Vitamin D-related genes and cardiometabolic markers in healthy children: a Mendelian randomisation study.

Observational studies show associations between low serum 25-hydroxyvitamin D (25(OH)D) and cardiometabolic risk markers. This Mendelian randomisation study examined associations between cardiometabolic markers in children and SNP in genes related to vitamin D metabolism (DHCR7; group-specific complement (GC); cytochrome P450 subfamily IIR1 (CYP2R1); and CYP24A1) and action (CYP27B1 and VDR). In 699 healthy 8-11-year-old children, we genotyped eleven SNP. We generated a genetic risk score based on SNP associated with low 25(OH)D and investigated associations between this and blood pressure, plasma lipids and insulin. Furthermore, we examined whether SNP related to vitamin D actions modified associations between 25(OH)D and the cardiometabolic markers. All GC and CYP2R1 SNP influenced serum 25(OH)D. A risk score based on four of the six SNP was associated with 3·4 (95 % CI 2·6, 4·2) mmol/l lower 25(OH)D per risk allele (P < 0·001), but was not associated with the cardiometabolic markers. However, interactions were indicated for the three VDR SNP (Pinteraction < 0·081) on associations between 25(OH)D and TAG, systolic blood pressure and insulin, which all decreased with increasing 25(OH)D only in major allele homozygotes (ß -0·02 (95 % CI -0·04, -0·01) mmol/l; ß -0·5 (95 % CI -0·9, -0·1) mmHg; and ß -0·5 (95 % CI -1·4, 0·3) pmol/l, respectively). In conclusion, genetic variation affected 25(OH)D substantially, but the genetic score was not associated with cardiometabolic markers in children. However, VDR polymorphisms modified associations with vitamin D, which warrants further investigation of VDR's role in the relationship between vitamin D and cardiometabolic risk.

Serum 25-Hydroxyvitamin D, Plasma Lipids, and Associated Gene Variants in Prepubertal Children.

Context: The associations of serum 25-hydroxyvitamin D [25(OH)D] with plasma lipids remain controversial in children. Objective: To examine the associations and interactions of 25(OH)D and related gene variants with lipids in children. Design: Cross-sectional. Setting: Kuopio, Finland. Participants: Population sample of 419 prepubertal white children aged 6 to 8 years. Main Outcome Measures: 25(OH)D, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Results: Serum 25(OH)D was negatively associated with total cholesterol (ß = -0.141, P = 0.004), LDL cholesterol (ß = -0.112, P = 0.023), HDL cholesterol (ß = -0.150, P = 0.002), and triglycerides (ß = -0.104, P = 0.035) adjusted for age and sex. Associations of 25(OH)D with total cholesterol, LDL cholesterol, and HDL cholesterol remained after adjustment for adiposity, physical activity, sedentary behavior, diet, daylight time, and parental education. Children in the highest quartile of 25(OH)D had the lowest total cholesterol (P = 0.022) and LDL cholesterol (P = 0.026) adjusted for age and sex. Cytochrome P450 family 2 subfamily R member 1 (CYP2R1) rs12794714, CYP2R1 rs10741657, and vitamin D binding protein (DBP) rs2282679 were associated with 25(OH)D adjusted for age and sex. CYP2R1 rs12794714 was associated with total cholesterol and LDL cholesterol and C10orf88 rs6599638 with HDL cholesterol adjusted for age, sex, and 25(OH)D. The gene variants did not explain or modify the associations of 25(OH)D with lipids. Conclusions: 25(OH)D was independently and inversely associated with total cholesterol, LDL cholesterol, and HDL cholesterol. CYP2R1 rs12794714, CYP2R1 rs10741657, and DBP rs2282679 were associated with 25(OH)D. CYP2R1 rs12794714 was associated with total cholesterol and LDL cholesterol and chromosome 10 open reading frame 88 (C10orf88) rs6599638 with HDL cholesterol independent of 25(OH)D. None of the gene variants modified the associations of 25(OH)D with lipids. Further studies are needed to detect the mechanisms for the associations of 25(OH)D with lipids.

Genetic variation in the vitamin d pathway in relation to risk of prostate cancer--results from the breast and prostate cancer cohort consortium.

BACKGROUND: Studies suggest that vitamin D status may be associated with prostate cancer risk although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D [25(OH)D] status. We examined prostate cancer risk in relation to single-nucleotide polymorphisms (SNP) in four genes shown to predict circulating levels of 25(OH)D. METHODS: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the National Cancer Institute (NCI) Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer. RESULTS: We observed a decreased risk of aggressive prostate cancer among men with the allele in rs6013897 near CYP24A1 associated with lower serum 25(OH)D [per A allele, OR, 0.86; 95% confidence interval (CI), 0.80-0.93; Ptrend = 0.0002) but an increased risk for nonaggressive disease (per A allele: OR, 1.10; 95% CI, 1.04-1.17; Ptrend = 0.002). Examination of a polygenic score of the four SNPs revealed statistically significantly lower risk of aggressive prostate cancer among men with a greater number of low vitamin D alleles (OR for 6-8 vs. 0-1 alleles, 0.66; 95% CI, 0.44-0.98; Ptrend = 0.003). CONCLUSIONS: In this large, pooled analysis, genetic variants related to lower 25(OH)D levels were associated with a decreased risk of aggressive prostate cancer. IMPACT: Our genetic findings do not support a protective association between loci known to influence vitamin D levels and prostate cancer risk.

[Features of cholecalciferol hydroxylation in the liver of rats in conditions of D-hypervitaminosis and activity of alpha-tocopherol].

It is shown, that hepatocytes contain two (microsomal and mitochondrial) vitamin D3 25-hydroxylase enzymes, which differ as to their activity and function with maximal activity at different concentrations to substrate, namely at 15 microM and 100 microM of vitamin D3, accordingly. Activity of vitamin D3 25-hydroxylase enzymes of hepatocytes is regulated by cholecalciferol and alpha-tocopherol. The general and microsomal vitamin D3 25-hydroxylase enzymes activity of hepatocytes is lowered, but mitochondrial isoform is increased under D-hypervitaminosis conditions. Vitamin E increases microsomal vitamin D3 25-hydroxylase activity and decreases mitochondrial isoform activity of rats hepatocytes under D-hypervitaminosis conditions. It is established that D-hypervitaminosis is accompanied by expressed hypercalcemia and hyperphosphatemia, by decreased contents of mineral components in the bone tissue and high activity of alkaline phosphatase in the blood serum. The physiological doses of vitamin E under these conditions normalized the mineral metabolism, contents of calcium, phosphates and activity of alkaline phosphatase isoform in the blood serum.

[Role of vitamin E in regulation of cholecalciferol hydroxylation in hypovitaminosis D and hypervitaminosis D].

It is established, that dose-dependent influence of vitamin E on vitamin D3 metabolism, is conditioned by degree of cholecalciferol sufficiency. Under a condition of D-hypovitaminosis, contents of 25OHD3 in blood serum is 2-fold reduced and vitamin D3 25-hydroxylase enzymes activity increased in rat hepatocytes. Vitamin E (0.726-7.26 IU) significantly stimulated the effect of vitamin D3 (40 IU) in animals with D-hypovitaminosis and led to further increase of 25OHD3 content in the blood serum and activity of vitamin D3 25-hydroxylase enzymes in hepatocytes. In D-hypervitaminosis the contents of 25OHD3 in blood serum was more than 3-fold increased and vitamin D3 25-hydroxylase enzymes activity was inhibited. Vitamin E (0,726-7,26 IU) lowered the vitamin D toxicity, decreased contents of 25OHD3 in blood serum and activity of vitamin D3 25-hydroxylase enzymes in hepatocytes. High doses of vitamin E (36.3 IU) under these conditions demonstrated negative effect on vitamin D3 metabolism. The mechanism of vitaminE participation in the vitamin D3 metabolism under D-hypovitaminosis and D-hypervitaminosis may be its influence on the activity of different vitamin D3 25-hydroxylase systems of hepatocytes.