The effect of a preparation of minerals, vitamins and trace elements on the cardiac gene expression pattern in male diabetic rats

BACKGROUND: Diabetic patients have an increased risk of developing cardiovascular diseases, which are the leading cause of death in developed countries. Although multivitamin products are widely used as dietary supplements, the effects of these products have not been investigated in the diabetic heart yet. Therefore, here we investigated if a preparation of different minerals, vitamins, and trace elements (MVT) affects the cardiac gene expression pattern in experimental diabetes. METHODS: Two-day old male Wistar rats were injected with streptozotocin (i.p. 100 mg/kg) or citrate buffer to induce diabetes. From weeks 4 to 12, rats were fed with a vehicle or a MVT preparation. Fasting blood glucose measurement and oral glucose tolerance test were performed at week 12, and then total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 41012 oligonucleotides. RESULTS: Significantly elevated fasting blood glucose concentration and impaired glucose tolerance were markedly improved by MVT-treatment in diabetic rats at week 12. Genes with significantly altered expression due to diabetes include functional clusters related to cardiac hypertrophy (e.g. caspase recruitment domain family, member 9; cytochrome P450, family 26, subfamily B, polypeptide; FXYD domain containing ion transport regulator 3), stress response (e.g. metallothionein 1a; metallothionein 2a; interleukin-6 receptor; heme oxygenase (decycling) 1; and glutathione S-transferase, theta 3), and hormones associated with insulin resistance (e.g. resistin; FK506 binding protein 5; galanin/GMAP prepropeptide). Moreover the expression of some other genes with no definite cardiac function was also changed such as e.g. similar to apolipoprotein L2; brain expressed X-linked 1; prostaglandin b2 synthase (brain). MVT-treatment in diabetic rats showed opposite gene expression changes in the cases of 19 genes associated with diabetic cardiomyopathy. In healthy hearts, MVT-treatment resulted in cardiac gene expression changes mostly related to immune response (e.g. complement factor B; complement component 4a; interferon regulatory factor 7; hepcidin). CONCLUSIONS: MVT-treatment improved diagnostic markers of diabetes. This is the first demonstration that MVT-treatment significantly alters cardiac gene expression profile in both control and diabetic rats. Our results and further studies exploring the mechanistic role of individual genes may contribute to the prevention or diagnosis of cardiac complications in diabetes

Mendelian randomization in health research: Using appropriate genetic variants and avoiding biased estimates

Mendelian randomization methods, which use genetic variants as instrumental variables for exposures of interest to overcome problems of confounding and reverse causality, are becoming widespread for assessing causal relationships in epidemiological studies. The main purpose of this paper is to demonstrate how results can be biased if researchers select genetic variants on the basis of their association with the exposure in their own dataset, as often happens in candidate gene analyses. This can lead to estimates that indicate apparent “causal” relationships, despite there being no true effect of the exposure. In addition, we discuss the potential bias in estimates of magnitudes of effect from Mendelian randomization analyses when the measured exposure is a poor proxy for the true underlying exposure. We illustrate these points with specific reference to tobacco research

The Contribution of the Functional IL6R Polymorphism rs2228145, eQTLs and Other Genome-Wide SNPs to the Heritability of Plasma sIL-6R Levels

The non-synonymous SNP rs2228145 in the IL6R gene on chromosome 1q21.3 is associated with a wide range of common diseases, including asthma, rheumatoid arthritis, type 1 diabetes and coronary heart disease. We examined the contribution of this functional IL6R gene polymorphism rs2228145 versus other genome-wide SNPs to the variance of sIL-6R levels in blood plasma in a large population-based sample (N ~5,000), and conducted an expression QTL analysis to identify SNPs associated with IL6R gene expression. Based on data from 2,360 twin families, the broad heritability of sIL-6R was estimated at 72 and 51 % of the total variance was explained by the functional SNP rs2228145. Converging findings from GWAS, linkage, and GCTA analyses indicate that additional variance of sIL-6R levels can be explained by other variants in the IL6R region, including variants at the 3′-end of IL6R tagged by rs60760897 that are associated with IL6R RNA expression. © 2014 Springer Science+Business Media

The Role of Emerging Risk Factors in Cardiovascular Outcomes

Purpose of Review This review discusses the recent evidence for a selection of blood-based emerging risk factors, with particular reference to their relation with coronary heart disease and stroke. Recent Findings For lipid-related emerging risk factors, recent findings indicate that increasing high-density lipoprotein cholesterol is unlikely to reduce cardiovascular risk, whereas reducing triglyceride-rich lipoproteins and lipoprotein(a) may be beneficial. For inflammatory and hemostatic biomarkers, genetic studies suggest that IL-6 (a pro-inflammatory cytokine) and several coagulation factors are causal for cardiovascular disease, but such studies do not support a causal role for C-reactive protein and fibrinogen. Patients with chronic kidney disease are at high cardiovascular risk with some of this risk not mediated by blood pressure. Randomized evidence (trials or Mendelian) suggests homocysteine and uric acid are unlikely to be key causal mediators of chronic kidney disease-associated risk and sufficiently large trials of interventions which modify mineral bone disease biomarkers are unavailable. Despite not being causally related to cardiovascular disease, there is some evidence that cardiac biomarkers (e.g. troponin) may usefully improve cardiovascular risk scores. Summary Many blood-based factors are strongly associated with cardiovascular risk. Evidence is accumulating, mainly from genetic studies and clinical trials, on which of these associations are causal. Non-causal risk factors may still have value, however, when added to cardiovascular risk scores. Although much of the burden of vascular disease can be explained by ‘classic’ risk factors (e.g. smoking and blood pressure), studies of blood-based emerging factors have contributed importantly to our understanding of pathophysiological mechanisms of vascular disease, and new targets for potential therapies have been identified.</p

The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis

Cardiolog