** (53.05)‡ (3.35)** (0.06)§ (1.62)**
− 73.88 (32.19)‡ — − 17.88 (21.49)
a
52.49 − 33.05 − 102.25 26.21 0.28 5.83
a
‡
P-value ⩽ 0.05. ¶P-value ⩽ 0.01. §P-value ⩽ 0.001. **P-value ⩽0.0001. aβ (s.e.), regression coefficient (s.e.). bVariables were centralized.
© 2014 Macmillan Publishers Limited
European Journal of Clinical Nutrition (2014) 1 – 7
Association of vitamin D with respiratory outcomes SJ Niruban et al
6 is required from randomized control trials in determining safer 25 (OH)D levels in the management of asthma in children. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS The research and analysis are based on the data from Statistics Canada and opinions expressed herein do not represent the views of Statistics Canada.
REFERENCES
Figure 1. Relationship between predicted risk of current wheeze and serum vitamin D level from the generalized additive model. The predicted risk is plotted for a male child at age 9 years with positive family history of asthma and absence of electric heating at home.
New Zealand, lower cord-blood 25(OH)D levels were associated with increased risk of wheezing at 15 months, 3 years and 5 years of age.36 In contrast, a Swedish birth cohort study reported that a higher intake of vitamin D during infancy was associated with an increased cumulative incidence of atopic dermatitis, allergic rhinitis and asthma from infancy to 6 years.8 Similar to the finding of this study, a birth cohort study from the United States also reported that early infant vitamin D supplementation was associated with an increased risk of asthma by 3 years of age among black children.15 The biological mechanism for the U-shaped relationship suggested is unknown, but might be related to the potential of vitamin D to modify the immune response as has been previously reported in a number of experimental studies. Based on a review of these experimental studies,37 the authors suggested that vitamin D helped blunt Th2 responses by having inhibitory effects on the production of a number of cytokines, providing a possible explanation for the increased risk of respiratory outcomes associated with lower vitamin D levels in our study. In contrast, excess supplementation of vitamin D in mice was associated with an increase in the production of Th2 cytokines and serum IgE,38 a marker of allergic diseases including asthma, providing a possible explanation for the increased risk of respiratory outcomes with higher levels of vitamin D levels in our study. It may be that the timing of vitamin D exposure during the immune response and the baseline level of vitamin D are both important contributors to any effect. Measured serum 25(OH)D level includes contributions from both cutaneous production and dietary intake (for example, fortified milk).2,13 The half-life of vitamin D is ~ 3 weeks and is affected by serum calcium levels.39–41 Cutaneous synthesis of vitamin D is dependent on skin pigmentation, age, behavioral and lifestyle factors.42,43 Our study was conducted in Canada, which is located in the northern hemisphere (43N latitude, and above),44 with children living in some of the data collection sites receiving sun light only for a short duration, as little as 3 h per day during the winter months.45 Consequently very limited cutaneous vitamin D synthesis occurs during this period.46 In addition, season, skin pigmentation, use of sunscreen and duration of daily sun exposure were not significant factors in our study. As reported in other studies, the confounding effect of these variables may be minimal among children.47,48 In summary, the observed association in these data between vitamin D levels with current wheeze and lung function appear to support a U-shaped dose–response relationship. Further evidence European Journal of Clinical Nutrition (2014) 1 – 7
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