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BACKGROUND - Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.
METHODS - We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.
RESULTS - We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (=3.0×10), lies upstream of , which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within and upstream of (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within , the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.
CONCLUSIONS - Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.
Copyright © 2018 by the American Society of Nephrology.
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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 - The purpose of this study is to determine if antioxidant supplementation influences the incidence of atrial arrhythmias in trauma intensive care unit (ICU) patients.
MATERIALS AND METHODS - In this retrospective pre-post study, critically ill injured patients aged ≥18 years, admitted to a single-center trauma ICU for ≥48 hours were eligible for inclusion. The control group consists of patients admitted from January 2000 to September 2005, before routine antioxidant supplementation in our ICU. The antioxidant group consists of patients admitted from October 2005 to June 2011 who received an antioxidant protocol for ≥48 hours. The primary outcome is the incidence of atrial arrhythmias in the first 2 weeks of hospitalization or before discharge.
RESULTS - Of the 4699 patients, 1622 patients were in the antioxidant group and 2414 patients were in the control group. Adjusted for age, sex, year, injury severity, past medical history, and medication administration, the unadjusted incidence of atrial arrhythmias was 3.02% in the antioxidant group versus 3.31% in the control group, with no adjusted difference in atrial arrhythmias among those exposed to antioxidants (odds ratio: 1.31 [95% confidence interval: 0.46, 3.75], P = 0.62). Although there was no change in overall mortality, the expected adjusted survival of patients in those without antioxidant therapy was lower (odds ratio: 0.65 [95% confidence interval: 0.43, 0.97], P = 0.04).
CONCLUSIONS - ICU antioxidant supplementation did not decrease the incidence of atrial arrhythmias, nor alter the time from admission to development of arrhythmia. A longer expected survival time was observed in the antioxidant group compared with the control group but without a change in overall mortality between groups.
Published by Elsevier Inc.
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.
Previous studies rarely evaluated the associations between vitamin D-binding protein and free vitamin D with colorectal cancer risk. We assessed these biomarkers and total 25-hydroxyvitamin D in relation to colorectal cancer risk in a sample of African Americans. Cases comprised 224 African American participants of the Southern Community Cohort Study diagnosed with incident colorectal cancer. Controls ( = 440) were selected through incidence density sampling and matched to cases on age, sex, and race. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between biomarker levels and colorectal cancer risk. Vitamin D was inversely associated with colorectal cancer risk where the OR per-SD increase in total and free 25-hydroxyvitamin D were 0.82 (95% CI, 0.66-1.02) and 0.82 (95% CI, 0.66-1.01), respectively. Associations were most apparent among cases diagnosed >3 years after blood draw: ORs for the highest tertile versus the lowest were 0.69 (95% CI, 0.21-0.93) for total 25-hydroxyvitamin D and 0.71 (95% CI, 0.53-0.97) for free 25-hydroxyvitamin D. Inverse associations were seen in strata defined by sex, BMI, and anatomic site, although not all findings were statistically significant. Vitamin D-binding protein was not associated with colorectal cancer risk. Our findings suggest that total and free 25-hydroxyvitamin D may be inversely associated with colorectal cancer risk among African Americans. These findings highlight a potential role for vitamin D in colorectal cancer prevention in African Americans. .
©2017 American Association for Cancer Research.
Context - Low 25-hydroxyvitamin D [25(OH)D] is associated with coronary heart disease (CHD) in people who are white and Chinese but not black or Hispanic. Vitamin D binding globulin (VDBG) avidly binds 25(OH)D, reducing its bioavailability, and differs in isoform and concentration by race.
Objective - Evaluate associations of VDBG with CHD and whether accounting for VDBG or estimating bioavailable 25(OH)D explains the heterogeneity of the association of 25(OH)D with CHD.
Design and Setting - We conducted a case-cohort study within the Multi-Ethnic Study of Atherosclerosis. Participants with an incident CHD event over 12 years of follow-up (n = 538) and a randomly assigned subcohort (n = 999) were included. We measured baseline 25(OH)D, VDBG, and isoforms using mass spectrometry and estimated bioavailable 25(OH)D from published equations.
Results - VDBG was associated with an increased risk of CHD [hazard ratio, 1.77 (95% confidence interval, 1.46 to 2.14) per standard deviation increment, P < 0.0001], without evidence of heterogeneity by race or isoform (each P for interaction > 0.1). Low total 25(OH)D was differentially associated with CHD events, by race, with or without adjustment for VDBG (P for interaction = 0.04 or 0.05, respectively). Associations of 25(OH)D with CHD were strengthened with adjustment for VDBG among participants who were white or Chinese, and bioavailable 25(OH)D was associated with CHD events only among white participants.
Conclusions - High VDBG concentration was associated with CHD events in all racial and ethnic groups. Incorporation of VDBG strengthened existing associations of 25(OH)D with CHD but did not explain racial heterogeneity in associations of 25(OH)D with CHD.
Copyright © 2017 Endocrine Society
Circulating concentrations of biomarkers that are related to vitamin status vary by factors such as diet, fortification, and supplement use. Published biomarker concentrations have also been influenced by the variation across laboratories, which complicates a comparison of results from different studies. We robustly and comprehensively assessed differences in biomarkers that are related to vitamin status across geographic regions. The trial was a cross-sectional study in which we investigated 38 biomarkers that are related to vitamin status and one-carbon and tryptophan metabolism in serum and plasma from 5314 healthy control subjects representing 20 cohorts recruited from the United States, Nordic countries, Asia, and Australia, participating in the Lung Cancer Cohort Consortium. All samples were analyzed in a centralized laboratory. Circulating concentrations of riboflavin, pyridoxal 5'-phosphate, folate, vitamin B-12, all- retinol, 25-hydroxyvitamin D, and α-tocopherol as well as combined vitamin scores that were based on these nutrients showed that the general B-vitamin concentration was highest in the United States and that the B vitamins and lipid soluble vitamins were low in Asians. Conversely, circulating concentrations of metabolites that are inversely related to B vitamins involved in the one-carbon and kynurenine pathways were high in Asians. The high B-vitamin concentration in the United States appears to be driven mainly by multivitamin-supplement users. The observed differences likely reflect the variation in intake of vitamins and, in particular, the widespread multivitamin-supplement use in the United States. The results provide valuable information about the differences in biomarker concentrations in populations across continents.
BACKGROUND - Disturbances in vitamin D metabolism are common in patients with end-stage renal disease and may contribute to vascular dysfunction.
STUDY DESIGN - Cross-sectional.
SETTING & PARTICIPANTS - We evaluated 558 of 602 participants at baseline of the Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study of a cohort of patients with chronic kidney disease awaiting arteriovenous fistula (AVF) creation surgery.
FACTOR - 4 vitamin D metabolites measured with liquid chromatography-tandem mass spectroscopy from samples obtained within 4 weeks prior to AVF surgery.
OUTCOMES - Vasodilator functions and measurements of arterial stiffness.
MEASUREMENTS - Trained HFM Study personnel measured brachial artery flow-mediated dilation, nitroglycerin-mediated dilation, and carotid-femoral and carotid-radial pulse wave velocities (PWVs) prior to AVF creation. We evaluated associations after basic adjustment for sex, age, and clinical site and more fully adjusted additionally for baseline education, smoking, body mass index, diabetes, dialysis status, and medication use.
RESULTS - Mean participant age was 55±13 (SD) years and 65% were receiving maintenance dialysis. None of the vitamin D metabolites were significantly associated with flow-mediated dilation, carotid-femoral PWV, or carotid-radial PWV in basic or fully adjusted analyses. Higher serum concentrations of bioavailable vitamin D and 1,25-dihydroxyvitamin D were associated with 0.62% and 0.58% greater nitroglycerin-mediated dilation values, respectively, in basic models; however, these associations were no longer statistically significant with full adjustment. There were no significant associations of vitamin D metabolites with carotid-femoral or carotid-radial PWV in fully adjusted analyses.
LIMITATIONS - Cross-sectional ascertainment of vitamin D metabolites and vascular functions late during the course of kidney disease.
CONCLUSIONS - Serum concentrations of vitamin D metabolites are not associated with vasodilator functions or vascular stiffness at baseline in a cohort study of patients with chronic kidney disease awaiting AVF creation surgery. Laboratory measurements of vitamin D metabolites are unlikely to provide useful information regarding vascular functions in this setting.
Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.