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Objective Reduction of brain glucose transporter GLUT1 results in severe neurological dysfunction. VEGF is required to restore and maintain brain glucose uptake across the blood brain barrier via GLUT1, which was shown to be acutely diminished in response to a high fat diet (HFD) in mice. The genetic and HFD-related regulation and association of VEGF and GLUT1 ( SLC2A1 ) in humans was investigated in the NUtriGenomic Analysis in Twins (NUGAT) study. Methods 92 healthy and non-obese twins were standardized to a high-carbohydrate low-fat diet for 6 weeks before switched to a 6-week HFD under isocaloric conditions. Three clinical investigation days were conducted: after 6 weeks of low-fat diet and after 1 and 6 weeks of HFD. Serum VEGF and other cytokine levels were measured using ELISA. Gene expression in subcutaneous adipose tissue was assessed by quantitative Real-Time PCR. Genotyping was performed using microarray. The Auditory Verbal Learning Task was conducted to measure cognitive performance. Results In this human study, we showed that the environmental regulation of SLC2A1 expression and serum VEGF by HFD was inversely correlated and both factors showed strong heritability (>90%). In response to the HFD containing 45% fat, serum VEGF levels increased ( P = 0.002) while SLC2A1 mRNA expression in adipose tissue decreased ( P = 0.001). Higher BMI was additionally associated with lower SLC2A1 expression. AA-genotypes of the rs9472159 polymorphism, which explained ∼39% of the variation in circulating VEGF concentrations, showed significantly reduced serum VEGF levels ( P = 6.4 × 10 −11 ) but higher SLC2A1 expression ( P = 0.009) in adipose tissue compared to CC/CA-genotypes after 6 weeks of HFD. Memory performance in AA-genotypes declined in response to the HFD compared to CC- and CA-genotypes. Conclusions The results provide evidence to suggest the translatability of the dietary regulation of VEGF and GLUT1 from mouse models to humans. Our data demonstrate that HFD induces a genetically determined and correlated decrease of GLUT1 and increase of VEGF which may affect memory performance. Clinical Trial Registration Number NCT01631123 [ABSTRACT FROM AUTHOR]

Background: Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking. Objectives: We analyzed the genetic and environmental contributions to BMI variation from infancy to early adulthood and the ways they differ by sex and geographic regions representing high (North America and Australia), moderate (Europe), and low levels (East Asia) of obesogenic environments. Design: Data were available for 87,782 complete twin pairs from 0.5 to 19.5 y of age from 45 cohorts. Analyses were based on 383,092 BMI measurements. Variation in BMI was decomposed into genetic and environmental components through genetic structural equation modeling. Results: The variance of BMI increased from 5 y of age along with increasing mean BMI. The proportion of BMI variation explained by additive genetic factors was lowest at 4 y of age in boys (a² = 0.42) and girls (a² = 0.41) and then generally increased to 0.75 in both sexes at 19 y of age. This was because of a stronger influence of environmental factors shared by co-twins in midchildhood. After 15 y of age, the effect of shared environment was not observed. The sex-specific expression of genetic factors was seen in infancy but was most prominent at 13 y of age and older. The variance of BMI was highest in North America and Australia and lowest in East Asia, but the relative proportion of genetic variation to total variation remained roughly similar across different regions. Conclusions: Environmental factors shared by co-twins affect BMI in childhood, but little evidence for their contribution was found in late adolescence. Our results suggest that genetic factors play a major role in the variation of BMI in adolescence among populations of different ethnicities exposed to different environmental factors related to obesity. [ABSTRACT FROM AUTHOR]

Abstract: Atherosclerotic renal artery stenosis (ARAS) is a predictor of increased morbidity and mortality. However, whether ARAS itself accelerates the arteriosclerotic process or whether ARAS is solely the consequence of atherosclerosis is unclear. We imaged renal arteries of 1561 hypertensive patients undergoing coronary angiography and followed this cohort for 9 years (range, 2.4–15.1 years; median, 31.2 months, interquartile range, 13.4/52.9 months). All patients received aspirin, renin-angiotensin system blockade, statins, and beta blockade as indicated. One hundred seventy-one patients had ARAS >50% diameter stenosis and 126 patients an arteriosclerotic plaque (ARAP) without significant stenosis. Blood pressures were not different in ARAS, ARAP, and non-ARAS patients. After adjustment for cardiovascular risk factors by propensity scores and matched pair analysis, ARAS patients had a lower ejection fraction and more coronary artery disease (CAD) than non-ARAS patients. The same was true for brain natriuretic peptide values, troponin I, and highly sensitive C-reative protein. Over 9 years, more ARAS patients died of any cause (34% vs 23%; P < .05). The prevalence of CAD in ARAP patients was higher than in non-ARAS patients and lower than in ARAS patients. The mortality of the ARAP patients at 9 years was 37%, not different from the ARAS patients. Atherosclerotic renal artery disease appears to be a marker for the severity of atherosclerosis rather than a causative factor for atherosclerosis progression. [Copyright &y& Elsevier]

The chymase gene is said to be important for the generation of angiotensin II in the heart and therefore is a candidate gene for heart disease. However, we were unable to find an association between allelic variants of the chymase gene and acute myocardial infarction or linkage between the chymase gene locus and heart size. [ABSTRACT FROM AUTHOR]

Decreased heart rate variability (HRV) is associated with congestive heart failure, post-myocardial infarction, ventricular arrhythmias, sudden cardiac death, and advancing age. A deletion/insertion polymorphism in the angiotensin-converting enzyme (ACE) gene and a substitution (M235T) in the angiotensinogen gene have been associated with risk for heart disease. The aim of this study was to determine the heritability of HRV and related parameters in monozygotic and dizygotic twins and to assess the influence of ACE and angiotensinogen polymorphisms. We studied 95 MZ pairs and 46 DZ pairs. We measured HRV and related parameters, ACE and angiotensinogen levels, plasma norepinephrine, ACE, and angiotensinogen genotypes. We found that HRV and related parameters were significantly influenced by genetic variability, although nonshared genetic effects were also important. Angiotensinogen and plasma norepinephrine were generally correlated with decreased HRV, whereas ACE was correlated with perturbances of normal rhythmic HRV. Nevertheless, the DD ACE genotype was associated with increased HRV (p <0.05), whereas angiotensinogen polymorphisms had no effect. We conclude that HRV and related parameters are in part heritable. Interestingly, the DD ACE genotype is associated with increased HRV. [ABSTRACT FROM AUTHOR]

Obesity, type 2 diabetes and associated metabolic diseases are characterized by low-grade systemic inflammation which involves interplay of nutrition and monocyte/macrophage functions. We suggested that some factors such as nutrient components, neuropeptides involved in the control of gastrointestinal functions, and gastrointestinal hormones might influence immune cell functions and in this way contribute to the disease pathogenesis. The aim of this study was to investigate the mRNA expression of twelve nutrition-associated receptors in peripheral blood mononuclear cells (PBMC), isolated monocytes and monocyte-derived macrophages and their regulation under the switching from the high-carbohydrate low-fat diet to the low-carbohydrate high-fat (LC/HFD) isocaloric diet in healthy humans. The mRNA expression of receptors for short chain fatty acids ( GPR41 , GPR43 ), bile acids ( TGR5 ), incretins ( GIPR , GLP1R ), cholecystokinin ( CCKAR ), neuropeptides VIP and PACAP ( VIPR1 , VIPR2 ), and neurotensin ( NTSR1 ) was detected in PBMC and monocytes, while GPR41 , GPR43 , GIPR , TGR5 , and VIPR1 were found in macrophages. Correlations of the receptor expression in monocytes with a range of metabolic and inflammatory markers were found. In non-obese subjects, the dietary switch to LC/HFD induced the increase of GPR43 and VIPR1 expression in monocytes. No significant differences of receptor expression between normal weight and moderately obese subjects were found. Our study characterized for the first time the expression pattern of nutrition-associated receptors in human blood monocytes and its dietary-induced changes linking metabolic responses to nutrition with immune functions in health and metabolic diseases. [ABSTRACT FROM AUTHOR]

Abstract: Background: Stimulation of collateral artery growth is a promising therapeutic option for patients with coronary artery disease. External counterpulsation is a non-invasive technique suggested to promote the growth of myocardial collateral arteries via increase of shear stress. The Art.Net.2 Trial tests invasively and functionally for the first time the hypothesis whether a treatment course with external counterpulsation (over 7 weeks) can induce the growth of myocardial collateral arteries. Methods: This study is designed as a prospective, controlled, proof-of-concept study. Inclusion criteria are (1) age 40 to 80 years, (2) stable coronary disease, (3) a residual significant stenosis of at least one epicardial artery and (4) a positive ischemic stress-test for the region of interest. As primary endpoint serves the pressure-derived collateral flow index (CFIp), the invasive gold-standard to assess myocardial collateral pathways. CFIp is determined by simultaneous measurement of mean aortic pressure (P a, mm Hg), distal coronary occlusive (wedge) pressure (P w, mm Hg) and central venous pressure (P v, mm Hg). The index is calculated as CFIp=(P w − P v)/(P a − P v). The pressure derived fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) are assessed as secondary invasive endpoints to investigate the effect of ECP on the myocardial vasculature. The non-invasive secondary endpoints include symptoms (CCS and NYHA classification), treadmill-testing and analysis of shear-stress related soluble proteins. Conclusions: The Art.Net.-2 Trial will report within the next months whether direct evidence can be brought that ECP promotes coronary collateral growth in patients with stable angina pectoris. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Comparing the chromosomal radiosensitivity of prostate cancer patients with that of healthy donors. Materials and methods: The study was performed on 81 prostate cancer patients characterised by a clinical stage of predominantly pT2c or pT3a and a median age of 67years. As healthy donors 60 male monozygotic twin pairs were recruited with a median age of 28years. Chromosomal radiosensitivity was measured using both G0- and G2-assay. Results: No difference between healthy donors and prostate cancer patients was detected concerning G0-radiosensitivity, since medians were similar (Hodges–Lehmann estimate: −0.05, 95% CI: −0.18–0.08, p =0.4167). However, a pronounced difference was determined for G2-radiosensitivity with prostate cancer patients showing a significantly higher sensitivity compared to healthy donors (Hodges–Lehmann estimate: −0.41, 95% CI: −0.53 to −0.30, p =1.75−9). Using the 90% quantile of G2-radiosensitivity in healthy donors as a threshold for discrimination the fraction of prostate cancer patients with elevated radiosensitivity increased to 49%. Conclusion: G2-, but not G0-radiosensitivity is a promising marker for predisposition of prostate cancer. [Copyright &y& Elsevier]

Abstract: Background and purpose: The radiosensitivity of human lymphocytes measured using a G0- or G2-assay has been linked with an individual’s risk of developing normal tissue complications following radiotherapy. This study was performed to increase basic knowledge of the genetics of the human radiation response, and chromosomal aberration induction in particular. Materials and methods: The study was carried out with blood samples taken from 15 monozygotic twin pairs. G0-assay was performed for cells irradiated with 6 Gy counting only deletions and G2-assay for cells irradiated with 0.5 Gy scoring only chromatid breaks. Results: The mean number of deletions measured at 6 Gy for all 30 samples using the G0-assay amounted to 2.96±0.37 (means±SD), which corresponds to a coefficient of variation (CV) of 13%. There is a highly significant intra-pair correlation for this number among twins (r 2 =0.911) demonstrating that this parameter is mostly determined by genetic factors. According to the mean number of deletions, a theoretical classification based on the definition <=MV−SD as resistant, MV±SD as normal and >=MV+SD as sensitive was made, identifying two pairs as sensitive or resistant, respectively, while nine were normal and two pairs are intermediate. For chromatid breaks measured at 0.5 Gy with the G2-assay the mean number was 1.35±0.42 (means±SD) corresponding to a CV of 31%. There was again a strong intra-pair correlation among twins with r 2 =0.837 showing that this sensitivity is also determined mostly by genetic factors. There was, however, no inter-assay correlation between the G0- and G2-sensitivity (r 2 =0.006) demonstrating that these two sensitivities depend on different genetic factors. Conclusion: The chromosomal radiosensitivity of lymphocytes as defined by G0- or G2-assay is largely determined by different genetic factors, which may allow the use of genetic profiling as an indicator of the respective individual radiosensitivity. [Copyright &y& Elsevier]

Examines the association of beta-2 Adrenoceptor genetic variation with genetic predisposition in hypertension in Europe. Use of multiplex sequencing; Examination on the promoter and N-terminal portion of beta-2 adrenoceptor gene; Effects of genotypes on blood pressure.

Examines a family with autosomal dominant hypertension and brachydactyly in Turkey. Residence of the responsible gene on chromosome 12p; Similarity of blood pressure reduction to single drug trials in hypertension; Sodium and potassium concentrations in the salivary electrolytes.