Elena Kamycheva

Serum parathyroid hormone levels predict coronary heart disease: the Tromsø Study

Background Primary hyperparathyroidism (PHPT) is associated with hypertension, coronary atherosclerosis and other cardiovascular diseases. We aimed to evaluate serum parathyroid hormone (PTH) levels as an independent risk factor for coronary heart disease (CHD) in subjects with serum calcium within the reference range. Design Population-based cross-sectional study. Methods The Tromsø Study was attended by 27159 subjects aged 25-79 years. Serum PTH was measured in 3570 subjects. They all completed a questionnaire on medical history, including questions on angina pectoris and myocardial infarction along with a food-frequency questionnaire. A total of 1459 men and 1753 women with serum calcium 2.20-2.60 mmol/l, serum creatinine< 121 μmol/l and who did not use diuretics were included in the present study. Linear regression was used to reveal associations between PTH, age, body mass index, serum calcium, calcium intake, cholesterol, blood pressure, glycosylated haemoglobin (HbA1c) and smoking status. A logistic regression model was used to find the independent predictors of CHD. Results When stratified for age the rate of CHD was higher in the subjects with serum PTH > 6.8 pmol/l than in those with normal or low serum PTH levels [relative risk 1.67, 95% confidence interval (CI) 1.26-2.23 in men and 1.78, 95% CI 1.22-2.57 in women]. The highest PTH quartile (> 3.50 pmol/l in men and > 3.30 pmol/l in women) predicted CHD, with odds ratios of 1.70 (95% CI 1.08-2.70) for men and 1.73 (95% CI 1.04-2.88) for women, versus the lowest PTH quartile (< 1.90 pmol/l for men and < 1.80 pmol/l for women). Conclusions Serum PTH predicts CHD in subjects with calcium levels within the reference range. This may indicate a role for PTH in the development of CHD.

Effects of a 1-year supplementation with cholecalciferol on interleukin-6, tumor necrosis factor-alpha and insulin resistance in overweight and obese subjects.

Insufficient vitamin D status has been linked to autoimmune diseases, cancer and metabolic disorders, like obesity and insulin resistance. In vitro and animal studies suggest that vitamin D may play a crucial role in immune activation and inflammation. The relation between vitamin D and pro-inflammatory cytokines is not completely established. Furthermore, it is not known if the effect of vitamin D on entities of metabolic syndrome is mediated through its effect on cytokines or other biomarkers. The objectives of this study were to investigate if there is a relationship between vitamin D status and such pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and high sensitive C-reactive protein (hs-CRP) in patients with overweigh and obesity. We also proposed that the intervention with high dose of cholecalciferol may have effect on the cytokine levels and result in corresponding changes in the measures of insulin resistance (HOMA-IR and QUICKI). Serum levels of IL-6, TNF-α and hs-CRP were measured in 332 overweight and obese subjects who completed a 1-year randomised intervention with either 40,000 IU vitamin D (cholecalciferol) per week or 20,000 IU vitamin D per week, or placebo. We found significant associations between IL-6, TNF-α, vitamin D and insulin resistance indices at baseline. One year intervention with vitamin D decreased serum IL-6 levels; however hs-CRP levels were significantly increased. Neither measures of insulin resistance, nor TNF-α were influenced by a 1-year vitamin D supplementation.

No Effect of High-Dose Vitamin D Supplementation on Glycemic Status or Cardiovascular Risk Factors in Subjects With Prediabetes

OBJECTIVE In observational studies, low serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance and other risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS We present 1-year data from an ongoing 5-year trial in 511 individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) randomly assigned to 20,000 IU/week vitamin D3 or placebo. An oral glucose tolerance test was performed at baseline and after 1 year. RESULTS Mean baseline serum 25(OH)D was 59.9 nmol/L and 61.1 nmol/L in the vitamin D and placebo groups, respectively, and increased by 45.8 nmol/L and 3.4 nmol/L, respectively. With adjustment for baseline concentrations, no differences in measures of glucose metabolism, insulin secretion or sensitivity, blood pressure, or hs-CRP were found after 1 year. There was a slight, but significant decrease in total and LDL cholesterol in the vitamin D group compared with the placebo group, but as there was also a decrease in HDL cholesterol, the change in the total/HDL cholesterol ratio did not differ significantly. Only analyzing subjects with 25(OH)D <50 nmol/L did not change the results. CONCLUSIONS This study shows that vitamin D supplementation does not improve glycemic indices, blood pressure, or lipid status in subjects with IFG and/or IGT.

Insulin sensitivity in subjects with secondary hyperparathyroidism and the effect of a low serum 25-hydroxyvitamin D level on insulin sensitivity

To investigate the relation between secondary hyperparathyroidism (SHPT) and insulin sensitivity, 15 subjects with SHPT (serum PTH >6.4 pmol/l, serum calcium <2.40 mmol/l, and normal serum creatinine) and 15 control subjects were investigated with an oral glucose tolerance test (OGTT) and a 3-h hyperglycemic clamp. Body composition was measured with dual-energy X-ray absorptiometry. No differences were found between the SHPT and control groups on any indices of glucose or insulin metabolism. However, when dividing the 30 subjects in the upper and lower halves according to serum 25-hydroxyvitamin D levels (<59 and >58 nmol/l), those in the lower half had significantly higher 2-h serum insulin value at the OGTT, significantly higher insulin secretion during the last hour of the clamp, andsignificantly lower insulin sensitivity index (ISI; glucose infusion rate/insulin secretion during the last hour of the clamp). In a multiple linear regression analysis correcting for age, gender, and body mass index (BMI), the serum 25-hydroxyvitamin D level was significantly and positively associated with the ISI. The amounts of total body and truncal fat were negatively and significantly associated with the ISI, whereas no association between measures of lean body mass were associated with insulin secretion or sensitivity.

Supplementation with vitamin D does not increase serum testosterone levels in healthy males.

Cross-sectional studies indicate a positive relation between serum 25-hydroxyvitamin D [25(OH)D] and testosterone. It is not known if this relation is causal, which in theory could be in both directions. A cross-sectional population based study was designed with pooled data from 3 vitamin D randomized clinical trials (RCTs) performed in Tromsø with weight reduction, insulin sensitivity, and depression scores as endpoints, and one testosterone RCT in subjects with low serum testosterone (<11.0 nmol/l) and with body composition as endpoint. Serum 25(OH)D and androgens were measured in 893 males in the cross-sectional part, at baseline and after 6-12 months of supplementation with vitamin D 20 000 IU-40 000 IU per week vs. placebo in the vitamin D RCTs (n=282), and at baseline and after one year treatment with testosterone undecanoate 1 000 mg or placebo injections (at baseline and after 6, 16, 28, and 40 weeks) in the testosterone RCT (n=37). In the cross-sectional study, serum 25(OH)D was found to be a significant and positive predictor of serum testosterone. In the vitamin D RCTs, no significant effect on serum total or free testosterone levels was seen, and in the testosterone RCT no significant effect on serum 25(OH)D was seen. This was unchanged in sub-analyses in subjects with low serum 25(OH)D (or testosterone) levels. In conclusion, in subjects without significant vitamin D deficiency, there is no increase in serum testosterone after high dose vitamin D supplementation. Similarly, in subjects with moderately low serum testosterone levels, substitution with testosterone does not increase serum 25(OH)D.

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.

Serum 25-hydroxyvitamin D and left ventricular systolic function in a non-smoking population: the Tromsø Study

The myocardium is considered to be an important target organ for parathyroid hormone and 1,25‐dihydroxyvitamin D, the active metabolite of vitamin D. Vitamin D inadequacy has also been linked to cardiovascular morbidity. We aimed to evaluate the relationship between serum 25‐hydroxyvitamin D [25(OH)D] and LV systolic function in a general population.

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 artery with the measurements of IMT and plaques was 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 with mean IMT and TPA; however, increased serum 25(OH)D may predict subclinical atherosclerosis in nonsmokers.

Vitamin D stored in fat tissue during a 5-year intervention affects serum 25-hydroxyvitamin D levels the following year.

Context Vitamin D and 25-hydroxyvitamin D [25(OH)D] are stored in adipose tissue, but the clinical relevance is uncertain. Objective To evaluate changes in serum 25(OH)D and adipose tissue vitamin D levels after stopping vitamin D supplementation. Design A prospective, double-blind cohort follow-up study. Setting Clinical Research Unit at University Hospital of North Norway. Patients Seventy-six subjects were included after participation in a 3- to 5-year prevention of type 2 diabetes study and were administered 20,000 IU of vitamin D or placebo per week. Intervention During the 12-month follow-up period, blood samples were drawn at the beginning and after 1, 3, 6, 9, and 12 months. Fat biopsies were taken at the start and end. Main Outcome Measures Changes in 25(OH)D level in serum and 25(OH)D and vitamin D levels in adipose tissue. Results Forty-one of 42 subjects who were given vitamin D and 33 of 34 subjects who were given placebo completed the study. At the inclusion, mean serum 25(OH)D levels were 122 and 71 nmol/L in the vitamin D and placebo groups, respectively. Serum 25(OH)D levels were significantly higher in the vitamin D group than in the placebo group throughout and were 84.5 and 73.1 nmol/L, respectively, after 12 months. In the vitamin D group, adipose tissue vitamin D levels decreased by 52% over 12 months. Conclusion Vitamin D and 25(OH)D stored in adipose tissue after 3 to 5 years of vitamin D supplementation may have a clinically relevant effect on serum 25(OH)D level the following year.

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

Background 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 (VDR), serum 25(OH)D levels and estrogen receptor 1 (ESR1), but without consensus. Therefore, we aimed to map and compare the risk genotypes for forearm and total hip low BMD. Methods and findings 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 (FokI, Cdx2, BsmI, rs2298850, rs10741657, rs3794060, rs6013897), ApaI-BsmI-TaqI haplotypes and ESR1 SNP rs4870044. Results 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 (β) of –0.031 (P = 0.024) for total hip BMD. β for ESR1 SNP rs4870044 was –0.016 (P = 0.036) for forearm BMD and –0.034 (P = 0.015) for total hip BMD. The other SNPs nor serum 25(OH)D were significantly associated with BMD. Conclusions Both forearm and total hip BMD were associated with ESR1 SNP rs4870044. Of the vitamin D–related genes, only CYP24A1 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.