Upstream stimulatory factor 1 (USF 1), is a transcription factor controlling expression of several genes involved in lipid and glucose homeostasis and co-localizes with familial combined hyperlipidemia (FCHL) and type 2 diabetes on chromosome 1q22-23. We sequenced USF1 in 24 UK FCHL probands, but found no rare or common cSNPs. Three common intronic single nucleotide ploymorphisms (SNP), 306A>G, 475C>T and 1748C>T, were identified and their association was examined with fasting and postprandial lipids and after an oral glucose tolerance test (OGTT) in the European Atherosclerosis Research Study II offspring study. There were no significant differences in allelic frequencies of the SNPs between cases and controls. Individually none of the SNPs showed significant associations with any parameter. In haplotype analysis, compared with other haplotypes, 475C/1748T showed significantly higher and 475T/1748T showed lower peak glucose (P=0.004 and 0.07, respectively) during the OGTT. There was significant case-control heterogeneity in the interaction of genotype with body mass index, on fasting low density lipoprotein with 306A>G and 1748C>T, and on borderline significance with fasting glucose with 475C>T (P=0.002, 0.0007 and 0.015, respectively). Furthermore, 475C>T showed interaction with both HSL-60C>G (case-control heterogeneity P=0.0002) on AUC TG and APOC3 -482C>T on plasma apoE levels (P=0.0012). Thus, in these healthy young men, variation in USF1 was the influencing feature of both glucose and lipid homeostasis showing case-control heterogeneity.

No abstract

on behalf of the EARSII Consortium and the HIFMECH Consortium Background-Angiopoietin-like 4 is a dual-function protein: an inhibitor of LPL, influencing plasma triglycerides (TGs), with angiogenic properties. We examined the association of common ANGPTL4 variants with CHD traits and risk in 5 studies (13 527 individuals). Methods and Results-The effects on plasma lipids of 6 tagging SNPs and the recently identified E40K were examined in a study of 2772 men. Only T266M (rs1044250, MAFϭ30%) and E40K (MAFϭ2%) were significantly associated with TG-lowering (Ϫ10.4%, PϽ0.004 and Ϫ20.4%, PϽ0.0001), respectively. T266M no longer showed significant associations when K40 carriers (K40ϩ) were excluded (Pϭ0.2). Combining data from 5 studies confirmed the TG-lowering effect of K40ϩ (weighted mean difference: Ϫ0.12 [95% CI Ϫ0.18, Ϫ0.05] mmol/L TG Pϭ0. 0001). Surprisingly, in the 3 prospective studies, the combined OR for CHD was 1.48 (1.11 to 1.96, Pϭ0.007), independent of TG. In individuals with a paternal history of MI (nϭ332) T266M, but not E40K, showed effects on postprandial AUC TG and glucose (Pϭ0.009 and Pϭ0.017, respectively) compared to controls (nϭ370). Conclusion-Although associated with an atheroprotective lipid profile, E40K was associated with increased CHD risk, suggesting Angptl4 influences parameters beyond lipid levels. T266M showed effects only under conditions of postprandial stress. The functionality of these potential "loss-of-function" variants needs validation. T he angiopoietin-like proteins (Angptl) are a family of secreted proteins involved in energy metabolism which share tertiary structural domains with angiopoietins, with an N-terminal coiled-coil domain and a fibrinogen-like C-Ter. 1 Angptl4 is also known as hepatic fibrinogen angiogenicrelated protein, fasting induced adipose factor, and PPAR angiogenic related protein, and these names collectively give insight into the expression and function of the protein.Angptl4 expression under conditions of fasting increases in the liver, 2 in adipose tissue in certain mouse strains, 3 and is especially prominent in heart and skeletal muscle. 4 Angptl4 is thus involved in the switch from fatty acids storage to ␤-oxidation and energy consumption. 5 Angptl4 is cleaved proteolytically in plasma and circulates as N-Ter and C-Ter fragments as well as the full length protein, with the N-Ter and full length protein undergoing oligomerization. 6 The involvement in lipid metabolism was demonstrated by intravenous injection of recombinant Angptl4 into mice, resulting in an increase in plasma TG levels attributable to lipoprotein lipase (LPL) inhibition. 7 In vitro studies showed that the N-Ter domain is responsible for this, by acting as an unfolding molecular-chaperone, destabilizing the LPL active dimer to inactive monomer. 8 The fibrinogen-like domain in angiopoietins bind Tie2 receptors, essential for angiogenic function, however Angptls do not bind Tie1 or Tie2 receptors and as such are orphan ligands. 9 Angptl4 has been suggested to regulate angiogenesis,...

No abstract

Background-A preponderance of small, dense LDL particles, elevated levels of plasma triglycerides (TG), and low levels of HDL characterize the atherogenic lipoprotein phenotype, which is associated with increased coronary artery disease (CAD) risk. Genetic and environmental factors influence LDL size, cholesteryl ester transfer protein (CETP) being one of the candidate genes. CETP mediates the transfer of cholesteryl ester from HDL to apolipoprotein (apo) B-containing lipoproteins in exchange for TG, promoting reverse cholesterol transfer and remodeling of lipoprotein particles. Methods and Results-We have identified a tetranucleotide repeat (fragment sizes from 324 to 464 bp; heterozygosity indexϭ0.74) within the CETP promoter and used it in quantitative sib-pair linkage analysis in 119 female dizygotic (DZ) twins. Linkage was found to LDL size (PϽ0.001), TG (PϽ0.005), and plasma apoB (Pϭ0.02). The distribution of the tetranucleotide repeats was bimodal, and there was strong allelic association of the "short" alleles with the B2 allele of CETP TaqIB polymorphic site (PϽ0.001). Conclusions-This report of linkage of the CETP gene to LDL particle size adds to the list of candidate genes linked to LDL size, supporting the hypothesis of multigenic determination of LDL size heterogeneity. Whether this promoter variation is itself functional or is a marker for a functional site in the CETP gene remains to be determined. (Circulation.