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Effect of vitamin D-binding protein genotype on the development of asthma in children.

ABSTRACT: Potential vitamin D-related influences on inflammatory diseases such as asthma are controversial, including the suggestion that vitamin D insufficiency is associated with increased asthma morbidity. Vitamin D-binding protein transports vitamin D metabolites in the circulation. Single nucleotide polymorphisms in the GC gene encoding vitamin D-binding protein are associated with circulating vitamin D metabolite levels in healthy infants and toddlers.To test the hypothesis that GC single nucleotide polymorphisms encoding the D432E and T436K variants predict subsequent development of asthma in healthy children.A retrospective medical record review was performed to determine the development of asthma in 776 children in whom GC genotype, vitamin D-binding protein concentration, and circulating 25-hydroxyvitamin D had been determined at 6 to 36 months of age. Demographic and detailed current clinical data were collected and criteria for asthma were recorded.GC genotype was available for 463 subjects. After an initial analysis of all subject data, the analysis was limited to the predominant Hispanic population (72.1%) to minimize potential confounding effects of ethnicity. Asthma was diagnosed in 87 children (26%). Subjects with the GC genotype encoding the ET/ET (Gc1s/Gc1s) variant had lower odds of developing asthma, representing a protective effect compared with subjects with the DT/DT (Gc1f/Gc1f) variant.In the Hispanic population of inner-city New Haven, Connecticut, the ET/ET (Gc1s/Gc1s) genotype of vitamin D-binding protein might confer protection against the development of asthma compared with the wild-type genotype DT/DT (Gc1f/Gc1f).

SUBMITTER: Navas-Nazario A

PROVIDER: S-EPMC4070170 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Effect of vitamin D-binding protein genotype on the development of asthma in children.

Navas-Nazario Aledie A Li Fang Yong FY Shabanova Veronika V Weiss Pnina P Cole David E C DE Carpenter Thomas O TO Bazzy-Asaad Alia A

Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 20140416 6

<h4>Background</h4>Potential vitamin D-related influences on inflammatory diseases such as asthma are controversial, including the suggestion that vitamin D insufficiency is associated with increased asthma morbidity. Vitamin D-binding protein transports vitamin D metabolites in the circulation. Single nucleotide polymorphisms in the GC gene encoding vitamin D-binding protein are associated with circulating vitamin D metabolite levels in healthy infants and toddlers.<h4>Objective</h4>To test the ...[more]

PMID: 24745702

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Project description:Osteoporosis is a bone disease leading to an increased fracture risk. It is considered a complex multifactorial genetic disorder with interaction of environmental and genetic factors. As a candidate gene for osteoporosis, we studied vitamin D binding protein (DBP, or group-specific component, Gc), which binds to and transports vitamin D to target tissues to maintain calcium homeostasis through the vitamin D endocrine system. DBP can also be converted to DBP-macrophage activating factor (DBP-MAF), which mediates bone resorption by directly activating osteoclasts. We summarized the genetic linkage structure of the DBP gene. We genotyped two single-nucleotide polymorphisms (SNPs, rs7041 = Glu416Asp and rs4588 = Thr420Lys) in 6,181 elderly Caucasians and investigated interactions of the DBP genotype with vitamin D receptor (VDR) genotype and dietary calcium intake in relation to fracture risk. Haplotypes of the DBP SNPs correspond to protein variations referred to as Gc1s (haplotype 1), Gc2 (haplotype 2), and Gc1f (haplotype3). In a subgroup of 1,312 subjects, DBP genotype was found to be associated with increased and decreased serum 25-(OH)D(3) for haplotype 1 (P = 3 x 10(-4)) and haplotype 2 (P = 3 x 10(-6)), respectively. Similar associations were observed for 1,25-(OH)(2)D(3). The DBP genotype was not significantly associated with fracture risk in the entire study population. Yet, we observed interaction between DBP and VDR haplotypes in determining fracture risk. In the DBP haplotype 1-carrier group, subjects of homozygous VDR block 5-haplotype 1 had 33% increased fracture risk compared to noncarriers (P = 0.005). In a subgroup with dietary calcium intake <1.09 g/day, the hazard ratio (95% confidence interval) for fracture risk of DBP hap1-homozygote versus noncarrier was 1.47 (1.06-2.05). All associations were independent of age and gender. Our study demonstrated that the genetic effect of the DBP gene on fracture risk appears only in combination with other genetic and environmental risk factors for bone metabolism.

Project description:Background An increasing number of studies have suggested that vitamin D can be used to treat childhood asthma, but its clinical effects are still unclear. We conducted this meta-analysis to examine the latest estimates of the effectiveness and safety of using vitamin D to treat childhood asthma. Methods The PubMed, The Cochrane Library, ScienceDirect, Embase, Scopus, Ovid MEDLINE, Web of Science, and Google Scholar databases were searched for randomized controlled trials (RCTs) describing vitamin D supplementation interventions for asthmatic children. Asthma exacerbation, vitamin D levels, the predicted percentage of forced expiratory volume in the first second (FEV1%) and adverse effects (AEs) were analyzed as the main outcome measures. Results After screening, eight RCTs with 738 children were included. Compared with placebos, vitamin D supplementation had a stronger effect on serum vitamin D levels [mean difference (MD) = 13.51 (4.24, 22.79), p = 0.004]. The pooled results indicated that no significant changes were found between the groups in asthma control, as measured by adopting the following indicators: asthma exacerbation [risk ratio (RR) = 0.92 (0.68, 1.25), p = 0.60]; Childhood Asthma Control Test (CACT) scores [MD = 0.15 (−0.43, 0.74), p = 0.61]; hospitalizations for asthma exacerbation [RR = 1.20 (0.48, 2.96), p = 0.70]; acute care visits [RR = 1.13 (0.77, 1.65), p = 0.63]; steroid use [RR = 1.03 (0.41, 2.57), p = 0.95]; and fractional exhaled nitric oxide (FeNO) [MD =-3.95 (−22.87, 14.97), p = 0.68]. However, vitamin D supplementation might reduce the FEV1% [MD = −4.77 (−9.35, −0.19), p = 0.04] and the percentage of predicted forced vital capacity (FVC%) [MD =-5.01 (−9.99, −0.02), p = 0.05] in patients. Subgroup analysis revealed no difference in AEs between the two groups. Conclusions Vitamin D supplementation significantly increased patients' serum vitamin D levels, but it had no benefit for asthma control. However, vitamin D supplementation might reduce patients' lung function. It is essential to systemically search for more large-scale, rigorous, and well-designed RCTs to fully confirm these conclusions. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021288838, PROSPERO CRD42021288838.

Project description:ImportanceSevere asthma exacerbations cause significant morbidity and costs. Whether vitamin D3 supplementation reduces severe childhood asthma exacerbations is unclear.ObjectiveTo determine whether vitamin D3 supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels.Design, setting, and participantsThe Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3 supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019.InterventionsParticipants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old).Main outcomes and measuresThe primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial.ResultsAmong 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3 group vs 253 days in the placebo group (mean group difference, -13.1 days [95% CI, -42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85]; P = .63). Vitamin D3 supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group, n = 11; placebo group, n = 9).Conclusions and relevanceAmong children with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3 supplementation to prevent severe asthma exacerbations in this group of patients.Trial registrationClinicalTrials.gov Identifier: NCT02687815.

Project description:RATIONALE:Vitamin D deficiency, often defined by total serum 25-hydroxyvitamin D (25[OH]D) <20 ng/ml, is common in critically ill patients, with associations with increased mortality and morbidity in the intensive care unit. Correction of vitamin D deficiency in critical illness has been recommended, and ongoing clinical trials are investigating the effect of repletion on patient outcome. The biologically active amount of 25(OH)D depends on the concentration and protein isoform of vitamin D-binding protein (VDBP), which is also an acute-phase reactant affected by inflammation and injury. OBJECTIVES:We performed a secondary analysis of a cohort of critically ill children in which we reported a high rate of vitamin D deficiency, to examine how VDBP level and genotype would impact vitamin D status. METHODS:We prospectively enrolled 511 children admitted to the pediatric intensive care unit over a 12-month period. MEASUREMENTS AND MAIN RESULTS:We measured serum VDBP in 479 children. We genotyped single nucleotide polymorphisms rs7041 and rs4588 in the VDBP gene (GC) to determine haplotypes GC1F, GC1S, and GC2 in 178 subjects who consented, then calculated bioavailable 25(OH)D from serum 25(OH)D, VDBP, albumin, and GC haplotype. The median serum VDBP level was 159 ?g/ml (interquartile range, 108-221), lower than has been reported in healthy children. Factors predicting lower levels in multivariate analysis included age <1 year, nonwhite race, being previously healthy, 25(OH)D <20 ng/ml and greater illness severity. In the subgroup that was genotyped, GC haplotype had the strongest association with VDBP level; carriage of one additional copy of GC1S was associated with a 37.5% higher level (95% confidence interval, 31.9-44.8; P?<?0.001). Bioavailable 25(OH)D was also inversely associated with illness severity (r?=?-0.24, P?<?0.001), and ratio to measured total 25(OH)D was variable and related to haplotype. CONCLUSIONS:Physiologic deficiency of 25(OH)D in critical illness may be more difficult to diagnose, given that lower VDBP levels increase bioavailability. Treatment studies conducted on the basis of total 25(OH)D level, without consideration of VDBP concentration and genotype, may increase the risk of falsely negative results.

Dataset Information

Effect of vitamin D-binding protein genotype on the development of asthma in children.

Publications

Effect of vitamin D-binding protein genotype on the development of asthma in children.

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