Variation In Plasma Levels Research Articles

Confounding factors for variation of clozapine plasma levels: drug interactions with proton pump inhibitor or infectious etiologies?

Clozapine is an atypical antipsychotic used to treat schizophrenia in patients only after failure of response of other antipsychotic drugs because of its agranulocytosis risk. Because of frequent occurrence of gastrointestinal adverse drug reactions (ADR), proton pump inhibitors (PPIs) are often prescribed in patients exposed to clozapine [1, 2] Clozapine is metabolized mainly through the 1A2 isoenzyme, CYP3A4, only in patients with reduced CYP1A2 activity and moderate contribution of CYP2C19 [3]. Agents that induce or inhibit CYP1A2 may increase or decrease, respectively, the metabolism of clozapine [2]. It is well known that smokers need to increase twofold the dose of clozapine compared with nonsmokers because of CYP1A2 induction by cigarette smoke [2]. We report a case of change in clozapine metabolism after substitution of a racemic PPI omeprazole by its (s)-isomer, esomeprazole, associated with a possible infectious event. Case report

Extending Rare-Variant Testing Strategies: Analysis of Noncoding Sequence and Imputed Genotypes

Next Generation Sequencing Technology has revolutionized our ability to study the contribution of rare genetic variation to heritable traits. However, existing single-marker association tests are underpowered for detecting rare risk variants. A more powerful approach involves pooling methods that combine multiple rare variants from the same gene into a single test statistic. Proposed pooling methods can be limited because they generally assume high-quality genotypes derived from deep-coverage sequencing, which may not be available. In this paper, we consider an intuitive and computationally efficient pooling statistic, the cumulative minor-allele test (CMAT). We assess the performance of the CMAT and other pooling methods on datasets simulated with population genetic models to contain realistic levels of neutral variation. We consider study designs ranging from exon-only to whole-gene analyses that contain noncoding variants. For all study designs, the CMAT achieves power comparable to that of previously proposed methods. We then extend the CMAT to probabilistic genotypes and describe application to low-coverage sequencing and imputation data. We show that augmenting sequence data with imputed samples is a practical method for increasing the power of rare-variant studies. We also provide a method of controlling for confounding variables such as population stratification. Finally, we demonstrate that our method makes it possible to use external imputation templates to analyze rare variants imputed into existing GWAS datasets. As proof of principle, we performed a CMAT analysis of more than 8 million SNPs that we imputed into the GAIN psoriasis dataset by using haplotypes from the 1000 Genomes Project.

Final Answer: Ghrelin Can Suppress Insulin Secretion in Humans, but Is It Clinically Relevant?

Ghrelin is a 28–amino acid peptide initially isolated from rat and human stomachs as an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a) (1) using an intracellular calcium influx assay on a stable cell expressing rat GHS-R. At the time of its discovery in 1999, ghrelin was known to increase growth hormone release from the pituitary gland by binding to GHS-R1a, and 1 year later, its role in food intake and body adiposity was described (2). Since then, numerous additional effects of ghrelin have been demonstrated, including regulating cell proliferation and survival, apoptosis, inflammation, angiogenesis, development and reproduction as well as metabolism. Recently, it has become of great research interest whether ghrelin also has a role in β-cell function. This research area is particularly important given its potential to lead to the development of novel strategies to increase insulin secretion for the treatment of type 2 diabetes. In humans, circulating ghrelin levels surge immediately before meals and fall to a nadir within 1 h after food intake, which results in a two- to threefold variation in plasma levels. Circulating ghrelin is primarily produced in the stomach, but smaller amounts are also produced in the brain, heart, lung, kidney, placenta, gastrointestinal tract, and pancreas. Within the islets of Langerhans of the pancreas, ghrelin production has been found in α-cells, β-cells, and the more recently discovered e-cells (3). Ghrelin peptides exist in two major forms, unacylated ghrelin and acylated ghrelin, and only the latter binds to GHS-R1a. Acylation is catalyzed by ghrelin O-acyltransferase (GOAT), which is, interestingly, highly expressed in the stomach and the pancreas in humans (4). Consistent with the multitude of effects of ghrelin, GHS-R1a is expressed in variety of tissues. Most importantly, with regard to insulin …

No Relationship BetweenTNF-αGenetic Variants and Combination Antiretroviral Therapy-Related Lipodystrophy Syndrome in HIV Type 1-Infected Patients: A Case-Control Study and a Meta-Analysis

Tumor necrosis factor alpha (TNF-α) is thought to be involved in the pathogenic and metabolic events associated with HIV-1 infection. We assessed whether carriage of the TNF-α gene promoter single nucleotide polymorphism (SNP) is associated with lipodystrophy and metabolic derangements in HIV-1-infected patients treated with cART. We also assessed variations in TNF-α receptor plasma levels. The study group comprised 286 HIV-1-infected patients (133 with and 153 without lipodystrophy) and 203 uninfected controls (UC). TNF-α -238G > A, -308G > A, and -863 C > A SNP were assessed using PCR-RFLPs on white cell DNA. Plasma sTNF-α R1 and R2 levels were measured by ELISA. Student's t test, the χ(2) test, Pearson correlations, and the logistic regression test were performed for statistical analysis. The TNF-α -308G > A SNP was significantly associated with lipodystrophy in the univariate analysis (p = 0.04). This association, however, was no longer significant in the multivariate analysis. A meta-analysis of the published literature and our own data, which included 284 patients with lipodystrophy and 338 without lipodystrophy, showed that there was no relationship between the TNF-α -238G > A and -308G > A SNP and lipodystrophy (p > 0.05 for all comparisons). HIV-1-infected patients had greater sTNF-α R2 plasma levels than UC (p = 0.001) whereas sTNF-α R1 and R2 levels were not significantly different in both the HIV-1-infected cohorts, lipodystrophy vs. nonlipodystrophy (p = NS). In our cohort of white Spaniards the TNF-α -238G > A, -308G > A, and -863C > A SNP were not associated with lipodystrophy in HIV-1-infected patients treated with cART. This finding was replicated in a meta-analysis of the published data, which showed no associations between the TNF-α -238G > A and -308G > A SNP and lipodystrophy. In HIV-1-infected patients under cART there is a systemic overproduction of sTNF-α R2, which is unrelated to the presence of lipodystrophy.

Atheromatosis Extent in Coronary Artery Disease is not Correlated with Apolipoprotein-E Polymorphism and its Plasma Levels, but Associated with Cognitive Decline

Apolipoprotein-E (apoE) ε4 allele is a known risk factor for Alzheimer's disease (AD). Polymorphism of apoE is also one of the most important genetic markers for coronary artery disease (CAD). The allelic variation in the apoE gene has a significant effect on inter-individual variation of lipids and lipoprotein plasma levels as well. This study investigated whether apoE polymorphism affects the plasma levels of apoE and the possible association to CAD extent and cognitive functions. Plasma apoE levels and apoE genotypes were evaluated of subjects with normal coronary arteries, and individuals with angiographycally confirmed mild/moderate or severe atheromatosis. The cognitive performance of the volunteers was also measured by mini-mental state examination (MMSE). Out of the 6 expected genotypes, only 5 were detected in participants: E3/3 (56.0%), E3/4 (23.6%), E4/4 (8.2%), E2/4 (3.3%), E2/3 (8.9%). The ε3 allele (72%) was the most frequent, followed by ε4 (22%) and ε2 (6%). No difference was found in plasma levels of either apoE or in apoE genotype frequencies among the groups, however MMSE scores of CAD patients irrespective of their atheromatosis extent were significantly lower than that seen in the normal population. Although neither apoE plasma levels, nor apoE polymorphism in patients presenting with mild/moderate or severe atheromatosis showed to be associated with CAD severity, the presence of atheromatosis in the heart vessels positively correlated with cognitive dysfunction.

Early fitness consequences and hormonal correlates of parental behaviour in the social rodent, Octodon degus

Males are expected to assist their mates whenever this behaviour raises survival of offspring with little expense in terms of mating opportunities. At a more proximate level, cortisol and testosterone hormones seem involved in the expression of parental care in mammals. We examined the consequences to postnatal offspring development and survival of the males' presence in the social rodent, Octodon degus. Offspring quality and quantity, and maternal condition of females were contrasted among females rearing their litters in the presence of the sire, females breeding in the presence of a non-breeding female, and females breeding solitarily. We related these differences to variation in parental behaviour and plasma levels of testosterone and cortisol. Twenty two females and their litters were studied under constant conditions of adult density, nest availability, food availability, and breeding experience. Males huddled over and groomed offspring. However, neither the number nor the mass of pups from dams that nested with the sire differed from those recorded to breeding females that nested with a non-breeding female and females that nested solitarily. Body weight loss and associated levels of plasma cortisol in dams nesting with the sire were similar to those of solitary females, but higher than mothers nesting with a non-breeding female. Thus, male care had no consequences to offspring, and seemed detrimental to breeding females. Circulating levels of cortisol and total testosterone were either poor (mothers) or no (fathers, non-breeding females) predictors of parental care.

Acute stress induces a rapid increase of testosterone in a songbird: Implications for plasma testosterone sampling

Testosterone (T) and glucocorticoids, such as corticosterone, have both been shown to be important for the way vertebrates in general, and birds specifically, react to their immediate environment. For both corticosterone and T, many sources of variation in plasma levels have been demonstrated. Interestingly, a small number of studies on bird species have indicated that acute stress can have a positive effect on plasma T levels, analogous to what has been observed for plasma corticosterone levels. Using captive male European starlings ( Sturnus vulgaris), we provide the first evidence in songbirds of a (twofold) increase in plasma T levels after the onset of acute stress, as elicited with a capture-handling-restraint method, when comparing plasma T levels during the first 4 min with plasma T levels between 12 and 33 min. Furthermore, no significant change in plasma T levels was observed within the first 4 min after the onset of acute stress. Notably, although plasma corticosterone was also significantly elevated, the stress-induced change in levels of corticosterone and T were not significantly correlated. Our findings indicate that, when measuring plasma T levels, it may be essential to use a standardized method with fast capture and blood sampling (i.e. within 3–4 min), similar to the method for corticosterone sampling. Furthermore, it is necessary for future studies to examine the effect of using different capture techniques on measured plasma T levels, which may be of particular importance when interpreting T samples gathered in field studies.

A Systematic Review of Aripiprazole—Dose, Plasma Concentration, Receptor Occupancy, and Response

To evaluate relationships between aripiprazole dose, plasma level, pharmacologic activity, and clinical outcome in order to evaluate the potential for therapeutic drug monitoring. In August 2008, we searched Embase, MEDLINE, and PubMed databases using the keywords aripiprazole, plasma levels, plasma concentration, and therapeutic drug monitoring. Twenty-one reports were retrieved. Eight studies investigating the relationship between blood concentrations of aripiprazole and dose, dopamine D(2)/D(3) occupancy, and/or outcome and adverse effects were then selected. All data concerning plasma or serum concentrations of aripiprazole were included if concentrations were reported in relation to a dose, dopamine occupancy, or clinical outcome. Those reports solely investigating drug interactions were not included. A strong correlation exists between aripiprazole dose and plasma concentration. Positron emission tomography analyses suggest that there are significant relationships between dopamine receptor occupancy and both aripiprazole dose and blood concentration. Dopamine receptor occupancy appears to reach a plateau at doses above 10 mg, supporting the observation found in dose-response studies that 10 mg/d is the optimal dose for aripiprazole. The dose range for aripiprazole is well defined, and it reliably predicts plasma level, dopamine receptor occupancy, and clinical response. Plasma level variation appears to have minimal impact on clinical response, but it may predict some adverse effects. A putative target plasma level range of between 150 and 210 ng/mL is suggested. Therapeutic drug monitoring has limited value in the clinical use of aripiprazole, but it may be useful in assuring adherence and optimizing response in individuals.

Homeostasis of glucose in the rainbow trout (Oncorhynchus mykiss Walbaum): the role of serotonin

In this study, we evaluated, for the first time, the 5-HT (serotonin)-mediated control of glucose homeostasis in the rainbow trout Oncorhynchus mykiss. Intraperitoneal administration of 5-HT increased plasma levels of glucose, adrenaline and noradrenaline. By contrast, intracerebroventricular administration of 5-HT did not cause any significant variation in plasma levels of glucose. The release of endogenous 5-HT following intraperitoneal administration of d-fenfluramine led to a significant increase in plasma levels of glucose and adrenaline. Intraperitoneal administration of (1) MIAN (a 5-HT2 receptor antagonist) did not block either the hyperglycaemic action or the increase in plasma levels of adrenaline induced by 5-HT, but did block the increase in plasma levels of noradrenaline, and (2) 5-CT (a 5-HT1 agonist) increased the plasma levels of glucose and of adrenaline, without altering those of noradrenaline. Administration of TFMPP (a 5-HT1B agonist) did not increase the plasma levels of glucose, and the hyperglycaemic action of 5-HT was not blocked by antagonists of 5-HT1A (WAY 100635), 5-HT1D (BRL 15572), 5-HT2B (SB 204741) or 5-HT7 (pimozide) receptors. It was demonstrated that, in rainbow trout, peripheral 5-HT, but not brain 5-HT intervenes in the modulation of glucose homeostasis with a hyperglycaemic effect. This effect is associated with the release of adrenaline and activation of 5-HT1-like receptors. As far as could be determined in the present study, these 5-HT1-like receptors are unrelated to either the 5-HT1A, 5-HT1B or 5-HT1D receptor subtypes of mammals. The 5-HT2-type receptors may mediate the release of noradrenaline, but not of adrenaline, and furthermore, do not appear to play an important role in the hyperglycaemic effect exerted by 5-HT.

Ghrelin and Cardiovascular Diseases

Ghrelin, a newly discovered bioactive peptide, is a natural endogenous ligand of the growth hormone (GH) secretagogue receptor and initially identified as a strong stimulant for the release of GH. Subsequent research has shown that ghrelin and its various receptors are ubiquitous in many other organs and tissues. Moreover, they participate in the regulation of appetite, energy, bodyweight, metabolism of glucose and fat, as well as modulation of gastrointestinal, cardiovascular, pulmonary, immune functions and cell proliferation/apoptosis. Increasing evidence has demonstrated that ghrelin has a close relationship with cardiovascular system. Ghrelin and its receptors are widely distributed in cardiovascular tissues, and there is no doubt that the effects of ghrelin in the cardiovascular system are mediated not only via its growth-hormone-releasing effect but also by its direct effects on the heart. Exogenous administration of ghrelin can dilate peripheral blood vessels, constrict coronary artery, improve endothelial function, as well as inhibit myocardial cell apoptosis. So, ghrelin may have cardiovascular protective effect, including lowering of blood pressure, regulation of atherosclerosis, and protection from ischemia/reperfusion injury as well as improving the prognosis of myocardial infarction and heart failure. Some of these new functions of ghrelin may provide new potential therapeutic opportunities for ghrelin in cardiovascular medicine. In this paper, we will review the existing evidence for cardiovascular effects of ghrelin, including the cardiovascular function, the variations in ghrelin plasma levels in pathophysiologicalogical conditions, the possible protective mechanisms of ghrelin, as well as its future potential therapeutic roles.

Reduction in Plasma Levels of Inflammatory and Oxidative Stress Indicators After Roux-En-Y Gastric Bypass

Obesity is considered to be associated with high levels of oxidative stress and inflammation. Anticipated weight loss secondary to bariatric surgery may offer an opportunity to evaluate this association. We studied a few markers of oxidative stress and inflammation in 20 obese patients submitted to Roux-en-Y gastric bypass (RYGBP). Variations in plasma levels of indicators of oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD), catalase, glutathione (GSH), glutathione disulfide (GSSG), and total radical antioxidant parameter (TRAP)) and inflammation (alpha1-acid glycoprotein (AGP) and C-reactive protein (CRP)), as well as variations in plasma levels of leptin, glucose, glycated hemoglobin (HbA1c), and insulin were investigated in the preoperative period and 12 months postsurgery in 20 class III obese individuals submitted to bariatric surgery (obese group) and 20 non-obese individuals (control group). Twelve months postsurgery, there was a significant reduction (p < 0.01) in median values of BMI (46.75/30.17 kg/m(2)) and in plasma levels of MDA (16.70/9.11 nmol/g prot), SOD (10.70/9.24 U/mgHb), GSSG (210.80/148.20 mM/g of Hb), AGP (125.70/75.80 mg/dL), CRP (1.31/0.38 mg/dL), and leptin (15.04/3.58 ng/mL). A significant drop (p < 0.05) in plasma levels of HbA1c (5.81/4.98%) was also observed. On the other hand, a significant increase in plasma levels of GSH (2.002/2.823 mM/g of Hb) and TRAP (585.40/815.48 microM Trolox), p < 0.01, and in catalase plasma levels (12.06/13.22 Deltat/mgHb/min), p < 0.05, was seen. No statistically significant variations in glucose (96.3/84.8 mg/dL) or insulin plasma levels (9.91/7.88 U/mL) occurred. Calculated homeostasis model assessment index did not statistically change 12 months postsurgery (2.36/1.66). In the preoperative period, the obese group individuals showed higher oxidation and inflammation levels and lower indices of antioxidant defense than those of the control group. One year after RYGBP, an improvement in antioxidant protection, associated with a reduction in inflammatory and oxidative markers, was observed, indicating that these individuals presented a lower degree of oxidative stress.

The dopamine D2 receptor antagonist sulpiride modulates striatal BOLD signal during the manipulation of information in working memory

RationaleDopamine (DA) plays an important role in working memory. However, the precise functions supported by different DA receptor subtypes in different neural regions remain unclear.ObjectiveThe present study used pharmacological, event-related fMRI to test the hypothesis that striatal dopamine is important for the manipulation of information in working memory.MethodsTwenty healthy human subjects were scanned twice, once after placebo and once after sulpiride 400 mg, a selective DA D2 receptor antagonist, while performing a verbal working memory task requiring different levels of manipulation.ResultsWhilst there was no overall effect of sulpiride on task-dependent activation, individual variation in sulpiride plasma levels predicted the effect of working memory manipulation on activation in the putamen, suggesting a dose-dependent effect of DA antagonism on a striatally based manipulation process. These effects occurred in the context of a drug-induced improvement in performance on trials requiring the manipulation of information in working memory but not on simple retrieval trials. No significant drug effects were observed in the prefrontal cortex.ConclusionsThese results support models of dopamine function that posit a ‘gating’ function for dopamine D2 receptors in the striatum, which enables the flexible updating and manipulation of information in working memory.

Lifestyle intervention improves microvascular reactivity and increases serum adiponectin in overweight hypertensive patients

Background and aims Obesity and hypoadiponectinemia are often associated with high blood pressure. Moreover, microvascular dysfunction is reported to be an early event in patients with hypertension and may be involved in the pathogenesis of organ damage. Methods and results We investigated the impact of 8-week moderate-intensity aerobic training on adiponectin plasma levels and skin microvascular reactivity in 24 overweight sedentary patients (18 men, age 44 ± 6 years, body mass index 28 ± 3 kg/m 2) with never-treated grade 1 essential hypertension. Twenty-four age- and sex-matched hypertensive patients, who were examined twice at 8-week intervals in the absence of exercise training, served as controls. Exercise training was followed by a significant reduction in waist circumference (from 97 ± 9 to 95 ± 9 cm, p < 0.05) and an increase in adiponectin plasma levels (from 11.9 ± 3 to 12.5 ± 4 mg/L, p < 0.05). An inverse correlation was found between adiponectin change and waist circumference change ( r = −0.43, p < 0.05). The area under the curve after post-occlusive reactive hyperemia at skin laser-Doppler examination increased significantly after aerobic training (from 876 ± 539 to 1468 ± 925 PU/s, p < 0.001). A positive correlation was found between exercise-induced variations of post-occlusive reactive hyperemia and adiponectin plasma levels ( r = 0.41, p < 0.05). Office or 24-h blood pressure values did not change significantly. Conclusion In sedentary overweight patients with mild hypertension, moderate aerobic training improves cutaneous microvascular reactivity and adiponectin plasma levels. These changes precede blood pressure reduction and may serve as biomarkers of the efficacy of non-drug treatment in hypertensive patients.

Stage-related plasma values of transforming growth factor-beta1 are steroid receptors dependent

Transforming growth factor-beta1 (TGF-beta1) is a biomarker associated with the progression of breast cancer, characteristic by switching activity from tumor suppressor in early stages to tumor promoter at advanced disease. However, what cause this switch is still not clear. On the other hand, the relationship between steroid receptors (estrogen ER and progesterone PR) as the major discriminators of breast cancer phenotype and this paradoxical biomarker is not fully determined. In this pilot study on 52 breast cancer patients, quantitative plasma values of TGF-beta1 were determined by quantitative ELISA and steroid receptor content was measured in cytosol fraction of breast cancer tissue using dextran-coated (DCC) method. We tried to investigate the possibility that steroid receptor status of patients at different stages of disease could be the trigger that somehow causes variation of TGF-beta1 plasma levels. In nonmetastatic breast cancer patients, there was no statistically significant increase in the plasma levels of TGF-beta1, when patients are stratified by steroid receptor status (ER- vs. ER+, PR- vs. PR+). We found for the first time, that indeed in metastatic breast cancer statistically significant elevated levels of TGF-beta1 are related to negative steroid receptor status and moreover that, there is correlation between quantitative values of these parameters in this stage. This finding deserves further investigation because it could provide a new insight into more aggressive nature of steroid receptor negative tumors.

Adipocyte fatty acid binding protein during refeeding of female patients with anorexia nervosa

Adipocyte fatty acid binding protein (A-FABP) has been suggested to play an important role in fat metabolism linking obesity and the metabolic syndrome. Increasing A-FABP plasma levels were observed during greatest weight loss after bariatric surgery suggesting that A-FABP may indicate changes in fat mass in dynamic situations. As there are no data on weight gain, we investigated the effect of refeeding anorexic patients on body composition and A-FABP plasma levels. Parameters of glucose and lipid metabolism as well as plasma levels of leptin and A-FABP were prospectively assessed in 16 female patients with anorexia nervosa during inpatient weight restoration. Body composition was determined by multifrequency body impedance analysis. After 28 days, fat mass increased from 4.4 +/- 2.5 kg at baseline to 5.5 +/- 2.2 kg (P < 0.01), constituting 40% of total weight gain. Conversely, A-FABP concentrations decreased from 32.56 +/- 35.59 ng/ml at baseline to 21.27 +/- 13.68 ng/ml (P < 0.05), which corresponds to a significant decrease in the proportion of A-FABP per kilogram fat mass from 7.86 +/- 5.23 to 4.09 +/- 2.12 ng/ml/kg (P </= 0.001). Variation in A-FABP plasma concentration was predictive for changes in total cholesterol levels (adjusted r (2) = 0.239; P < or = 0.05), but not for gain in weight, fat mass, or percent body fat. The present results indicate that variation in A-FABP plasma levels reflect alterations in nutritional status in patients with anorexia nervosa.

Personality traits and endocrine response as possible asymmetry factors of agonistic outcome in karate athletes

Individual variations of plasma levels of hormones testosterone (T) and cortisol (C), before (pre) and after (post) Kumite (real fight) and Kata (ritualized fight) were measured in male karate athletes and analyzed in relation with the agonistic outcome (i.e. winning or losing the fight) and personality trait measures. T and C increased only during Kumite contest and pre- and post-competition C levels were higher in losers than winners. Losers showed higher levels of harm avoidance and anxiety as well as lower level of novelty seeking than winners. Importantly, novelty seeking negatively correlates with pre C and the higher the level of risk assessment, emotionality and insecurity indexes the higher the pre C level. In conclusion, personality traits might be an important factor asymmetry between athletes influencing both the probability of winning or losing an agonistic interaction and the different anticipatory endocrine response to the incipient fight.

Genetic and Metabolic Determinants of Plasma PCSK9 Levels

PCSK9 is a secreted protein that influences plasma levels of low-density lipoprotein cholesterol (LDL-C) and susceptibility to coronary heart disease. PCSK9 is present in human plasma, but the factors that contribute to differences in plasma concentrations of PCSK9 and how they impact on the levels of lipoproteins have not been well-characterized. The aim of the study was to measure PCSK9 levels in a large, ethnically diverse population (n = 3138) utilizing a sensitive and specific sandwich ELISA. We conducted an observational study in the Dallas Heart Study, a multiethnic, probability-based sample of Dallas County. Plasma levels of PCSK9 varied over approximately 100-fold range (33-2988 ng/ml; median, 487 ng/ml). Levels were significantly higher in women (517 ng/ml) than in men (450 ng/ml), and in postmenopausal women compared to premenopausal women (P < 0.0001), irrespective of estrogen status. Plasma levels of PCSK9 correlated with plasma levels of LDL-C (r = 0.24) but explained less than 8% of the variation in LDL-C levels (r(2) = 0.073). Other factors that correlated with PCSK9 levels included plasma levels of triglycerides, insulin, and glucose. Individuals with loss-of-function mutations in PCSK9 and reduced plasma levels of LDL-C also had significantly lower plasma levels of PCSK9 after adjusting for age, gender, and LDL-C levels (P < 0.0001). Multiple metabolic and genetic factors contribute to variation in plasma levels of PCSK9 in the general population. Although levels of PCSK9 correlate with plasma levels of LDL-C, they account for only a small proportion of the variation in the levels of this lipoprotein.

Genetic determinants of plasma HDL-cholesterol levels in prepubertal children

Introduction Genetic determinants have been related to variation of high-density lipoprotein cholesterol (HDL-C) levels, but the extension of this association remains controversial. In our study, we analyzed the contribution of several polymorphisms on HDL-C-related genes to variation of plasma HDL-C in prepubertal children. Methods We studied 1269 (641 males and 628 females) 6–8 years old healthy children, who participated in a cross-sectional study examining cardiovascular risk factors in Spain. Common genetic variants in the apolipoprotein AI, apolipoprotein AII, cholesteryl ester transfer protein (CETP), hepatic lipase, ATP-binding cassette transporter A1, and paraoxonase genes were determined by PCR. Results CETP TaqI B2 carrier girls had significantly higher HDL-C levels than B1B1 girls. B2B2 boys had significantly higher ( p < 0.001) HDL-C than B1B1and B1B2 boys. In linear regression analysis, CETP TaqIB appears as the main predictor of HDL-C plasma levels, accounting for 4.5% and 1.8% of HDL-C variation in girls and boys respectively. Conclusions Our data showed that among the studied polymorphisms only the CETP TaqIB polymorphism contributes to the variation in HDL-C levels in prepubertal children, particularly in girls, but overall these polymorphisms explain a small part of the variation of HDL-C plasma levels at this age.

Scavenger Receptor BI-mediated Selective Uptake Is Required for the Remodeling of High Density Lipoprotein by Endothelial Lipase

Endothelial lipase (EL) is a negative regulator of high density lipoprotein (HDL) cholesterol plasma levels, and scavenger receptor BI (SR-BI) is involved in remodeling of HDL. The present study investigates the requirement of SR-BI for the effects of EL-mediated phospholipid hydrolysis on HDL metabolism in vivo. In vitro, selective uptake from EL-modified HDL was 129% higher than selective uptake from control HDL in SR-BI-overexpressing cells (p=0.01). In vivo overexpression of human EL by means of recombinant adenovirus decreased HDL plasma levels significantly (p<0.01). Fast protein liquid chromatography analysis and agarose gel electrophoresis revealed that EL expression resulted in the generation of small pre-beta HDL particles in wild-type mice, whereas in SR-BI-/- mice small HDL were preferentially removed. In kinetic experiments the fractional catabolic rate (FCR) of HDL cholesteryl ester increased by 110% (p<0.001), and the FCR of HDL apolipoproteins increased by 64% (p<0.001) in response to EL overexpression in wild-type mice. In SR-BI-/- mice a similar increase in the HDL apolipoprotein FCR occurred (p<0.001); however, there was no further increase in HDL cholesteryl ester catabolism. The apparent whole body selective uptake was increased 3-fold by EL in wild-type mice (p<0.001), whereas there was no selective uptake in SR-BI knock-out mice. EL overexpression increased hepatic selective uptake as well as holoparticle uptake (each p<0.01) in wild-type mice, whereas in SR-BI knock-out mice only holoparticle uptake increased (p<0.01). Our results indicate that SR-BI-mediated selective uptake of HDL cholesteryl ester is essential for the remodeling of large alpha-migrating HDL particles by EL.

Polymorphism FXII 46C&gt;T and cardiovascular risk: additional data from Spanish and Tunisian patients

BackgroundPrevious studies showed an association between Coagulation Factor XII 46C>T polymorphism and variation in FXII plasma levels, as 46C>T seems to affect the translation efficiency. Case-control studies in Spanish samples indicated that genotype T/T is an independent risk factor for venous thrombosis, ischemic stroke and acute coronary artery disease. In this study, we tried to reaffirm the importance of 46C>T in two samples from Spain and Tunisia.FindingsA Transmission Disequilibrium Test (TDT) based on 101 family trios from Barcelona with one offspring affected by ischemic heart disease and a classical case-control study based on 76 patients with IHD and 118 healthy individuals from North and Centre-South Tunisia were conducted. Subjects were genotyped for 46C>T and data were analyzed accordingly, revealing no association in any of the two samples (TDT: P = 0.16, relative risk 1.17; case-control study: P = 0.59, odds ratio 1.36).ConclusionThe results suggest that 46C>T is not a risk factor for ischemic heart disease in any of the two analyzed samples and therefore the polymorphism seems not to be a universal risk factor for cardiovascular diseases.