A 3-SNP gene risk score and a metabolic risk score both predict hypertriglyceridemia and cardiovascular disease risk.

BACKGROUND: Evidence on the causal link between plasma triglyceride (TG) levels and risk for cardiovascular disease (CVD) has recently emerged. Individuals with the metabolic syndrome have an increased risk for acquiring elevated TG levels later in life. Moreover, common DNA sequence variations in genes affecting TG levels identify individuals at risk for elevated plasma TG levels. OBJECTIVE: We evaluated whether a 3-single nucleotide polymorphism (SNP) TG gene risk score (GRS) and a metabolic risk score (MetRS) both improved CVD risk prediction. METHODS: A 3-SNP GRS and MetRS were generated in the EPIC-Norfolk cohort (n = 20,074) based on 3 SNPs in LPL and APOA5 or the number of Metabolic Syndrome criteria present (maximum 5), respectively. The associations between the 3-SNP GRS, MetRS, TG levels, and CVD risk were evaluated. RESULTS: The 3-SNP GRS and MetRS were both linearly associated with plasma TG levels, that is, +0.25 mmol/L [95% CI 0.22-0.27] per allele change (P < .001) and +0.72 mmol/L [95% CI 0.70-0.73] per increase of number of metabolic syndrome risk score points (P < .001), respectively. We observed a positive association between the 3-SNP GRS and the risk of CVD with an adjusted hazard ratio (HR) of 1.35 [95% CI 1.04-1.74] for the highest versus the lowest GRS, which was independent of the MetRS. For the MetRS, the adjusted HR was 2.03 [95% CI 1.73-2.40] for the highest versus the lowest MetRS. CONCLUSION: Both the 3-SNP GRS and the MetRS are associated with increased plasma TG levels and increased risk for CVD

Adipocyte ATP-binding cassette G1 promotes triglyceride storage, fat mass growth, and human obesity

The role of ATP-binding Cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of Lipoprotein Lipase (LPL).As both ABCG1 and LPL are expressed in adipose tissue, we hypothesize that ABCG1 is implicated in adipocyte TG storage and could be then a major actor in adipose tissue fat accumulation.Silencing of Abcg1 expression by RNAi in 3T3-L1 preadipocytes compromised LPL-dependent TG accumulation during initial phase of differentiation. Generation of stable Abcg1 Knockdown 3T3-L1 adipocytes revealed that Abcg1 deficiency reduces TG storage and diminishes lipid droplet size through inhibition of Pparγ expression. Strikingly, local inhibition of adipocyte Abcg1 in adipose tissue from mice fed a high fat diet led to a rapid decrease of adiposity and weight gain. Analysis of two frequent ABCG1 SNPs (rs1893590 (A/C) and rs1378577 (T/G)) in morbidly obese individuals indicated that elevated ABCG1 expression in adipose tissue was associated with an increased PPARγ expression and adiposity concomitant to an increased fat mass and BMI (haplotype AT&gt;GC). The critical role of ABCG1 regarding obesity was further confirmed in independent populations of severe obese and diabetic obese individuals.For the first time, this study identifies a major role of adipocyte ABCG1 in adiposity and fat mass growth and suggests that adipose ABCG1 might represent a potential therapeutic target in obesity

Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects

Background: Gut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism. Methods: Healthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment. Results: Oral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 μmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1). Conclusions: Oral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus

Intestinal Ralstonia pickettii augments glucose intolerance in obesity

An altered intestinal microbiota composition has been implicated in the pathogenesis of metabolic disease including obesity and type 2 diabetes mellitus (T2DM). Low grade inflammation, potentially initiated by the intestinal microbiota, has been suggested to be a driving force in the development of insulin resistance in obesity. Here, we report that bacterial DNA is present in mesenteric adipose tissue of obese but otherwise healthy human subjects. Pyrosequencing of bacterial 16S rRNA genes revealed that DNA from the Gram-negative species Ralstonia was most prevalent. Interestingly, fecal abundance of Ralstonia pickettii was increased in obese subjects with pre-diabetes and T2DM. To assess if R. pickettii was causally involved in development of obesity and T2DM, we performed a proof-of-concept study in diet-induced obese (DIO) mice. Compared to vehicle-treated control mice, R. pickettii-treated DIO mice had reduced glucose tolerance. In addition, circulating levels of endotoxin were increased in R. pickettii-treated mice. In conclusion, this study suggests that intestinal Ralstonia is increased in obese human subjects with T2DM and reciprocally worsens glucose tolerance in DIO mice.Peer reviewe

Genome-Wide Association Studies in Atherosclerosis

Cardiovascular disease remains the major cause of worldwide morbidity and mortality. Its pathophysiology is complex and multifactorial. Because the phenotype of cardiovascular disease often shows a marked heritable pattern, it is likely that genetic factors play an important role. In recent years, large genome-wide association studies have been conducted to decipher the molecular mechanisms underlying this heritable and prevalent phenotype. The emphasis of this review is on the recently identified 17 susceptibility loci for coronary artery disease. Implications of their discovery for biology and clinical medicine are discussed. A description of the landscape of human genetics in the near future in the context of next-generation sequence technologies is provided at the conclusion of this review

Interactions of the Apolipoprotein A5 Gene Polymorphisms and Alcohol Consumption on Serum Lipid Levels

Little is known about the interactions of apolipoprotein (Apo) A5 gene polymorphisms and alcohol consumption on serum lipid profiles. The present study was undertaken to detect the interactions of ApoA5-1131T>C, c.553G>T and c.457G>A polymorphisms and alcohol consumption on serum lipid levels.A total of 516 nondrinkers and 514 drinkers were randomly selected from our previous stratified randomized cluster samples. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. The levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), ApoA1 and ApoB were higher in drinkers than in nondrinkers (P<0.05-0.001). The genotypic and allelic frequencies of three loci were not different between the two groups. The interactions between -1131T>C genotypes and alcohol consumption on ApoB levels (P<0.05) and the ApoA1/ApoB ratio (P<0.01), between c.553G>T genotypes and alcohol consumption on low-density lipoprotein cholesterol (LDL-C) levels (P<0.05) and the ApoA1/ApoB ratio (P<0.05), and between c.457G>A genotypes and alcohol consumption on TG levels (P<0.001) were detected by factorial regression analysis after controlling for potential confounders. Four haplotypes (T-G-G, C-G-G, T-A-G and C-G-T) had frequencies ranging from 0.06 to 0.87. Three haplotypes (C-G-G, T-A-G, and C-G-T) were significantly associated with serum lipid parameters. The -1131T>C genotypes were correlated with TG, and c.553G>T and c.457G>A genotypes were associated with HDL-C levels in nondrinkers (P<0.05 for all). For drinkers, the -1131T>C genotypes were correlated with TC, TG, LDL-C, ApoB levels and the ApoA1/ApoB ratio (P<0.01 for all); c.553G>T genotypes were correlated with TC, TG, HDL-C and LDL-C levels (P<0.05-0.01); and c.457G>A genotypes were associated with TG, LDL-C, ApoA1 and ApoB levels (P<0.05-0.01).The differences in some serum lipid parameters between the drinkers and nondrinkers might partly result from different interactions of the ApoA5 gene polymorphisms and alcohol consumption

Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: A stepped-wedge cluster randomised trial

Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. Methods: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. Discussion: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care

Automated entire thrombus density measurements for robust and comprehensive thrombus characterization in patients with acute ischemic stroke

Background and Purpose: In acute ischemic stroke (AIS) management, CT-based thrombus density has been associated with treatment success. However, currently used thrombus measurements are prone to inter-observer variability and oversimplify the heterogeneous thrombus composition. Our aim was first to introduce an automated method to assess the entire thrombus density and then to compare the measured entire thrombus density with respect to current standard manual measurements. Materials and Method: In 135 AIS patients, the density distribution of the entire thrombus was determined. Density distributions were described usingmedians, interquartile ranges (IQR), kurtosis, and skewedness. Differences between themedian of entire thrombusmeasurements and commonly applied manualmeasurements using 3 regions of interest were determined using linear regression. Results: Density distributions varied considerably with medians ranging from 20.0 to 62.8 HU and IQRs ranging from 9.3 to 55.8 HU. The average median of the thrombus density distributions (43.5 ± 10.2 HU) was lower than the manual assessment (49.6 ± 8.0 HU) (p<0.05). The difference between manual measurements and median density of entire thrombus decreased with increasing density (r = 0.64; p<0.05), revealing relatively higher manual measurements for low density thrombi such that manual density measurement tend overestimates the real thrombus density. Conclusions: Automatic measurements of the full thrombus expose a wide variety of thrombi density distribution, which is not grasped with currently used manual measurement. Furthermore, d