Individual participant data (IPD)-level meta-analysis of randomised controlled trials with vitamin D-fortified foods to estimate Dietary Reference Values for vitamin D.

CONTEXT AND PURPOSE: Individual participant data-level meta-regression (IPD) analysis is superior to meta-regression based on aggregate data in determining Dietary Reference Values (DRV) for vitamin D. Using data from randomized controlled trials (RCTs) with vitamin D3-fortified foods, we undertook an IPD analysis of the response of winter serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among children and adults and derived DRV for vitamin D. METHODS: IPD analysis using data from 1429 participants (ages 2-89 years) in 11 RCTs with vitamin D-fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D DRV estimates across a range of serum 25(OH)D thresholds using unadjusted and adjusted models. RESULTS: Our IPD-derived estimates of vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25 and ≥ 30 nmol/L are 6 and 12 µg/day, respectively (unadjusted model). The intake estimates to maintain 90%, 95% and 97.5% of concentrations ≥ 50 nmol/L are 33.4, 57.5 and 92.3 µg/day, respectively (unadjusted) and 17.0, 28.1 and 43.6 µg/day, respectively (adjusted for mean values for baseline serum 25(OH)D, age and BMI). CONCLUSIONS: IPD-derived vitamin D intakes required to maintain 90%, 95% and 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L are much higher than those derived from standard meta-regression based on aggregate data, due to the inability of the latter to capture between person-variability. Our IPD provides further evidence that using food-based approaches to achieve an intake of 12 µg/day could prevent vitamin D deficiency (i.e., serum 25(OH)D < 30 nmol/L) in the general population.

Common variants in CYP2R1 and GC genes are both determinants of serum 25-hydroxyvitamin D concentrations after UVB irradiation and after consumption of vitamin D3-fortified bread and milk during winter in Denmark.

BACKGROUND: Little is known about how the genetic variation in vitamin D modulating genes influences ultraviolet (UV)B-induced 25-hydroxyvitamin D [25(OH)D] concentrations. In the Food with vitamin D (VitmaD) study, we showed that common genetic variants rs10741657 and rs10766197 in 25-hydroxylase (CYP2R1) and rs842999 and rs4588 in vitamin D binding protein (GC) predict 25(OH)D concentrations at late summer and after 6-mo consumption of cholecalciferol (vitamin D3)-fortified bread and milk. OBJECTIVES: In the current study, called the Vitamin D in genes (VitDgen) study, we analyzed associations between the increase in 25(OH)D concentrations after a given dose of artificial UVB irradiation and 25 single nucleotide polymorphisms located in or near genes involved in vitamin D synthesis, transport, activation, or degradation as previously described for the VitmaD study. Second, we aimed to determine whether the genetic variations in CYP2R1 and GC have similar effects on 25(OH)D concentrations after artificial UVB irradiation and supplementation by vitamin D3-fortified bread and milk. DESIGN: The VitDgen study includes 92 healthy Danes who received 4 whole-body UVB treatments with a total dose of 6 or 7.5 standard erythema doses during a 10-d period in winter. The VitmaD study included 201 healthy Danish families who were given vitamin D3-fortified bread and milk or placebo for 6 mo during the winter. RESULTS: After UVB treatments, rs10741657 in CYP2R1 and rs4588 in GC predicted UVB-induced 25(OH)D concentrations as previously shown in the VitmaD study. Compared with noncarriers, carriers of 4 risk alleles of rs10741657 and rs4588 had lowest concentrations and smallest increases in 25(OH)D concentrations after 4 UVB treatments and largest decreases in 25(OH)D concentrations after 6-mo consumption of vitamin D3-fortified bread and milk. CONCLUSION: Common genetic variants in the CYP2R1 and GC genes modify 25(OH)D concentrations in the same manner after artificial UVB-induced vitamin D and consumption of vitamin D3-fortified bread and milk.

Vitamin D status and its determinants in children and adults among families in late summer in Denmark.

The impact of the familial relationship on vitamin D status has not been investigated previously. The objective of the present cross-sectional study was to assess serum 25-hydroxyvitamin D (25(OH)D) concentration and its determinants in children and adults among families in late summer in Denmark (56°N). Data obtained from 755 apparently healthy children (4-17 years) and adults (18-60 years) recruited as families (n 200) in the VitmaD study were analysed. Blood samples were collected in September-October, and serum 25(OH)D concentration was measured by liquid chromatography-tandem MS. Information on potential determinants was obtained using questionnaires. The geometric mean serum 25(OH)D concentration was 72·1 (interquartile range 61·5-86·7) nmol/l (range 9-162 nmol/l), with 9 % of the subjects having 25(OH)D concentrations < 50 nmol/l. The intra-family correlation was 0·27 in all subjects, 0·24 in the adults and 0·42 in the children. Serum 25(OH)D concentration was negatively associated with BMI (P< 0·001) and positively associated with dietary vitamin D intake (P= 0·008), multivitamin use (P= 0·019), solarium use (P= 0·006), outdoor stay (P= 0·001), sun preference (P= 0·002) and sun vacation (P< 0·001), but was not associated with lifestyle-related factors in the adults when these were assessed together with the other determinants. In conclusion, the majority of children and adults among the families had serum 25(OH)D concentrations >50 nmol/l in late summer in Denmark. Both dietary and sun-related factors were determinants of vitamin D status and the familial component was stronger for the children than for the adults.

Common variants in CYP2R1 and GC genes predict vitamin D concentrations in healthy Danish children and adults.

Environmental factors such as diet, intake of vitamin D supplements and exposure to sunlight are known to influence serum vitamin D concentrations. Genetic epidemiology of vitamin D is in its infancy and a better understanding on how genetic variation influences vitamin D concentration is needed. We aimed to analyse previously reported vitamin D-related polymorphisms in relation to serum 25(OH)D concentrations in 201 healthy Danish families with dependent children in late summer in Denmark. Serum 25(OH)D concentrations and a total of 25 SNPs in GC, VDR, CYP2R1, CYP24A1, CYP27B1, C10or88 and DHCR7/NADSYN1 genes were analysed in 758 participants. Genotype distributions were in Hardy-Weinberg equilibrium for the adult population for all the studied polymorphisms. Four SNPs in CYP2R1 (rs1562902, rs7116978, rs10741657 and rs10766197) and six SNPs in GC (rs4588, rs842999, rs2282679, rs12512631, rs16846876 and rs17467825) were statistically significantly associated with serum 25(OH)D concentrations in children, adults and all combined. Several of the SNPs were in strong linkage disequilibrium, and the associations were driven by CYP2R1-rs10741657 and rs10766197, and by GC-rs4588 and rs842999. Genetic risk score analysis showed that carriers with no risk alleles of CYP2R1-rs10741657 and rs10766197, and/or GC rs4588 and rs842999 had significantly higher serum 25(OH)D concentrations compared to carriers of all risk alleles. To conclude, our results provide supporting evidence that common polymorphisms in GC and CYP2R1 are associated with serum 25(OH)D concentrations in the Caucasian population and that certain haplotypes may predispose to lower 25(OH)D concentrations in late summer in Denmark.