We investigated candidate genomic regions associated with computed tomography (CT)-derived measures of adiposity in Hispanic from the IRAS Family Study. In 1190 Hispanic individuals from 92 families from the San Luis Valley, CO and San Antonio, TX, we measured CT-derived visceral adipose tissue (VAT); subcutaneous adipose tissue (SAT); and visceral: subcutaneous ratio (VSR). A genome-wide association study (GWAS) was completed using the Illumina HumanHap 300 BeadChip (~317K single nucleotide polymorphisms (SNPs)) in 229 individuals from the San Antonio site (Stage 1). Two hundred ninety-seven SNPs with evidence for association with VAT, SAT, or VSR, adjusting for age and sex (p<0.001), were genotyped in the remaining 961 Hispanic samples. The entire Hispanic cohort (n = 1190) was then tested for association, adjusting for age, sex, site of recruitment and admixture estimates (Stage 2). In Stage 3, additional SNPs were genotyped in four genic regions showing evidence of association in Stage 2.
Several SNPs were associated in the GWAS (p<1×10−5) and were confirmed to be significantly associated in the entire Hispanic cohort (p<0.01), including: rs7543757 for VAT; rs4754373, and rs11212913 for SAT; and rs4541696, and rs4134351 for VSR. Numerous SNPs were associated with multiple adiposity phenotypes. Targeted analysis of four genes whose SNPs were significant in Stage 2 suggest candidate genes for influencing the distribution (RGS6) and amount of adiposity (NGEF).
Several candidate loci, including RGS6 and NGEF, are associated with CT-derived adipose fat measures in Hispanic Americans in a three-stage genetic association study.
genetic association; visceral fat; subcutaneous fat; obesity; body mass index
The goal of this study was to identify genes and regions in the human genome that are associated with the acute insulin response to glucose (AIRg), an important predictor of type 2 diabetes, in Hispanic-American participants from the Insulin Resistance Atherosclerosis Family Study (IRAS FS).
A two-stage genome-wide association scan (GWAS) was performed in IRAS FS Hispanic-American samples. In the first stage, 318K single nucleotide polymorphisms (SNPs) were assessed in 229 Hispanic-American DNA samples (from 34 families) from San Antonio, TX. SNPs with the most significant associations with AIRg were genotyped in the entire set of IRAS FS Hispanic-American samples (n = 1190). In chromosomal regions with evidence of association, additional SNPs were genotyped to capture variation in genes.
No individual SNP achieved genome-wide levels of significance (P < 5 × 10-7); however, two regions — chromosomes 6p21 and 20p11 — had multiple highly-ranked SNPs that were associated with AIRg. Additional genotyping in these regions supported the initial evidence for variants contributing to variation in AIRg. One region resides in a gene desert between PXT1 and KCTD20 on 6p21 while the region on 20p11 has several viable candidate genes (ENTPD6, PYGB, GINS1 and R4-691N24.1).
A GWAS in Hispanic-American samples identified several candidate genes and loci that may be associated with AIRg. These associations explain a small component of variation in AIRg. The genes identified are involved in phosphorylation and ion transport and provide preliminary evidence that these processes have importance in beta cell response.
genetic association; insulin secretion; beta cell response; Hispanic American
Recently, a genome-wide association scan was completed in the IRAS (Insulin Resistance Atherosclerosis Study) Family Study (IRASFS) Hispanic-American cohort. Multiple single-nucleotide polymorphisms (SNPs) in the G-protein signaling 6 (RGS6) gene were found to be associated with adiposity phenotypes. RGS6 has shown downstream antagonistic interplay with opioid receptors, targets of fatty/sugary food agonists. The possibility that RGS6 promotes tolerance and tachyphylaxis among the opioid receptor is a plausible pathway for overconsuming fat/sugar-laden food. Therefore, we hypothesized that RGS6 variants are associated with intake of fatty/sugary foods. In 932 Hispanics from San Antonio and San Luis Valley, CO, the following dietary intake variables were assessed using the Block Brief 2000 food frequency questionnaire: total calories, total fat, % calories from fat, % calories from saturated fat, protein, % calories from protein, carbohydrates, % calories from carbohydrates, and daily frequency of servings of fats/oils/sweets. We tested for association between 23 SNPs in RGS6 and dietary intake using a variance components measured genotype approach. All models were adjusted for gender, recruitment site, admixture, BMI, and age. Using an additive genetic model, rs1402064 was associated with higher intake of fats/oils/sweets, total calories, total fat and saturated fat (P = 0.0007, 0.026, 0.023, and 0.024). SNPs rs847330 and rs847354 were associated with higher intake of fats/oils/sweets (P = 0.002 and 0.018), total fat (P = 0.040 and 0.048) and saturated fat (P = 0.044 and 0.041). Finally, rs769148 was associated with higher intake of fats/oils/sweets (P = 0.002). RGS6 is a new candidate gene for adiposity traits that may be associated with a behavioral tendency toward fat-laden food intake.
—The majority of type 2 diabetes Genome Wide Association Studies (GWAS) to date have been performed in European-derived populations and have identified few variants that mediate their effect through insulin resistance. The aim of this study was to evaluate two quantitative, directly assessed measures of insulin resistance (SI and DI) in Hispanic Americans using an agnostic, high-density SNP scan and validate these findings in additional samples.
—A two-stage GWAS was performed in IRAS-FS Hispanic-American samples. In Stage 1, 317K single nucleotide polymorphisms (SNPs) were assessed 229 DNA samples. SNPs with evidence of association with glucose homeostasis and adiposity traits were then genotyped on the entire set of Hispanic-American samples (n=1190). This report focuses on the glucose homeostasis traits: insulin sensitivity index (SI) and disposition index (DI).
—Although evidence of association did not reach genome-wide significance (P=5×10−7), in the combined analysis SNPs had admixture-adjusted PADD=0.00010–0.0020 with 8–41% differences in genotypic means for SI and DI.
—Several candidate loci have been identified which are nominally associated with SI and/or DI in Hispanic Americans. Replication of these findings in independent cohorts and additional focused analysis of these loci is warranted.
Type 2 Diabetes; Insulin Sensitivity; Disposition Index; Hispanic Americans
Variants of uncoupling protein genes UCP1 and UCP2 have been associated with a range of traits. We wished to evaluate contributions of known UCP1 and UCP2 variants to metabolic traits in the Insulin Resistance and Atherosclerosis (IRAS) Family Study.
We genotyped five promoter or coding single nucleotide polymorphisms (SNPs) in 239 African American (AA) participants and 583 Hispanic participants from San Antonio (SA) and San Luis Valley. Generalized estimating equations using a sandwich estimator of the variance and exchangeable correlation to account for familial correlation were computed for the test of genotypic association, and dominant, additive and recessive models. Tests were adjusted for age, gender and BMI (glucose homeostasis and lipid traits), or age and gender (obesity traits), and empirical P-values estimated using a gene dropping approach.
UCP1 A-3826G was associated with AIRg in AA (P = 0.006) and approached significance in Hispanic families (P = 0.054); and with HDL-C levels in SA families (P = 0.0004). Although UCP1 expression is reported to be restricted to adipose tissue, RT-PCR indicated that UCP1 is expressed in human pancreas and MIN-6 cells, and immunohistochemistry demonstrated co-localization of UCP1 protein with insulin in human islets. UCP2 A55V was associated with waist circumference (P = 0.045) in AA, and BMI in SA (P = 0.018); and UCP2 G-866A with waist-to-hip ratio in AA (P = 0.016).
This study suggests a functional variant of UCP1 contributes to the variance of AIRg in an AA population; the plausibility of this unexpected association is supported by the novel finding that UCP1 is expressed in islets.
IN THE SAN LUIS VALLEY DIABETES STUDY (SLVDS) researchers studied hypertension morbidity and risk factors in 1788 Hispanics and non-Hispanic whites (NHW) from the rural San Luis Valley in Colorado. Hypertension was defined by The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V) criteria. In this population-based study, the prevalence, incidence, and risk factors for hypertension did not differ significantly between non-diabetic Hispanics and NHW participants. Hypertension risk increased with age, heart rate, serum triglycerides, insulin area, and obesity (in young participants). Compared with the prevalence rates in non-diabetic participants, the rates were significantly higher in people with diabetes and increased with the duration of diabetes and central obesity. The risk of hypertension in diabetic Hispanics appeared to be somewhat lower than that in NHW diabetics.
The primary circulating form of vitamin D, 25-hydroxy-vitamin D [25(OH)D], is associated with multiple medical outcomes, including rickets, osteoporosis, multiple sclerosis and cancer. In a genome-wide association study (GWAS) of 4501 persons of European ancestry drawn from five cohorts, we identified single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH)D concentrations: rs2282679 (P = 2.0 × 10−30), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P = 4.1 × 10−22) and rs1155563 (P = 3.8 × 10−25). Suggestive signals for association with 25(OH)D were also observed for SNPs in or near three other genes involved in vitamin D synthesis or activation: rs3829251 on chromosome 11q13.4 in NADSYN1 [encoding nicotinamide adenine dinucleotide (NAD) synthetase; P = 8.8 × 10−7], which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase that synthesizes cholesterol from 7-dehydrocholesterol; rs6599638 in the region harboring the open-reading frame 88 (C10orf88) on chromosome 10q26.13 in the vicinity of ACADSB (acyl-Coenzyme A dehydrogenase), involved in cholesterol and vitamin D synthesis (P = 3.3 × 10−7); and rs2060793 on chromosome 11p15.2 in CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1, encoding a key C-25 hydroxylase that converts vitamin D3 to an active vitamin D receptor ligand; P = 1.4 × 10−5). We genotyped SNPs in these four regions in 2221 additional samples and confirmed strong genome-wide significant associations with 25(OH)D through meta-analysis with the GWAS data for GC (P = 1.8 × 10−49), NADSYN1/DHCR7 (P = 3.4 × 10−9) and CYP2R1 (P = 2.9 × 10−17), but not C10orf88 (P = 2.4 × 10−5).
We evaluated vitamin D status in HIV+ and HIV− postmenopausal African-American (AA) and Hispanic women. Most women (74–78%) had insufficient 25-hydroxyvitamin D (25OHD) levels, regardless of HIV status. 25OHD was lower in AA women and women lacking supplement use, providing support for screening and supplementation. Among HIV+ women, 25OHD was associated with current CD4 but not type of antiretroviral therapy.
To evaluate vitamin D status and factors associated with vitamin D deficiency and insufficiency in HIV-infected (HIV+) postmenopausal minority women.
In this cross-sectional study, 89 HIV+ and 95 HIV− postmenopausal women (33% AA and 67% Hispanic) underwent assessment of 25OHD, 1,25-dihydroxyvitamin D, parathyroid hormone, markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry.
The prevalence of low 25OHD did not differ by HIV status; the majority of both HIV+ and HIV− women (74–78%) had insufficient levels (<30 ng/ml). Regardless of HIV status, 25OHD was significantly lower in AA subjects, and higher in subjects who used both calcium and multi-vitamins. In HIV+ women on antiretroviral therapy (ART), 25OHD was directly associated with current CD4 count (r= 0.32; p<0.01) independent of age, ethnicity, BMI, or history of AIDS-defining illness. No association was observed between 1,25(OH)2D and CD4 count or between serum 25OHD, 1,25(OH)2D or PTH and type of ART.
In postmenopausal minority women, vitamin D deficiency was highly prevalent and associated with AA race and lack of supplement use, as well as lower current CD4 cell count. These results provide support for screening and repletion of vitamin D in HIV+ patients.
African-American; Hispanic; HIV+ postmenopausal women; Vitamin D
We systematically investigated the association of 48 SNPS in four vitamin D metabolizing genes [CYP27A1, GC, CYP27B1 and CYP24A1] with serum 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels and the association of these SNPS and an additional 164 SNPS in eight downstream mediators of vitamin D signaling [VDR, RXRA, RXRB, PPAR, NCOA1, NCOA2, NCOA3 and SMAD3] with prostate cancer risk in the 749 incident prostate cancer cases and 781 controls of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. 25(OH)D (all cases and controls) and 1,25(OH)2D (a subset of 150 controls) levels were measured by radioimmunoassay and SNP data were genotyped as part of a genome-wide scan. Among investigated SNPS, only four tag SNPS in GC, the major serum 25(OH)D carrier, were associated with 25(OH)D levels; no SNPS were associated with 1,25(OH)2D levels. None of the 212 SNPS examined were associated with cancer risk overall. Among men in the lowest tertile of serum 25(OH)D (<48.9 nmol/l), however, prostate cancer risk was related to tag SNPS in or near the 3′ untranslated region (UTR) of VDR, with the strongest association for rs11574143 [odds ratio (95% confidence interval) for risk allele carriers versus wild-type: 2.49 (1.51–4.11), P = 0.0007]; the genotype associations were null among men in tertile 2 and tertile 3. Results from the most comprehensive evaluation of serum vitamin D and its related genes to date suggest that tag SNPS in the 3′ UTR of VDR may be associated with risk of prostate cancer in men with low vitamin D status.
The “nonclassic” role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been recently widely recognized. In type 1 diabetes mellitus (T1D), it plays an immunomodulatory role through the vitamin D receptor (VDR) present on pancreatic and immune cells. Specific VDR allelic variants have been associated with T1D in many countries. Furthermore, vitamin D deficiency has been prevalent in T1D, and the seasonal and latitude variability in the incidence of T1D can be partly explained by the related variability in vitamin D level. In fact, retrospective studies of vitamin D supplementation during pregnancy or infancy showed a lower incidence of T1D. We will review the different mechanisms of the vitamin D protective effect against insulitis and
present the available data on the role of vitamin D deficiency in the control, progression, and
complications of T1D.
Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D.
We created a tanning, a skin color and a freckling score as combinations of SNPs that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and PSA-detected prostate cancer in 3123 white British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study.
The freckling score was inversely associated with 25(OH)D levels (change in 25(OH)D per score unit −0.27; 95%CI: −0.52, −0.01), and the tanning score was positively associated with prostate cancer risk (OR 1.05; 95%CI: 1.02,1.09), after adjustment for population stratification and potential confounders.
Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer.
The use of pigmentation related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk.
pigmentation; tanning; sun exposure; vitamin D; prostate cancer
Mendelian randomization (MR) studies use genetic variants mimicking the influence of a modifiable exposure to assess and quantify a causal association with an outcome, with an aim to avoid problems with confounding and reverse causality affecting other types of observational studies.
We evaluated genetic markers that index differences in 25-hydroxyvitamin D (25(OH)D) as instruments for MR studies on vitamin D.
Methods and Findings
We used data from up-to 6,877 participants in the 1958 British birth cohort with information on genetic markers and 25(OH)D. As potential instruments, we selected 20 single nucleotide polymorphisms (SNP) which are located in the vitamin D metabolism pathway or affect skin pigmentation/tanning, including 4 SNPs from genome-wide association (GWA) meta-analyses on 25(OH)D. We analyzed SNP associations with 25(OH)D and evaluated the use of allele scores dividing genes to those affecting 25(OH)D synthesis (DHCR7, CYP2R1) and metabolism (GC, CYP24A1, CYP27B1). In addition to the GWA SNPs, only two SNPs (CYP27B1, OCA2) showed evidence for association with 25(OH)D, with the OCA2 association abolished after lifestyle adjustment. Per allele differences varied between −0.02 and −0.08 nmol/L (P≤0.02 for all), with a 6.1 nmol/L and a 10.2 nmol/L difference in 25(OH)D between individuals with highest compared lowest number of risk alleles in synthesis and metabolism allele scores, respectively. Individual SNPs but not allele scores showed associations with lifestyle factors. An exception was geographical region which was associated with synthesis score. Illustrative power calculations (80% power, 5% alpha) suggest that approximately 80,000 participants are required to establish a causal effect of vitamin D on blood pressure using the synthesis allele score.
Combining SNPs into allele scores provides a more powerful instrument for MR analysis than a single SNP in isolation. Population stratification and the potential for pleiotropic effects need to be considered in MR studies on vitamin D.
Disadvantages faced by Hispanic children in the U.S., compared to non-Hispanic Whites, have been widely reported. Economic differences account for some of the gaps, but the social isolation of Hispanic families also serves as a barrier to children’s success. Whereas Hispanic families tend to have strong kinship networks, their social ties often do not encompass the school and other authority systems. As a result, Hispanic families may have less access to social capital, that is, relations of trust and shared expectations that foster the flow of relevant information and support social norms that contribute to children’s academic and social development. To study the role of social capital in child development, we embarked on a school-randomized trial in two cities with large Hispanic populations: San Antonio, Texas, and Phoenix, Arizona. In this paper, we report on first-year data from what will be a three-year longitudinal study, including 24 of an eventual 52 schools and about 1,300 of what will be a sample of over 3,000 children. We aimed to manipulate social capital through an intervention called Families and Schools Together (FAST), a multi-family after-school program that enhances relations among families, between parents and schools, and between parents and children through a sequence of structured activities over 8 weekly sessions. In the first year, 12 schools were randomly assigned to participate in FAST, and 12 served as controls. Data come from district administrative records, surveys of parents prior to FAST, and surveys of parents and teachers immediately after FAST. Surveys prior to FAST confirm that Hispanic parents have less extensive parent-school networks compared to non-Hispanic Whites. Comparisons of school means on post-FAST surveys indicate that parents in FAST schools experience more extensive social networks than those in control schools, but the differences are much more apparent in Phoenix than in San Antonio. Similarly, a pattern of better behavioral outcomes for children in FAST schools is evident in Phoenix but not San Antonio. Individual-level comparisons suggest that for some outcomes, effects may be larger for non-Hispanic Whites than for Hispanics, which would undermine potential contributions to reducing inequality.
The wide spectrum of vitamin D activity has focused attention on its potential role in the elevated burden of disease in a northern Canadian First Nations (Dené) cohort. Vitamin D insufficiency, and gene polymorphisms in the vitamin D receptor (VDR) and vitamin D binding protein (VDBP) have been implicated in susceptibility to infectious and chronic diseases. The objectives of this study were to determine the contribution of vitamin D from food, and measure the serum concentrations of 25-hydroxyvitamin D3 (25-OHD3) and VDBP in Dené participants. Single nucleotide polymorphisms (SNPs) associated with the dysregulation of the innate immune response were typed and counted. Potential correlations between the SNPs and serum concentrations of 25-OHD3 and VDBP were evaluated. Venous blood was collected in summer and winter over a one-year period and analyzed for 25-OHD3 and VDBP concentrations (N = 46). A questionnaire was administered to determine the amount of dietary vitamin D consumed. Sixty-one percent and 30% of the participants had 25-OHD3 serum concentrations <75 nmol/L in the winter and summer respectively. Mean vitamin D binding protein concentrations were within the normal range in the winter but below normal in the summer. VDBP and VDR gene polymorphisms affect the bioavailability and regulation of 25-OHD3. The Dené had a high frequency of the VDBP D432E-G allele (71%) and the Gc1 genotype (90%), associated with high concentrations of VDBP and a high binding affinity to 25-OHD3. The Dené had a high frequency of VDR Fok1-f allele (82%), which has been associated with a down-regulated Th1 immune response. VDBP and VDR polymorphisms, and low winter 25-OHD3 serum concentrations may be risk factors for infectious diseases and chronic conditions related to the dysregulation of the vitamin D pathway.
Children with calcium-deficiency rickets may have increased vitamin D requirements and respond differently to vitamin D2 and vitamin D3. Our objective was to compare the metabolism of vitamins D2 and D3 in rachitic and control children. We administered an oral single dose of vitamin D2 or D3 of 1.25 mg to 49 Nigerian children—28 with active rickets and 21 healthy controls. The primary outcome measure was the incremental change in vitamin D metabolites. Baseline serum 25-hydroxyvitamin D [25(OH)D] concentrations ranged from 7 to 24 and 15 to 34 ng/mL in rachitic and control children, respectively (p < .001), whereas baseline 1,25-dihydroxyvitamin D [1,25(OH)2D] values (mean ± SD) were 224 ± 72 and 121 ± 34 pg/mL, respectively (p < .001), and baseline 24,25-dihydroxyvitamin D [24,25(OH)2D] values were 1.13 ± 0.59 and 4.03 ± 1.33 ng/mL, respectively (p < .001). The peak increment in 25(OH)D was on day 3 and was similar with vitamins D2 and D3 in children with rickets (29 ± 17 and 25 ± 11 ng/mL, respectively) and in control children (33 ± 13 and 31 ± 16 ng/mL, respectively). 1,25(OH)2D rose significantly (p < .001) and similarly (p = .18) on day 3 by 166 ± 80 and 209 ± 83 pg/mL after vitamin D2 and D3 administration, respectively, in children with rickets. By contrast, control children had no significant increase in 1,25(OH)2D (19 ± 28 and 16 ± 38 pg/mL after vitamin D2 and D3 administration, respectively). We conclude that in the short term, vitamins D2 and D3 similarly increase serum 25(OH)D concentrations in rachitic and healthy children. A marked increase in 1,25(OH)2D in response to vitamin D distinguishes children with putative dietary calcium-deficiency rickets from healthy children, consistent with increased vitamin D requirements in children with calcium-deficiency rickets. © 2010 American Society for Bone and Mineral Research.
metabolic bone; vitamin D; calcium; pediatric; nutrition
To assess the relationship between maternal and fetal mineral homeostasis, serum calcium, magnesium, inorganic phosphate, parathyroid hormone, and vitamin D metabolite concentrations in venous cord sera from 15 preterm singletons and 3 twin pairs were compared with the levels found in maternal sera. Cord calcium, magnesium, and phosphorus levels were significantly higher than the respective levels in maternal samples. There was a significant relationship between the two compartments for all three analyses. Cord serum 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D levels were significantly lower than those observed for the mothers. Association of the cord concentration with that of the mothers was observed only for the first two metabolites. There was no relationship between the maternal 1,25-dihydroxyvitamin D levels and gestational age, calcium, magnesium, inorganic phosphate, or 25-hydroxyvitamin D. Cord 1,25-dihydroxyvitamin D correlated significantly only with cord calcium levels. Immunoreactive parathyroid hormone levels were within normal limits both in cord and maternal samples. Our data suggest that after 31 weeks of gestation: (1) calcium, magnesium, and inorganic phosphate cross the placental barrier against a concentration gradient; (2) the fetus depends on the maternal supply for 25-hydroxyvitamin D and 24,25 dihydroxyvitamin D; (3) the feto-placental unit synthesizes 1,25-dihydroxyvitamin D according to fetal needs.
Evidence suggests low vitamin D and elevated parathyroid hormone (PTH) concentrations may increase risk for cardiovascular disease. However, little is known about the association between vitamin D or PTH and subclinical atherosclerosis. This cross-sectional study included 654 community-dwelling older adults aged 55–96 years (mean age, 75.5 years) without a history of coronary heart disease, revascularization, or stroke enrolled in the Rancho Bernardo Study who completed a clinic examination in 1997–1999 and provided a blood sample for determination of serum 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and PTH concentrations. Carotid artery intima-media wall thickness (IMT) was measured as an indicator of atherosclerosis at two sites with B-mode ultrasound. After adjusting for age, sex, smoking, alcohol intake, waist-to-hip ratio, exercise, season of blood draw, diabetes, and hypertension, geometric mean internal carotid IMT (ptrend 0.022), but not common carotid IMT (ptrend 0.834) decreased in a dose-dependent fashion with increasing concentration of 25(OH)D. There was no association of 1,25(OH)2D or PTH with either measure of carotid IMT. In subgroup analyses, 1,25(OH)2D was inversely associated with internal carotid IMT among those with hypertension (p for interaction 0.036). These findings from a population-based cohort of older adults suggest a potential role for vitamin D in the development of subclinical atherosclerosis. Additional research is needed to determine whether vitamin D may influence the progression of atherosclerosis, including the effects of supplementation on the atherosclerotic process.
Atherosclerosis; Vitamin D; Parathyroid Hormone; Cardiovascular Diseases
Metabolites of vitamin D were measured in plasma from 83 patients with idiopathic infantile hypercalcaemia syndrome who were mentally handicapped but had normal calcium values at the time of the study. No significant difference was detected in the mean plasma concentrations of 25-hydroxyvitamin D2, 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D3, or 25,26-dihydroxyvitamin D3 between patients and age matched controls. The mean plasma concentration of 25-hydroxyvitamin D3 was significantly lower in patients than controls but this may be a secondary phenomenon related to less sunlight exposure. In addition, two hypercalcaemic patients with this syndrome were studied during the first year of life, and were found to have normal concentrations of vitamin D metabolites. These findings do not support a role for abnormal vitamin D metabolism in the pathogenesis of this syndrome.
Higher serum concentrations of 25-hydroxyvitamin D (25(OH)D), an indicator of vitamin D synthesis and intake, have been associated with better mental health and cognitive function. Concentrations of 1,25-dihydroxyvitamin D3 (the active vitamin D3 metabolite) have been associated with openness and extrovert behaviour, but 25(OH)D concentrations have not been associated with behavioural problems in humans.
We investigated the prospective association between the different forms of 25(OH)D - 25(OH)D3 and 25(OH)D2– and childhood behavioural problems in Avon Longitudinal Study of Parents and Children (ALSPAC). Serum 25(OH)D3 and 25(OH)D2 concentrations were assessed at mean age 9.9 years. Incident behavioural problems were assessed with Strengths and Difficulties Questionnaire (SDQ; emotional symptoms, conduct problems, hyperactivity-inattention problems, peer relationship problems and pro-social behaviour subscales and total difficulties score) at mean age 11.7. Sample sizes varied between 2413-2666 depending on the outcome.
Higher 25(OH)D3 concentrations were weakly associated with lower risk of prosocial problems (fully adjusted odds ratio: OR (95% confidence interval: CI) 0.85 (0.74, 0.98)). Serum 25(OH)D3 or 25(OH)D2 concentrations were not associated with other subscales of SDQ or total difficulties score after adjusting for concfounders and other measured analytes related to vitamin D.
Our findings do not support the hypothesis that 25-hydroxyvitamin D status in childhood has important influences on behavioural traits in humans.
The discovery that many tissues express the vitamin D receptor and are able to transform the 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D (active metabolite) has led to the hypothesis that vitamin D could have a role in the pathogenesis and prevention of diabetes mellitus. Accumulating evidence has linked vitamin D deficiency with immunological disturbance in type 1 diabetes mellitus. Several epidemiological studies have shown lower serum 25-hydroxyvitamin D concentrations in diabetic individuals compared to nondiabetic individuals.
Patients and methods
A total of 105 Lebanese patients with type 1 diabetes mellitus were recruited. Levels of HbA1c and vitamin D were recorded during two phases with phase 1 being the period from June–September 2009 and phase 2 from January–April 2009.
Vitamin D levels at the end of sunny season (phase 2), reflecting the previous sunny months, were found to be higher than in the early summer season (phase 1) reflecting the previous cloudy months season, with a mean change of 0.70 ± 6.87 ng/mL (P = 0.029). HbA1c levels were higher in phase 2 than in phase 1 with an increase of 0.175% ± 1.46% (P = 0.113).
Vitamin D levels were higher at the end of the sunny season than at the end of cloudy season. HbA1c was also lower (but not significantly so) in the early summer season (cloudy months). There was a weak correlation between seasonal changes of vitamin D levels and the control of blood glucose as monitored by HbA1c in a cohort of Lebanese patients with type 1 diabetes mellitus.
type 1 diabetes; vitamin D; HbA1c; seasonal variation
Epidemiologic data suggest that the incidence and severity of many types of cancer inversely correlates with indices of vitamin D status. The vitamin D receptor (VDR) is highly expressed in epithelial cells at risk for carcinogenesis including those resident in skin, breast, prostate and colon, providing a direct molecular link by which vitamin D status impacts on carcinogenesis. Consistent with this concept, activation of VDR by its ligand 1,25-dihydroxyvitamin D (1,25D) triggers comprehensive genomic changes in epithelial cells that contribute to maintenance of the differentiated phenotype, resistance to cellular stresses and protection of the genome. Many epithelial cells also express the vitamin D metabolizing enzyme CYP27B1 which enables autocrine generation of 1,25D from the circulating vitamin D metabolite 25-hydroxyvitamin D (25D), critically linking overall vitamin D status with cellular anti-tumor actions. Furthermore, pre-clinical studies in animal models has demonstrated that dietary supplementation with vitamin D or chronic treatment with VDR agonists decreases tumor development in skin, colon, prostate and breast. Conversely, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis, increases oxidative DNA damage, and enhances susceptibility to carcinogenesis in these tissues. Because VDR expression is retained in many human tumors, vitamin D status may be an important modulator of cancer progression in persons living with cancer. Collectively, these observations have reinforced the need to further define the molecular actions of the VDR and the human requirement for vitamin D in relation to cancer development and progression.
vitamin D receptor; cancer; vitamin D; prevention; diet
Vitamin D deficiency is becoming more apparent in many populations. Genetic factors may play a role in the maintenance of vitamin D levels. The objective of this study was to perform a genome-wide analysis (GWAS) of vitamin D levels, including replication of prior GWAS results. We measured 25-hydroxyvitamin D (25(OH)D) levels in serum collected at the time of enrollment and at year 4 in 572 Caucasian children with asthma, who were part of a multi-center clinical trial, the Childhood Asthma Management Program. Replication was performed in a second cohort of 592 asthmatics from Costa Rica and a third cohort of 516 Puerto Rican asthmatics. In addition, we attempted replication of three SNPs that were previously identified in a large GWAS of Caucasian individuals. The setting included data from a clinical trial of childhood asthmatics and two cohorts of asthmatics recruited for genetic studies of asthma. The main outcome measure was circulating 25(OH)D levels. The 25(OH)D levels at the two time-points were only modestly correlated with each other (intraclass correlation coefficient = 0.33) in the CAMP population. We identified SNPs that were nominally associated with 25(OH)D levels at two time-points in CAMP, and replicated four SNPs in the Costa Rican cohort: rs11002969, rs163221, rs1678849, and rs4864976. However, these SNPs were not significantly associated with 25(OH)D levels in a third population of Puerto Rican asthmatics. We were able to replicate the SNP with the strongest effect, previously reported in a large GWAS: rs2282679 (GC), and we were able to replicate another SNP, rs10741657 (CYP2R1), to a lesser degree. We were able to replicate two of three prior significant findings in a GWAS of 25(OH)D levels. Other SNPs may be additionally associated with 25(OH)D levels in certain populations.
DNA repair genes are important for maintaining genomic stability and limiting carcinogenesis. We analyzed all single nucleotide polymorphisms (SNPs) of 125 DNA repair genes covered by the Illumina HumanHap300 (v1.1) BeadChips in a previously conducted genome-wide association study (GWAS) of 1,154 lung cancer cases and 1,137 controls and replicated the top-hits of XRCC4 SNPs in an independent set of 597 cases and 611 controls in Texas populations. We found that six of 20 XRCC4 SNPs were associated with a decreased risk of lung cancer with a P value of 0.01 or lower in the discovery dataset, of which the most significant SNP was rs10040363 (P for allelic test = 4.89 ×10−4). Moreover, the data in this region allowed us to impute a potentially functional SNP rs2075685 (imputed P for allelic test = 1.3 ×10−3). A luciferase reporter assay demonstrated that the rs2075685G>T change in the XRCC4 promoter increased expression of the gene. In the replication study of rs10040363, rs1478486, rs9293329, and rs2075685, however, only rs10040363 achieved a borderline association with a decreased risk of lung cancer in a dominant model (adjusted OR = 0.80, 95% CI = 0.62–1.03, P = 0.079). In the final combined analysis of both the Texas GWAS discovery and replication datasets, the strength of the association was increased for rs10040363 (adjusted OR = 0.77, 95% CI = 0.66–0.89, Pdominant = 5×10−4 and P for trend = 5×10−4) and rs1478486 (adjusted OR = 0.82, 95% CI = 0.71 −0.94, Pdominant = 6×10−3 and P for trend = 3.5×10−3). Finally, we conducted a meta-analysis of these XRCC4 SNPs with available data from published GWA studies of lung cancer with a total of 12,312 cases and 47,921 controls, in which none of these XRCC4 SNPs was associated with lung cancer risk. It appeared that rs2075685, although associated with increased expression of a reporter gene and lung cancer risk in the Texas populations, did not have an effect on lung cancer risk in other populations. This study underscores the importance of replication using published data in larger populations.
XRCC4; variant; Genetic susceptibility; genome-wide association study; replication study
This study provides the first ever measurements of vitamin D metabolites in the eye, demonstrates that the cornea is capable of activating and utilizing vitamin D, and shows that vitamin D can enhance corneal epithelial barrier function.
The purpose of this study was to determine whether 25-hydroxyvitamin D3 (25(OH)D3) and/or its active metabolite, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), can enhance corneal epithelial barrier function. The authors also determined if corneas contain mRNA for the vitamin D receptor (VDR) and 1α-hydroxylase, the enzyme required to convert 25(OH)D3 to 1,25(OH)2D3, and measured vitamin D metabolite concentrations in aqueous and vitreous humor.
RT-PCR was used to examine mouse, rabbit, and human corneal epithelial VDR and 1α-hydroxylase mRNA. Vitamin D metabolites were measured using a selective vitamin D derivatizing agent and mass spectroscopy. Barrier function experiments were performed by measuring inulin permeability (IP) and/or transepithelial resistance (TER) in control, 25(OH)D3-, and 1,25(OH)2D3-treated human and rabbit corneal epithelial monolayers cultured on permeable inserts. Ca2+ was removed, then reintroduced to the culture medium while IP and TER readings were taken. Occludin levels were examined using Western blotting.
All corneal samples were positive for both VDR and 1α-hydroxylase mRNA. All vitamin D metabolites except for unhydroxylated vitamin D3 were detected in aqueous and vitreous humor. Epithelial cells showed increased TER, decreased IP, and increased occludin levels when cultured with 25(OH)D3 and 1,25(OH)2D3.
We conclude that corneas contain mRNA for VDR and 1α-hydroxylase as well as significant vitamin D concentrations. 25(OH)D3 and its active metabolite 1,25(OH)2D3, both enhance corneal epithelial barrier function.
Chronic kidney disease is characterized, in part, as a state of decreased production of 1,25-dihydroxyvitamin D (1,25(OH)2D); however, this paradigm overlooks the role of vitamin D catabolism. We developed a mass spectrometric assay to quantify serum concentration of 24,25-dihydroxyvitamin D (24,25(OH)2D), the first metabolic product of 25-hydroxyvitamin D (25(OH)D) by CYP24A1, and determined its clinical correlates and associated outcomes among 278 participants with chronic kidney disease in the Seattle Kidney Study. For eGFRs of 60 or more, 45–59, 30–44, 15–29, and under 15 ml/min/1.73m2, the mean serum 24,25(OH)2D concentrations significantly trended lower from 3.6, 3.2, 2.6, 2.6, to 1.7 ng/ml, respectively. Non-Hispanic Black race, diabetes, albuminuria, and lower serum bicarbonate were also independently and significantly associated with lower 24,25(OH)2D concentrations. The 24,25(OH)2D concentration was more strongly correlated with that of parathyroid hormone than was 25(OH)D or 1,25(OH)2D. A 24,25(OH)2D concentration below the median was associated with increased risk of mortality in unadjusted analysis, but this was attenuated with adjustment for potential confounding variables. Thus, chronic kidney disease is a state of stagnant vitamin D metabolism characterized by decreases in both 1,25(OH)2D production and vitamin D catabolism.