Genetic variations in the Vitamin D receptor predict type 2 diabetes and myocardial infarction in a community-based population: The tromsø study

Background Though the associations between low serum 25-hydroxyvitamin D (25(OH)D) levels and health outcomes such as type 2 diabetes (T2D), myocardial infarction (MI), cancer, and mortality are well-studied, the effect of supplementation with vitamin D is uncertain. This may be related to genetic differences. Thus, rs7968585, a single nucleotide polymorphism (SNP) of the vitamin D receptor (VDR), has recently been reported as a predictor of composite health outcome. We therefore aimed to evaluate whether rs7968585 predicts separate clinical outcomes such as T2D, MI, cancer, and mortality in a community-based Norwegian population. Methods and Findings Measurements and DNA were obtained from the participants in the Tromsø Study in 1994– 1995, registered with the outcomes of interest and a randomly selected control group. The impact of the rs7968585 genotypes was evaluated with Cox proportional hazards. A total of 8,461 subjects were included among whom 1,054 subjects were registered with T2D, 2,287 with MI, 3,166 with cancer, and 4,336 with death. Mean follow-up time from birth was 60.8 years for T2D and MI, 61.2 years for cancer, while mean follow-up time from examination date was 16.5 years for survival. Mean serum 25(OH)D levels did not differ across the rs7968585 genotypes. With the major homozygote genotype as reference, the minor homozygote subjects had hazard ratios of 1.25 (95% CI 1.05–1.49) for T2D and 1.14 (1.02–1.28) for MI (P = 0.011 and 0.023, respectively, without the Bonferroni correction). No significant interaction between serum 25(OH)D status and the rs7968585 genotype was found for any of the endpoints. Conclusions The VDR-related SNP rs7968585 minor allele is a significant and positive predictor for T2D and possibly for MI. Since the functional mechanism of this SNP is not yet understood, and the association with T2D is reported for the first time, confirmatory studies are needed

C3-epimerization of 25-hydroxyvitamin D increases with increasing serum 25-hydroxyvitamin D levels and shows a high degree of tracking over time

Objective: Evaluate the effects of serum 25-hydroxyvitamin D (25(OH)D) levels, vitamin D binding protein (DBP) and genetic factors on C3-epimerization of 25(OH)D and follow the tracking of the epimer during one year. Design: Cross-sectional and longitudinal study. Methods: Data from eight previously conducted, Tromsø based studies (3 observational, 5 randomized controlled trials) were combined. 25(OH)D serum samples were re-analyzed with a LC-MS/MS method that also resolves and measures the metabolite C3-epi-25(OH)D3. Data on vitamin D binding protein (DBP) phenotype (based on single nucleotide polymorphisms (SNPs) rs4588 and rs7041) and genetic determinants for serum 25(OH)D (SNPs rs2282679, rs10741657, rs3829251 and rs6013897) were collected where available. Results: 2219 subjects were included. Median (5th, 95th percentiles) baseline serum values of 25(OH)D3, C3-epi-25(OH)D3, and %-C3-epi-25(OH)D3 were 49.1 (22.1, 92.8) nmol/L, 2.3 (0.9, 6.0) nmol/L and 4.4 (2.7, 8.4) %, respectively. The highest baseline values were 230.5 nmol/L for 25(OH)D3, 79.7 nmol/L for C3-epi-25(OH)D3 and 48.2% for %-C3-epi-25(OH)D3. There was a strong correlation between serum 25(OH)D3 and C3-epi-25(OH)D3. The %-C3-epi-25(OH)D3 value increased with increasing serum 25(OH)D3, but leveled off at ~7% at a 25(OH)D3 concentration of ~120–140 nmol/L. There was a significant degree of tracking for %-C3-epi-25(OH)D3 (correlation coefficient rho between baseline and 1-year values 0.39, P < 0.001). The %-C3-epi-25(OH)D3 level was not related to serum DBP level, DBP phenotype nor to SNPs related to serum 25(OH)D3 level. The serum 25(OH)D3 level could explain less than 3% of %-C3-epi-25(OH)D3 variation. Conclusions: There are considerable individual and reproducible differences in percent C3-epimerization of uncertain clinical importance

Tracking of serum 25-hydroxyvitamin D during 21 years

Background/objectives - Our objective was to evaluate the degree of tracking for serum levels of 25-hydroxyvitamin D [25(OH)D] over time, by using data from three previously conducted surveys of the Tromsø study collected in the years 1994/1995 (Tromsø 4), 2007/2008 (Tromsø 6), and 2015/2016 (Tromsø 7). Subjects/methods - Subjects with valid 25(OH)D measurements in all three surveys were included. 25(OH)D z-scores were used to adjust for seasonal variation. Z-scores and sextiles were used to illustrate tracking of 25(OH)D. Results - 1702 subjects (572 males, 1130 females) fulfilled the inclusion criteria. Median (5th, 95th percentiles) age for these subjects was 55 (33, 65) years in Tromsø 4, and mean (SD) 25(OH)D levels were 57 (18) nmol/L, 59 (19) nmol/L, and 72 (21) nmol/L for Tromsø 4, Tromsø 6, and Tromsø 7, respectively. There was significant tracking of serum 25(OH)D over the 21 years period between the surveys of the Tromsø study. The correlation coefficient r between 25(OH)D z-scores from Tromsø 4 and Tromsø 6 was 0.40, and declined to 0.29 for the correlation between Tromsø 4 and Tromsø 7. Twenty-six percent of the subjects in the lowest 25(OH)D z-score sextile in Tromsø 4 were in the three highest sextiles of 25(OH)D in Tromsø 7. Similarly, 35% of those in the highest sextile in Tromsø 4 were in the lowest three sextiles in Tromsø 7. -Conclusions - The degree of tracking for serum 25(OH)D declines over time, and the use of a single serum 25(OH)D measurement as an indicator of the vitamin-D status is questionable if used in long-lasting observational studies

Vitamin D supplementation does not improve CVD risk factors in vitamin D-insufficient subjects

Objective: Low serum 25(OH)D levels are associated with cardiovascular disease (CVD) and some of its risk factors. However, in interventional studies, the effects of vitamin D supplementation have been uncertain, possibly due to inclusion of vitamin D-sufficient subjects. Our aim was therefore to examine effects of vitamin D supplementation on CVD risk factors in vitamin D-insufficient subjects. Design: Double-blinded randomized controlled trial. Methods: A 4-month interventional study with high-dose vitamin D (100,000 IU loading dose, followed by 20,000 IU/week) or placebo with measurements of blood pressure, lipids (total-, LDL- and HDL-cholesterol, triglycerides, apolipoproteins A1 and B), and glucose metabolism parameters (blood glucose, HbA1c, serum human receptors for advanced glycation end products (sRAGE), insulin, C-peptide and HOMA-IR). Results: A total of 422 subjects with mean serum 25(OH)D level 34 nmol/L were included, with 411 subjects completing the study. Serum 25(OH)D levels increased with 56 nmol/L and decreased with 4 nmol/L in the vitamin D and placebo group, respectively. We found no statistically significant differences between the two groups in any of the measured CVD risk factors, except for a minor increase in sRAGE in the vitamin D group. Stratified analyses of subjects with low baseline serum 25(OH)D levels alone, or combined with blood pressure, lipid and HOMA-IR values above the median for the cohort, did not skew the results in favour of vitamin D supplementation. Conclusion: Supplementation with vitamin D in subjects with baseline vitamin D insufficiency does not improve CVD risk factor profile.</p

Evaluation of Serum 25-Hydroxyvitamin D as a Predictor of Carotid Intima-Media Thickness and Carotid Total Plaque Area in Nonsmokers: The Tromso Study

Objective. Altered calcium homeostasis has been linked to increased intima-media thickness (IMT) and plaques. We aimed to investigate whether serum 25-hydroxyvitamin D (25(OH)D) and serum calcium are associated with IMT and plaques in nonsmoking population. Methods.Ultrasound of the right carotid arterywith themeasurements of IMT and plaqueswas performed in 4194 nonsmoking subjects with available measurements of serum 25(OH)D and total calcium. Linear regression was applied to study the linear relationships between variables. Multinomial logistic regression was used to evaluate predictors of increased IMT and total plaque area (TPA), adjusted for age, body mass index, systolic blood pressure, and total cholesterol. Results.There was no significant linear relationship between mean IMT, TPA, and either serum 25(OH)D or total serum calcium. One SD increase in serum 25(OH)D was independently associated with increased odds of being in the highest quartile of IMT in men (OR 1.30, 95% CI 1.12, 1.51). In women, 1 SD increase in serum 25(OH)D was independently associated with increased risk of being in the upper tertile of TPA (OR 1.15, 95% CI 1.01, 1.33). Conclusions. Impaired calcium homeostasis has no consistent association withmean IMT and TPA; however, increased serum 25(OH)D may predict subclinical atherosclerosis in nonsmokers

Serum calcium and the calcium-sensing receptor polymorphism rs17251221 in relation to coronary heart disease, type 2 diabetes, cancer and mortality: the Tromsø Study

Serum calcium measured in 27,158 subjects in 1994 and the calcium-sensing receptor polymorphism rs17251221 genotyped in 9,404 subjects were related to cardiovascular risk factors, incident myocardial infarction (MI), type 2 diabetes (T2DM), cancer and death during follow-up until 2008–2010. In a Cox regression model with adjustment for age, gender, smoking and body mass index, subjects with serum calcium 2.50–2.60 mmol/L had a significantly increased risk of incident MI [n = 1,802, hazards ratio (HR) 1.40, 95 % confidence interval (CI) 1.18, 1.66] and T2DM (n = 705, HR 1.49, 95 % CI 1.15, 1.94) and a significantly reduced risk of cancer (n = 2,222, HR 0.73, 95 % CI 0.62, 0.86) as compared to subjects with serum calcium 2.20–2.29 mmol/L. For rs17251221 there was a mean difference in serum calcium of 0.05 mmol/L between major and minor homozygote genotypes. No consistent, significant relation between rs17251221 and risk factors or the major hard endpoints were found. The minor homozygote genotype (high serum calcium) had a significant twofold increased risk (HR 2.32, 95 % CI 1.24, 4.36) for prostate cancer, as compared to the major homozygote. This may be clinically important if confirmed in other cohorts

Bone mineral density is associated with vitamin D related rs6013897 and estrogen receptor polymorphism rs4870044: The Tromsø study

<div><p>Background</p><p>Bone mineral density (BMD) is determined by bone remodeling processes regulated by endocrine, autocrine and genetic mechanisms. Thus, some studies have reported that BMD is associated with single nucleotide polymorphisms (SNPs) associated with vitamin D receptor (<i>VDR</i>), serum 25(OH)D levels and estrogen receptor 1 (<i>ESR1</i>), but without consensus. Therefore, we aimed to map and compare the risk genotypes for forearm and total hip low BMD.</p><p>Methods and findings</p><p>Data were derived from a population-based study in northern Norway; the Tromsø Study. Distal forearm BMD was measured with a single x-ray absorptiometric device, while total hip BMD was measured with a dual-energy x-ray absorptiometric device. There were 7,317 and 4,082 successful analyses of distal forearm and total hip BMD, respectively, and at least one SNP of interest. We evaluated plausible BMD modulating factors and associations of BMD and SNPs related to vitamin D metabolism (<i>FokI</i>, <i>Cdx2</i>, <i>BsmI</i>, rs2298850, rs10741657, rs3794060, rs6013897), <i>ApaI-BsmI-TaqI</i> haplotypes and <i>ESR1</i> SNP rs4870044.</p><p>Results</p><p>Age, BMI, physical activity and smoking were significantly associated with BMD. In a linear regression model with adjustment for age and gender and with the major homozygote as reference, rs6013897 had a standardized beta coefficient (<i>β</i>) of –0.031 (<i>P</i> = 0.024) for total hip BMD. <i>β</i> for <i>ESR1</i> SNP rs4870044 was –0.016 (<i>P</i> = 0.036) for forearm BMD and –0.034 (<i>P</i> = 0.015) for total hip BMD. The other SNPs nor serum 25(OH)D were significantly associated with BMD.</p><p>Conclusions</p><p>Both forearm and total hip BMD were associated with ESR1 SNP rs4870044. Of the vitamin D–related genes, only <i>CYP24A1</i> gene rs6013897 was associated with total hip BMD, but the association was weak and needs confirmation in other studies. Serum 25(OH)D was not associated with BMD in our population, probably due to the generally sufficient vitamin D levels in the population.</p></div