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Context - Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry.
Objective - The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries.
Design - Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL).
Patients or Other Participants - In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study.
Main Outcome Measures - Blood concentrations of 25(OH)D were measured for all participants.
Results - Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively.
Conclusions - Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.
BACKGROUND AND OBJECTIVES - Vitamin D supplements are prescribed to correct low circulating concentrations of 25-hydroxyvitamin D. In CKD, vitamin D metabolism is complicated by decreased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by CYP27B1 and possibly decreased conversion of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D by CYP24A1. The aim of this study was to determine the effects of vitamin D supplementation on vitamin D metabolism in health and CKD.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We conducted a treatment-only intervention study of 25 individuals with CKD (eGFR<60 ml/min per 1.73 m) and 44 individuals without CKD from three academic centers, all with screening 25-hydroxyvitamin D <30 ng/ml. Each participant was prescribed vitamin D (ergocalciferol) 50,000 IU orally twice weekly for 5 weeks. We tested whether changes in plasma concentrations of vitamin D metabolites and vitamin D metabolic ratios differed by CKD status. Plasma 1,25-dihydroxyvitamin D-to-25-hydroxyvitamin D ratio and 24,25-dihydroxyvitamin D-to-25-hydroxyvitamin D ratio were calculated as estimates of CYP27B1 and CYP24A1 function, respectively.
RESULTS - With treatment, plasma 25-hydroxyvitamin D and total 25-hydroxyvitamin D concentrations increased similarly for participants with and without CKD. For participants without CKD, 1,25-dihydroxyvitamin D increased (2.8±1.3-32.9±1.4 pg/ml), whereas 1,25-dihydroxyvitamin D decreased (45.6±1.9-14.6±1.9 pg/ml), resulting in no significant change in total 1,25-dihydroxyvitamin D; 1,25-dihydroxyvitamin D-to-25-hydroxyvitamin D ratio decreased (3.0±0.2-1.7±0.2 pg/ng), and 24,25-dihydroxyvitamin D-to-25-hydroxyvitamin D ratio increased (115.7±7.8-195.2±7.9 pg/ng). Individuals with CKD had lower baseline levels and smaller changes in magnitude for 1,25-dihydroxyvitamin D (2.1±1.6-24.4±1.6 pg/ml; interaction =0.01), 1,25-dihydroxyvitamin D-to-25-hydroxyvitamin D ratio (1.8±0.2-1.1±0.2 pg/ng; interaction =0.05), and 24,25-dihydroxyvitamin D-to-25-hydroxyvitamin D ratio (72.0±9.1-110.3±9.3 pg/ng; interaction <0.001). Fibroblast growth factor-23 and parathyroid hormone were not significantly changed in either group.
CONCLUSIONS - Vitamin D supplementation decreases conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D and induces vitamin D catabolism as evidenced by changes in D metabolites and vitamin D metabolic ratios. These effects occur without significant changes in fibroblast growth factor-23 or parathyroid hormone and are blunted in CKD.
PODCAST - This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_02_CJASNPodcast_17_09.mp3.
Copyright © 2017 by the American Society of Nephrology.
Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Although much is known about magnesium, its interactions with calcium and vitamin D are less well studied. Magnesium intake is low in populations who consume modern processed-food diets. Low magnesium intake is associated with chronic diseases of global concern [e.g., cardiovascular disease (CVD), type 2 diabetes, metabolic syndrome, and skeletal disorders], as is low vitamin D status. No simple, reliable biomarker for whole-body magnesium status is currently available, which makes clinical assessment and interpretation of human magnesium research difficult. Between 1977 and 2012, US calcium intakes increased at a rate 2-2.5 times that of magnesium intakes, resulting in a dietary calcium to magnesium intake ratio of >3.0. Calcium to magnesium ratios <1.7 and >2.8 can be detrimental, and optimal ratios may be ∼2.0. Background calcium to magnesium ratios can affect studies of either mineral alone. For example, US studies (background Ca:Mg >3.0) showed benefits of high dietary or supplemental magnesium for CVD, whereas similar Chinese studies (background Ca:Mg <1.7) showed increased risks of CVD. Oral vitamin D is widely recommended in US age-sex groups with low dietary magnesium. Magnesium is a cofactor for vitamin D biosynthesis, transport, and activation; and vitamin D and magnesium studies both showed associations with several of the same chronic diseases. Research on possible magnesium and vitamin D interactions in these human diseases is currently rare. Increasing calcium to magnesium intake ratios, coupled with calcium and vitamin D supplementation coincident with suboptimal magnesium intakes, may have unknown health implications. Interactions of low magnesium status with calcium and vitamin D, especially during supplementation, require further study.
© 2016 American Society for Nutrition.
Previous studies demonstrate associations of low 25-hydroxyvitamin D (25(OH)D) concentrations with low bone mineral density (BMD) and fractures, motivating widespread use of vitamin D supplements for bone health. However, previous studies have been limited to predominantly White populations despite differences in the distribution and metabolism of 25(OH)D by race/ethnicity. We determined associations of serum 25(OH)D, 24,25-dihydroxyvitamin D (24,25(OH2)D3), and parathyroid hormone (PTH) with BMD among 1773 adult participants in the Multi-Ethnic Study of Atherosclerosis (MESA) in a staggered cross-sectional study design. Vitamin D metabolites were measured using liquid chromatography-mass spectroscopy and PTH using a 2-site immunoassay from serum collected in 2000-2002. Volumetric trabecular lumbar BMD was measured from computed tomography scans performed in 2002-2005 expressed as g/cm(3). We used linear regression and graphical methods to compare associations of vitamin D metabolite and PTH concentrations with BMD as the outcomes measure among White (n=714), Black (n=353), Chinese (n=249), and Hispanic (n=457) participants. Serum 25(OH)D and 24,25(OH2)D3 concentrations were highest among Whites and lowest among Blacks. BMD was greatest among Black participants. Higher serum 25(OH)D was only associated with higher BMD among Whites and Chinese participants (P-for-interaction=0.054). Comparing the lowest category of 25(OH)D (<20 ng/ml) to the highest (≥30 ng/ml), the adjusted mean difference in BMD was -8.1g/cm3 (95% CI -14.8, -1.4) for Whites; -10.2g/cm3 (-20.4, 0.0) for Chinese vs. 8.8 g/cm3 (-2.8, 20.5) for Black and -1.1g/cm3 (-8.3, 6.2) for Hispanic. Similar results were observed for serum 24,25(OH2)D3. Serum PTH was not associated with BMD. In a multi-ethnic population, associations of 25(OH)D with BMD were strongest among White and Chinese participants and null among Black and Hispanic participants. Further studies are needed to determine optimal biomarkers for bone health for multiple ethnic groups.
Copyright © 2015 Elsevier Inc. All rights reserved.
BACKGROUND - Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations.
OBJECTIVE - We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study.
METHODS - Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.
RESULTS - Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-μg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P = 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences.
CONCLUSIONS - Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans.
© 2015 American Society for Nutrition.
AIM - Few epidemiological studies have investigated the association between circulating concentrations of the active vitamin D metabolite 1,25(OH)2D and metabolic syndrome. We sought to determine whether blood levels of 1,25(OH)2D are associated with metabolic syndrome and its individual components, including waist circumference, triglycerides, blood pressure, and glucose, and high-density lipoprotein. We also investigated these associations for the more abundant precursor vitamin D metabolite, 25(OH)D.
METHODS - Participants from two completed clinical trials of colorectal neoplasia with available metabolic syndrome data and blood samples for measurement of 1,25(OH)2D (n=1048) and 25(OH)D (n=2096) were included. Cross-sectional analyses of the association between concentrations of 1,25(OH)2D, 25(OH)D, metabolic syndrome, and its components were conducted.
RESULTS - A statistically significant inverse association was observed for circulating concentrations of 1,25(OH)2D and metabolic syndrome, with adjusted ORs (95% CIs) of 0.73 (0.52-1.04) and 0.52 (0.36-0.75) for the second and third tertiles of 1,25(OH)2D, respectively (p-trend <0.001). Significant inverse relationships were also observed between 1,25(OH)2D and high triglycerides (p-trend <0.001), and low high-density lipoprotein (p-trend <0.001). For 25(OH)D concentrations, significant inverse associations were found for metabolic syndrome (p-trend <0.01), high waist circumference (p-trend <0.04) and triglyceride levels (p-trend <0.01). Participants with 25(OH)D ≥30 ng/ml and in the highest tertile of 1,25(OH)2D demonstrated significantly lower odds of metabolic syndrome, with an OR (95% CI) of 0.38 (0.19-0.75) compared to those in the lowest category for both metabolites.
CONCLUSION - These results provide new evidence that the relatively rarely-studied active hormonal form of vitamin D, 1,25(OH)2D, is associated with metabolic syndrome and its components, and confirm prior findings for 25(OH)D. The finding that 1,25(OH)2D is related to high-density lipoprotein, while 25(OH)D is not, suggests that there may be an independent mechanism of action for 1,25(OH)2D in relation to metabolic dysregulation.
Copyright © 2015 Elsevier Inc. All rights reserved.
BACKGROUND - Few studies have investigated vitamin D status in association with modifiable lifestyle factors and clinical characteristics among breast cancer patients, with no studies among Chinese women, who may be at higher risk of vitamin D deficiency. We aimed to evaluate circulating 25-hydroxyvitamin D (25(OH)D) levels in association with clinical and lifestyle factors among 1,940 Chinese breast cancer patients.
METHODS - Participants included breast cancer cases aged 22-77 from a population-based case-control study conducted in Shanghai, China during 1996-1998 (n = 1,044) and 2002-2005 (n = 896). Circulating 25(OH)D levels were measured in plasma samples (95% collected ≤6 months post-diagnosis). Prevalence ORs and 95% CIs were derived from multinomial logistic regression models, adjusting for age, season, and other factors.
RESULTS - About 23% and 48% of women were vitamin D deficient (<30 nmol/L) or insufficient (30-50 nmol/L), respectively. Tumor characteristics were not associated with vitamin D status. Higher BMI was associated with increased odds of vitamin D deficiency (ORs (95% CIs): 1 (reference), 1.12 (0.85,1.47), and 1.57 (1.02,2.42), for <23, 23-<27.5, and ≥27.5 kg/m(2), respectively, Ptrend <0.06). Total physical activity was associated with reduced odds of vitamin D deficiency (ORs (95% CIs):1 (reference), 0.84 (0.59,1.20), 0.65 (0.45,0.93), and 0.69 (0.48,1.00), for <7.65, 7.65-<10.6, 10.6-<13.5, ≥13.5 MET-hours/day, respectively, Ptrend <0.02). Smoking was associated with vitamin D insufficiency and deficiency (ORs (95% CIs): 2.50 (1.07,5.84) and 2.78 (1.11,6.95), respectively).
CONCLUSIONS - In the largest study to date, the prevalence of low vitamin D status was high among Chinese breast cancer patients and associated with higher BMI, smoking, and lower physical activity. Our findings support careful monitoring of vitamin D status and recommendations for supplementation and other lifestyle modifications that may improve vitamin D status in breast cancer patients.
OBJECTIVE - 25-Hydroxyvitamin D [25(OH)D] levels after recovery from tuberculosis (TB) may reflect pre-morbid levels and therefore provide insight into pathogenesis. We assessed 25(OH)D levels after recovery from TB disease, and compared to levels in persons without TB disease.
METHODS - Case-control study. Cases were persons who had recovered from culture-confirmed Mycobacterium tuberculosis disease. Controls were persons without TB disease. Total 25(OH)D was measured from stored plasma specimens using liquid chromatography-mass spectrometry.
RESULTS - 29 persons with prior TB disease and 36 controls were included. Median 25(OH)D levels were 24.7 ng/mL (IQR, 18.3-34.1) in prior TB disease, and 33.6 ng/mL (IQR, 26.2-42.4) in controls (Mann-Whitney; P = 0.01). Multivariable linear regression analysis showed that black race (adjusted mean difference [β] = -8.3 ng/mL; 95% CI -14.5, -2.2; P < 0.01), enrollment in winter (β = -10.4 ng/mL; 95% CI -17.0, -3.8; P < 0.01) and prior TB disease (β = -5.8 ng/mL; 95% CI -11.4, -0.3; P = 0.05) were associated with lower 25(OH)D levels.
CONCLUSIONS - Persons who had recovered from TB disease had lower 25(OH)D levels compared to controls without TB disease, after adjusting for important confounders. Larger, longitudinal studies are needed to further characterize the possible role of low 25(OH)D in the pathogenesis of TB disease and TB recurrence after recovery.
Copyright © 2013 Elsevier Ltd. All rights reserved.
BACKGROUND - Corticosteroids increase risk for decreased bone mineral density, which can be worsened by vitamin D insufficiency (VDI) or deficiency (VDD).
PROCEDURE - In the Vanderbilt cancer survivorship clinic, we obtained screening total 25-hydroxy vitamin D levels (VDL) in 171 cancer survivors <23 years old who were treated with prolonged corticosteroids for their cancer, and compared this group to a control group of 97 healthy pediatric patients.
RESULTS - VDD was diagnosed in 15.8% and VDI in 34.5% of cancer survivors and VDD/VDI combined was associated with body mass index (BMI) >85th percentile (Odds ratio [OR] = 5.4; P < 0.001), older age (OR = 2.2; P = 0.012), non-Caucasian or Hispanic race (OR = 4.5; P = 0.008) and summer versus winter season (OR = 0.12; P < 0.001). In multivariable analysis, VDI/VDD prevalence did not differ from the control group (VDI/VDD (43.3%)). In the combined survivor/control group multivariable analysis, cancer diagnosis did not increase VDI/VDD risk, but significant associations persisted with elevated BMI (P < 0.001), age (P = 0.004), non-Caucasian or Hispanic race (P < 0.001), and seasonality (P < 0.001).
CONCLUSION - VDD/VDI is equally common in pediatric cancer survivors treated with corticosteroids and healthy children. The impact of VDD/VDI in cancer survivors may be greater due to risk for impaired bone health superimposed on that conferred from corticosteroid exposure. Thus, screening VDLs should be obtained in pediatric cancer survivors treated with corticosteroids, particularly in those with elevated BMI, older age, or non-Caucasian race. Prospective studies evaluating the impact of interventions to minimize VDD/VDI on long-term bone health in survivors are required.
© 2013 Wiley Periodicals, Inc.