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apoE, a key regulator of plasma lipids, mediates altered functionalities in lipoprotein metabolism and thus affects the risk of coronary artery disease (CAD). The significance of different apoE polymorphisms remains unclear; although the ε4 allele is clearly associated with increased cholesterol levels (which inform CAD risk), direct studies about apoE polymorphisms on CAD risk and development have yielded controversial results. Furthermore, certain species of ceramides—complex lipids abundant in plasma LDL—are markers of increased risk of myocardial infarction and cardiovascular death. Using a high-throughput MS approach, we quantified 30 molecular plasma ceramide species from a cohort of 2,160 apoE-genotyped (rs7412, rs429358) young adults enrolled in the population-based Cardiovascular Risk in Young Finns Study. We then searched this lipidome data set to identify new indications of pathways influenced by apoE polymorphisms and possibly related to CAD risk. This approach revealed a previously unreported association between apoE polymorphism and a consistently documented high-risk CAD marker, Cer(d18:1/16:0). Compared with the apoE ε3/3 reference group, plasma levels of apoE ε4 were elevated and those of apoE ε2 were lowered in all subjects without evidence of apoE-by-sex interactions. apoE associated with seven ceramides that are connected to atherogenically potent macrophages and/or lipoprotein particles; these associations could indicate a plausible linkage between apoE polymorphism and ceramide metabolism, leading to adverse plasma LDL metabolism and atherogenesis. In conclusion, new evidence from plasma ceramides links apoE polymorphism with an increased risk of CAD and extends our understanding of the role of apoE in health and disease.

BACKGROUND AND AIMS: High concentrations of low density lipoprotein (LDL) triglycerides have been associated with prevalent angiographic coronary artery disease. The present analysis was designed to investigate the association of LDL triglycerides with cardiovascular mortality and to explore possible mechanisms that may link LDL triglycerides to cardiovascular risk. METHODS: LDL triglycerides were measured in 3,140 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. They were prospectively followed for cardiovascular mortality (median duration 9.9 years). Genome wide association data for LDL triglycerides were available for 2,900 LURIC participants. Genetic data and measurements of hepatic lipase activity were available for 478 participants of the HERITAGE Family study. Genome wide association data for cardiovascular disease were available for 184,305 participants of the CARDIoGRAMplusC4D consortium. RESULTS: There was a continuous positive association between LDL triglycerides and cardiovascular mortality (hazard ratio for 5(th) vs. 1(st) quintile = 2.53, p < 0.001) and this association was similar in males and females. Genome wide association analysis in LURIC revealed that LDL triglycerides were strongly associated with variation in the hepatic lipase region (p < 10(−15) for rs1800588 and rs10468017). The LDL triglyceride raising alleles in rs1800588 and rs10468017 were associated with low hepatic lipase activity in HERITAGE and increased cardiovascular risk in CARDIoGRAMplusC4D. Two-sample Mendelian randomization analysis (HERITAGE and CARDIoGRAMplusC4D) using rs1800588 and rs10468017 as instrumental variable suggested that low hepatic lipase activity may cause increased cardiovascular risk (p = 0.013). CONCLUSIONS: Low hepatic lipase activity may link high LDL triglycerides to increased cardiovascular risk.

Aim Plasma levels of certain ceramides are increased in patients with ischemic heart disease (IHD). Many risk factors for IHD are also risk factors for chronic kidney disease (CKD), but it is currently uncertain whether plasma ceramide levels are increased in patients with CKD. Methods We measured six previously identified high-risk plasma ceramide concentrations [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] in 415 middle-aged individuals who attended our clinical Cardiology and Diabetes services over a period of 9 months. Results A total of 97 patients had CKD (defined as e-GFR CKD-EPI < 60 ml/min/1.73 m 2 and/or urinary albumin-to-creatinine ratio ≥ 30 mg/g), 117 had established IHD and 242 had type 2 diabetes. Patients with CKD had significantly (P = 0.005 or less) higher levels of plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1) compared to those without CKD. The presence of CKD remained significantly associated with higher levels of plasma ceramides (standardized beta coefficients ranging from 0.124 to 0.227, P < 0.001) even after adjustment for body mass index, smoking, hypertension, diabetes, prior IHD, plasma LDL-cholesterol, hs-C-reactive protein levels and use of any lipid-lowering medications. Notably, more advanced stages of CKD and abnormal albuminuria were both associated (independently of each other) with increased levels of plasma ceramides. These results were consistent in all subgroups considered, including patients with and without established IHD or those with and without diabetes. Conclusion Increased levels of plasma ceramides are associated with CKD independently of pre-existing IHD, diabetes and other established cardiovascular risk factors.

Introduction: Ceramides are enriched in atherosclerotic plaques, and a set of circulating ceramides including Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), and Cer(d18:1/24:0) has recently emerged as predictors of cardiovascular outcomes in coronary artery disease patients. Hypothesis: We hypothesize that they have the power to predict cardiovascular events in patients with peripheral artery disease (PAD). Methods: We measured the serum concentrations of the above mentioned ceramides in a cohort of 380 patients with sonographically proven PAD, of whom 107 had type 2 diabetes (T2DM). Prospectively, we recorded 221 cardiovascular events over a mean follow-up time of 6.3±2.3 years. Results: Cardiovascular event risk was higher in T2DM patients than in those who did not have diabetes (69 vs. 52%, p=0.001). The ceramides Cer(18:1/16:0) and Cer(18:1/24:1) and the respective ratios Cer(18:1/16:0) / Cer(18:1/24:0) and Cer(18:1/24:1) / Cer(18:1/24:0) were significant predictors of cardiovascular events both univariately and after multivariate adjustment including the presence of T2DM (figure). Conversely, T2DM predicted cardiovascular events independently from the investigated ceramides (adjusted HR 1.76 [1.31-2.35], p

Estimation of heritability is fundamental in genetic studies. In recent years, heritability estimation using linear mixed models (LMMs) has gained popularity, because these estimates can be obtained from unrelated individuals collected in genome wide association studies. Typically, heritability estimation under LMMs uses either the maximum likelihood (ML) or the restricted maximum likelihood (REML) approach. Existing methods for the construction of confidence intervals and estimators of standard errors for both ML and REML rely on asymptotic properties. However, these assumptions are often violated due to the bounded parameter space, statistical dependencies, and limited sample size, leading to biased estimates, and inflated or deflated confidence intervals. Here, we show that often the probability that the genetic component is estimated as zero is high even when the true heritability is bounded away from zero, emphasizing the need for accurate confidence intervals. We further show that the estimation of confidence intervals by state-of-the-art methods is highly inaccurate, especially when the true heritability is either relatively low or relatively high. Such biases are present, for example, in estimates of heritability of gene expression in the GTEx study, and of lipid profiles in the LURIC study. We propose a computationally efficient method, Accurate LMM-Based confidence Intervals (ALBI), for the estimation of the distribution of the heritability estimator, and for the construction of accurate confidence intervals. Our method can be used as an add-on to existing methods for heritability and variance components estimation, such as GCTA, FaST-LMM, GEMMA, or EMMA. ALBI is available at http://www.cs.tau.ac.il/~heran/cozygene/software/albi.html.

Background Studies have shown that osteoporosis and atherosclerosis are comorbid conditions sharing common risk factors and pathophysiological mechanisms. Understanding these is crucial in order to develop shared methods for risk stratification, prevention, diagnosis and treatment. The aim of this study was to apply a system-level bioinformatics approach to lipidome-wide data in order to pinpoint the lipidomic architecture jointly associated with surrogate markers of these complex comorbid diseases. Subjects and methods The study was based on the Cardiovascular Risk in Young Finns Study cohort from the 2007 follow-up (n = 1494, aged 30–45 years, women: 57%). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyse the serum lipidome, involving 437 molecular lipid species. The subclinical osteoporotic markers included indices of bone mineral density and content, measured using peripheral quantitative computer tomography from the distal and shaft sites of both the tibia and the radius. The subclinical atherosclerotic markers included carotid and bulbus intima media thickness measured with high-resolution ultrasound. Weighted co-expression network analysis was performed to identify networks of densely interconnected lipid species (i.e. lipid modules) associated with subclinical markers of both osteoporosis and atherosclerosis. The levels of lipid species (lipid profiles) of each of the lipid modules were summarized by the first principal component termed as module eigenlipid. Then, Pearson's correlation (r) was calculated between the module eigenlipids and the markers. Lipid modules that were significantly and jointly correlated with subclinical markers of both osteoporosis and atherosclerosis were considered to be related to the comorbidities. The hypothesis that the eigenlipids and profiles of the constituent lipid species in the modules have joint effects on the markers was tested with multivariate analysis of variance (MANOVA). Results Among twelve studied molecular lipid modules, we identified one module with 105 lipid species significantly and jointly associated with both subclinical markers of both osteoporosis (r = 0.24, p-value = 2 × 10−20) and atherosclerosis (r = 0.16, p-value = 2 × 10−10). The majority of the lipid species in this module belonged to the glycerolipid (n = 60), glycerophospholipid (n = 13) and sphingolipid (n = 29) classes. The module was also enriched with ceramides (n = 20), confirming their significance in cardiovascular outcomes and suggesting their joint role in the comorbidities. The top three of the 37 statistically significant (adjusted p-value Conclusion This study identified a novel lipid module associated with both surrogate markers of both subclinical osteoporosis and subclinical atherosclerosis. Alterations in the metabolism of the identified lipid module and, more specifically, the TAG related molecular lipids within the module may provide potential new biomarkers for testing the comorbidities, opening avenues for the emergence of dual-purpose prevention measures.

Kindlins (FERMT) are cytoplasmic proteins required for integrin (ITG) activation, leukocyte transmigration, platelet aggregation and thrombosis. Characterization of kindlins and their association with atherosclerotic plaques in human(s) is lacking.Exploratory microarray (MA) was first performed followed by selective quantitative validation of robustly expressed genes with qRT-PCR low-density array (LDA). In LDA, ITGA1 (1.30-fold, p = 0.041) and ITGB3 (1.37-fold, p = 0.036) were upregulated in whole blood samples of patients with coronary artery disease (CAD) compared to healthy controls. In arterial plaques, both robustly expressed transcript variants of FERMT3 (MA: 5.90- and 3.4-fold; LDA: 3.99-fold, p0.0001 for all) and ITGB2 (MA: 4.81- and 4.92-fold; LDA: 5.29-fold, p0.0001 for all) were upregulated while FERMT2 was downregulated (MA: -1.61-fold; LDA: -2.88-fold, p0.0001 for both). The other integrins (ITGA1, ITGAV, ITGB3, ITGB5) were downregulated. All these results were replicated in at least one arterial bed. The latter FERMT3 transcript variant associated with unstable plaques (p = 0.0004). FERMT3 correlated with M2 macrophage markers and in hierarchical cluster analysis clustered with inflammatory and macrophage markers, while FERMT2 correlated with SMC-rich plaque markers and clustered with SMC markers. In confocal immunofluorescence analysis, FERMT3 protein colocalized with abundant CD68-positive cells of monocytic origin in the atherosclerotic plaques, while co-localization of FERMT3 with HHF35 indicative of smooth muscle cells was low.Kindlin-3 (FERMT3) is upregulated in atherosclerotic, especially unstable plaques, mainly in cells of monocytic origin and of M2 type. Simultaneous upregulation of ITGB2 suggests a synergistic effect on leukocyte adherence and transmigration into the vessel wall.

Myotonic dystrophy type 2 (DM2) is a multisystemic disorder caused by a (CCTG)n repeat expansion in intron 1 of CNBP. Transcription of the repeats causes a toxic RNA gain of function involving their accumulation in ribonuclear foci. This leads to sequestration of splicing factors and alters pre-mRNA splicing in a range of downstream effector genes, which is thought to contribute to the diverse DM2 clinical features. Hyperlipidemia is frequent in DM2 patients, but the treatment is problematic because of an increased risk of statin-induced adverse reactions. Hypothesizing that shared pathways lead to the increased risk, we compared the skeletal muscle expression profiles of DM2 patients and controls with patients with hyperlipidemia on statin therapy. Neural precursor cell expressed, developmentally downregulated-4 (NEDD4), an ubiquitin ligase, was one of the dysregulated genes identified in DM2 patients and patients with statin-treated hyperlipidemia. In DM2 muscle, NEDD4 mRNA was abnormally spliced, leading to aberrant NEDD4 proteins. NEDD4 was down-regulated in persons taking statins, and simvastatin treatment of C2C12 cells suppressed NEDD4 transcription. Phosphatase and tensin homologue (PTEN), an established NEDD4 target, was increased and accumulated in highly atrophic DM2 muscle fibers. PTEN ubiquitination was reduced in DM2 myofibers, suggesting that the NEDD4-PTEN pathway is dysregulated in DM2 skeletal muscle. Thus, this pathway may contribute to the increased risk of statin-adverse reactions in patients with DM2.

The -219G/T (rs405509) and +113G/C (rs440446) polymorphisms within the regulatory region of the apolipoprotein E (APOE) gene have been related to the transcriptional activity of the gene. We examined the effect of the stated polymorphisms and their construct haplotypes with the APOE ɛ2/ɛ3/ɛ4 polymorphism on lipid levels and insulin resistance in the Turkish Adult Risk Factor Study. Randomly selected 1774 adults (mean age, 55.0 ± 11.7 years; 51.2% women) participating in the population-based Turkish Adult Risk Factor Study were cross-sectionally analyzed for the -219G/T, +113G/C, and ɛ2/ɛ3/ɛ4 polymorphisms as well as their haplotypes. Insulin resistance was defined as the 70th percentile in the sample (2.51) of the homeostatic model assessment (HOMA). The frequencies of the -219T and +113C alleles were 0.477 and 0.423, respectively; and those of haplotype 1 (GGɛ3) and haplotype 2 (TCɛ3) were 44.1% and 41.9%, respectively. The -219G/T and +113G/C genotypes (both P.04) and diplotypes of haplotype 2 (TCɛ3) (P.014) were inversely related to serum fasting insulin and the HOMA index, even after controlling for 8 relevant covariates, but not to serum lipids. Within the APOE3 group, haplotype 2 (TC-/TC+) heterozygotes had an odds ratio of 0.66 (95% confidence interval, 0.42-0.99) for HOMA of insulin resistance after adjusting for 8 covariates. APOE promoter polymorphisms and their diplotypes are independently related with serum fasting insulin levels and HOMA index among Turks.

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at post-transcriptional level. Dysregulation of miRNA expression may lead to severe pathophysiologies in human cells. Niemann-Pick type C (NPC) disease is a complex lipid storage disease characterized by late endosomal-lysosomal accumulation of multiple lipid molecules. Our aim was to characterize the miRNA profile in NPC fibroblasts as they may play an active role in the NPC disease associated changes in the cellular physiology. To investigate the miRNA expression, total RNAs were isolated from cultured human NPC fibroblasts and healthy fibroblasts and then, TaqMan Low-Density Array system containing 365 mature human miRNAs was used. Expression differences between the healthy and NPC cells were detected according to the relative quantification values. Target genes were predicted by using three different algorithms and classified regarding NPC related biological processes and cellular components. We found that three miRNAs, miR-196a, miR-196b and miR-296 were up-regulated (3.5-fold increase, p0.05) whereas 38 miRNAs were significantly down-regulated in NPC cells (3.5-fold decrease, p0.05). Among these non-coding RNAs, miR-98 was the most down-regulated (-33.3-fold) miRNA and miR-143, the lipid biosynthesis associated miRNA, had a 20-fold decreased expression in the NPC cells. Additionally, gene ontology analyses of the target genes suggested a distinct role for each miRNA. Our results show that NPC fibroblasts have an altered miRNA expression profile and certain miRNAs have importance in disease pathogenesis as well as the therapeutic capacity to correct lipid related pathophysiologies in the NPC cells.

Summary Purpose To characterize the clinical features and molecular genetic background in a family with various epilepsy phenotypes including febrile seizures, childhood absence epilepsy, and possible temporal lobe epilepsy. Methods Clinical data were collected. DNA and RNA were extracted from peripheral blood. A genome-wide microsatellite marker scan was performed and regions with a multipoint location score ≥1.5 were fine mapped. Functional candidate genes identified from databases and by comparing gene expression profiles of genes between affected and unaffected individuals were sequenced. Copy number variation was evaluated with array-based comparative genomic hybridization. Results The seizure phenotype was benign. Inheritance was consistent with an autosomal dominant model and reduced penetrance. The highest two-point LOD score of 2.8 was identified at marker D17S1606 in a 37cM interval on chromosome 17q12-q24. Loci on 5q11.2 and on 18p11-q11, showed LOD scores ≥1.5 after fine mapping. Sequencing of nine ion-channel genes and two ( RPIP8 and SLC25A39 ) differentially expressed genes from 17q12-q24, as well as IMPA2 from 18p11-q11 did not reveal a pathogenic alteration. No clinically relevant copy number variation was identified. Conclusions Our findings suggest complex inheritance of seizure susceptibility in the family with contribution from three loci, including a possible new locus on chromosome 17q. The underlying molecular defects remain unknown.

Serum C-reactive protein (CRP) is an independent risk factor for cardiovascular disease and metabolic syndrome (MetS). The aim of this study was to analyze the CRP gene allelic variations in the Turkish adult risk factor (TARF) study and relate them with serum CRP levels as well as MetS and its components.We analyzed CRP gene polymorphisms (-286CTA [rs3091244], +1444CT [rs1130864], +1059GC [rs1800947], and +1846GA [rs1205]) as well as their haplotypes, in addition to measuring CRP levels (n=1138) and collecting risk factor data from 1987 adults (mean age 54.3+/-11.9 years, 51.3% women) participating in the TARF Study. MetS was defined by using the criteria of the National Cholesterol Education Program modified for pre-diabetes and in men for abdominal obesity.After adjustment for the major cardiovascular risk factors, four CRP SNPs (-286CTA, +1059GC, +1444CT, and +1846GA) were significantly associated with serum CRP levels in women (p0.05), whereas the -286CTA and +1444CT polymorphisms were associated with CRP levels in men (p0.05). The haplotype analyses revealed four common CRP haplotypes. The haplotype 1 (CGCA) in women and the haplotype 3 (TGTG) in men were associated with serum CRP levels and hypertension (p0.05). However, no haplotype association was observed for MetS or its components.CRP gene allelic variation is associated with serum CRP levels as well as hypertension in Turkish adults.

Beta-lactoglobulin (betaLG) is a protein that binds ligands like fatty acids and retinol into the hydrophobic pocket. Our purpose was to study bovine and reindeer betaLG as transporter molecules and compare their transport properties across Caco-2 cell membrane. The reindeer betaLG has more valuable binder characteristics than bovine betaLG because it has only one genetic phenotype and it seems to exhibit better immunological properties. The permeation of betaLG in Caco-2 cells was evaluated by immunoblotting, and the permeation of the model substances retinol, palmitic acid and cholesterol with and without betaLG was determined using [(3)H]-labelled ligands. Both bovine and reindeer betaLG were able to pass across a Caco-2 cell monolayer similarly. Unbound and betaLG-bound [(3)H]retinol and [(3)H]palmitic acid were equally transported across the Caco-2 cell layer, whereas [(3)H]cholesterol could not pass across Caco-2 cells with or without betaLG at any of the studied circumstances. Thus, the bovine and reindeer milk betaLG is not a suitable protein to enhance transport of ligands across the Caco-2 cell membrane, used for predicting intestinal absorption.

Sterol regulatory element-binding protein cleavage-activating protein (SCAP) and apolipoprotein E (apo E) regulate cellular and plasma lipid metabolism. Therefore, variations in the corresponding genes might influence weight reduction and obesity-associated metabolic changes. We investigated the relationships of SCAP (Ile796Val) and apo E polymorphisms on metabolic changes during weight reduction by using a 12-week very low-energy diet. Body composition, serum lipids, plasma glucose, and insulin were assessed in 78 healthy premenopausal women (initial body mass index, 34 +/- 4 kg/m(2); age, 40 +/- 4 years) before and after the intervention. The SCAP genotype groups did not differ in the responses of any parameters measured during weight reduction. Apo E did not differentiate the weight loss, but the changes in total and low-density lipoprotein cholesterol for the genotype groups apo E epsilon2/3, epsilon3/3, as well as epsilon3/4 and epsilon4/4 combined were -0.94 +/- 0.56 and -0.59 +/- 0.32, -0.71 +/- 0.49 and -0.49 +/- 0.45, and -0.55 +/- 0.47 and -0.37 +/- 0.39 mmol/L, respectively (P < .05 for both). In conclusion, neither the SCAP Ile796Val nor the apo E polymorphism was associated with weight loss in obese premenopausal women. However, the apo E-but not SCAP genotype-seems to be one of the modifying factors for serum cholesterol concentrations during very low-energy diet in obese premenopausal women.

Background The hepatic lipase (HL) gene C-480T promoter polymorphism affects gene transcription and enzyme activity and leads to CC, CT, and TT genotypes. Recently, HL expression was detected in macrophages. It has been postulated that HL might have a direct role in the pathogenesis of atherosclerosis without changes in the plasma profile. We hypothesized that the difference of plasma cholesterol level may not influence the effect of HL genotype on coronary reactivity. Methods A total of 108 young men (aged 34 ± 5 years) were genotyped and divided into three groups. These groups contained 45, 49 and 14 men having either normal (4.9 ± 1.2 mmol/L), mildly (5.5 ± 0.8 mmol/L) or severely (7.8 ± 1.9 mmol/L, subjects with familial hypercholesterolemia) elevated mean plasma cholesterol level, respectively. Myocardial blood flow (MBF) was measured at rest and during adenosine or dipyridamole-induced hyperemia with positron emission tomography using [15O] H2O. Results The effect of HL genotype on the indices of MBF was parallel within all cholesterol groups and therefore they were combined. In all subjects, basal flow did not differ between the genotypes. However, men with CC genotype had a significantly higher hyperemic blood flow (3.86 ± 1.26 mL g−1 min−1 versus 3.20 ± 1.38 mL g−1 min−1, p = 0.007), higher coronary flow reserve (CFR, 4.80 ± 1.77 versus 3.77 ± 1.43, p = 0.001) and lower coronary resistance during hyperemia (25.63 ± 9.98 mmHg min g mL−1 versus 35.00 ± 23.95 mmHg min g mL−1, p = 0.003) than T allele carriers. In multivariate regression analysis, after adjustment for age, body mass index, serum lipids, blood pressure, adenosine or dipyridamole administration, and study group, HL polymorphism was an independent predictor of blood flow during hyperemia (p = 0.016), coronary resistance (p = 0.014), and CFR (p = 0.005), respectively. Conclusions The HL C-480T polymorphism is associated with CFR, which is an early indicator of atherosclerosis, independently of the level of plasma cholesterol in young men.

The goal of this study was to evaluate the role of asymmetric dimethylarginine (ADMA) in the regulation of hemodynamic functions in hypertensive men. It has been suggested that ADMA, as an endogenous nitric oxide synthase inhibitor, is linked to hypertension and vascular reactivity. Sixty-seven men aged 51.1 years (range, 45-55 years) were studied. Plasma ADMA and symmetric dimethylarginine were determined by high-performance liquid chromatography-tandem mass spectrometry. Blood pressure (BP) was measured by 24-hour ambulatory recordings and casual measurements. Hemodynamic regulation was assessed by noninvasive methods. The nitric oxide production was estimated based on plasma nitrate (NO(3)(-)) determination. Results showed that plasma arginine derivatives or l-arginine/ADMA ratio was not associated with BP values observed during 24-hour monitoring or in casual measurements. Systemic vascular resistance, pulse wave velocity, or cardiac output was not associated with plasma ADMA or plasma NO(3)(-) levels. No association was found between plasma ADMA and NO(3)(-) either. Interestingly, subjects on antihypertensive treatment had lower plasma ADMA concentrations than nontreated subjects (0.30+/-0.08 and 0.36+/-0.11 micromol/L, respectively, P=.04) despite higher BP values. In conclusion, these results suggest that plasma ADMA does not have a determinative role in the regulation of hemodynamic functions in Finnish middle-aged men.

Sterol regulatory element binding proteins-1 and -2 (SREBPs) are transcription factors controlling lipid homeostasis in human cells. The G-allele carriers of the SREBF-1 gene C-G polymorphism in exon 18c and coding for glycine at the protein level (G952G) have shown to associate more frequently with obesity and type 2 diabetes than the C-allele carriers. However, the C-allele has suggested to be linked to dyslipidemia. Thus, our aim was to study effect of the SREBF-1 gene polymorphism (G952G) on sterol metabolism in man. Ninety-five subjects with moderate hypercholesterolemia participated in this study and 14 homozygous CC carriers of the SREBF-1 (G952G) gene were found. Plasma lathosterol concentration and lathosterol-to-cholesterol ratio, markers of endogenous cholesterol synthesis, were significantly higher in CC homozygous subject compared to others. Similarly muscle cholesterol (p=0.045) and lathosterol (p=0.054) concentrations were elevated in the CC homozygotes supporting the view that endogenous cholesterol synthesis rate is SREBF-1 genotype-dependent.

The purpose of this study was to evaluate the hypothesis that high serum levels of ADMA, an indicator of endothelial dysfunction, are associated with an elevated risk of acute coronary events in middle-aged men. To test the hypothesis that lipid lowering medication with statins lowers circulating ADMA levels, we also investigated the effect of simvastatin and atorvastatin treatment on plasma ADMA concentration. In a prospective nested case-control study in 150 middle-aged non-smoking men from Eastern Finland, those who were in the highest quartile for serum ADMA (>0.62 μmol/l) had a 3.9-fold (95% CI: 1.25-12.3, P = 0.02) increase in risk of acute coronary events compared with other quartiles. In an 8-week randomised double-blind placebo-controlled trial, plasma ADMA concentrations remained unchanged in simvastatin 80mg/day (n = 16), atorvastatin 40mg/day (n = 16) and placebo (n = 16) groups over the study period. Our findings indicate that high serum levels of ADMA, a potential marker for endothelial dysfunction, may increase the risk of acute coronary syndromes. However, aggressive treatment with either simvastatin or atorvastatin did not reduce plasma ADMA levels. © 2003 Elsevier Ireland Ltd. All rights reserved.

ObjectivesThe goal of this study was to examine the relationship between plasma asymmetric dimethylarginine (ADMA) level and hyperemic myocardial blood flow (MBF) in subjects with borderline hypertension (BHT) and familial hypercholesterolemia (FH).BackgroundAsymmetric dimethylarginine is an endogenous competitive inhibitor of nitric oxide synthase that may modulate vascular function.MethodsWe measured plasma ADMA levels and myocardial flow in 77 young men (mean age 35 ± 5 years), including 47 healthy controls, 16 men with BHT, and 14 men with FH. Basal and dipyridamole-induced myocardial flow was measured using positron emission tomography. Plasma ADMA levels were measured using high-pressure liquid chromatography.ResultsAsymmetric dimethylarginine levels were significantly elevated in the BHT group compared with controls (0.59 ± 0.13 μmol/l vs. 0.43 ± 0.12 μmol/l, p < 0.001), and they had significantly lower dipyridamole flow (2.85 ± 1.20 ml/min/g vs. 3.69 ± 1.68 ml/min/g, p < 0.05). In a multivariate regression model adjusted for the study group, dipyridamole flow was inversely associated with ADMA (p < 0.05), age (p < 0.05), and apolipoprotein B concentration (p < 0.05).ConclusionsWe conclude that plasma ADMA concentration is related to dipyridamole-induced vasodilatory function in young men, independently of blood pressure elevation and hypercholesterolemia. Subjects with BHT have significantly increased plasma ADMA levels, which may partly explain the impaired hyperemic MBF in this condition.

We measured serum ubiquinone and dolichol concentrations in 13 men while they abused anabolic androgenic steroids (AAS) and during the following withdrawal period. Serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and triglycerides were also determined. AAS administration increased serum ubiquinone by 68% (P < .001) and decreased serum dolichol by 30% (P < .002). Both nonsterol isoprenoid levels in plasma correlated with the AAS dose, ubiquinone positively (P < .001) and dolichol negatively (P < .002). When the subjects were taking steroids, the ubiquinone to LDL ratio was 42% higher than during the withdrawal period. In conclusion, our study suggests that AAS have an influence on the by-products of the mevalonate pathway.

Mannan-binding lectin (MBL) is a serum acute-phase protein and a complement component secreted by the liver. Its deficiency caused by point mutations in the MBL gene has recently been associated with severe atherosclerosis. In this study, we investigated the effect of MBL variant alleles on coronary artery reactivity, which is an early marker of coronary dysfunction and predicts the development of atherosclerosis and coronary artery disease. The study population consisted of 51 apparently healthy, normo- or mildly hypercholesterolemic young men. Myocardial blood flow was measured at baseline and during adenosine-induced hyperemia with positron emission tomography (PET), and MBL genotyping was performed using restriction fragment-length polymorphism. As a result, MBL variant alleles had no effect on coronary artery reactivity. This finding suggests that MBL deficiency is not an independent risk factor for coronary dysfunction and early atherogenic changes but rather a co-factor in the development of atherosclerosis. Thus, the connection of MBL variant alleles with environmental risk factors in atherosclerosis should further be assessed.