1,721,004 research outputs found
Elevated Serum Concentrations of Remnant Cholesterol Associate with Increased Carotid Intima-Media Thickness in Children and Adolescents
No full textOBJECTIVE: To evaluate the relationship between remnant cholesterol and carotid intima-media thickness (cIMT), a surrogate marker for atherosclerosis, in children and adolescents.STUDY DESIGN: Anthropometric, laboratory, liver and carotid ultrasonographic data were obtained from 767 youths (594, overweight/obese; 173, normal weight). Fasting RC was calculated from the standard lipid profile. cIMT ≥ 0.56 mm (corresponding to the 90th percentile of values observed in normal-weight children) was chosen to define elevated cIMT. Logistic regression analysis was used to estimate the risk of elevated cIMT according to tertiles of RC levels.RESULTS: In the entire cohort, the mean concentration of RC was 17.9±10.3 mg/dl and mean cIMT value was 0.51±0.8 mm. Remnant cholesterol significantly correlated with age, sex, body mass index (BMI), waist circumference, blood pressure, lipids, liver enzymes, and insulin resistance (HOMA-IR). cIMT value increased progressively with rising RC tertiles (Pfor trend<0.001). Compared with subjects in the lowest RC tertile, those in the middle and highest RC tertiles had a 2.3- and 2.4-fold increased risk of elevated cIMT, independently of age, sex, pubertal stage, BMI and apolipoprotein B (all Padj≤0.003). When the effects of overweight/obesity on the association between RC and cIMT were determined, normal-weight as well as overweight/obese subjects in the highest RC tertile had a 3.8- and 2.3-fold increased risk to have elevated cIMT compared with the respective study groups in the lowest tertile, after adjustment for conventional risk factors (Padj=0.038 and Padj=0.003, respectively).CONCLUSION: In youths elevated levels of remnant cholesterol might represent a marker of early atherosclerotic damage
How ANGPTL3 Inhibition Will Help Our Clinical Practice?
No full textPurpose of review: This review aims to summarize the most recently published literature highlighting the potential of pharmacological inhibition of ANGPTL3 in treating patients suffering from dyslipidemias. The rational for this strategy will be discussed considering evidence describing the role of ANGPTL3 in lipid metabolism and the consequences of its deficiency in humans. Recent findings: Recent trials have demonstrated the efficacy and safety of ANGPTL3 inhibition in treating homozygous familial hypercholesterolemia even in those patients carrying biallelic null/null variants, thus supporting the notion that the LDL-lowering effect of ANGPLT3 inhibition is LDLR-independent. The use of ANGPTL3 inhibition strategies has expanded its indications in hypertrygliceridemic patients with functional lipoprotein lipase activity. Contemporarily, the pharmacological research is exploring novel approaches to ANGPTL3 inhibition such as the use of a small interfering RNA targeting the ANGPTL3 transcript in the liver, a protein-based vaccine against ANGPTL3, and a CRISP-Cas-9 method for a liver-selective knock-out of ANGPTL3 gene. First, we will describe the molecular function of ANGPTL3 in lipoprotein metabolism. Then, we will revise the clinical characteristics of individuals carrying loss-of-function mutations of ANGPTL3, a rare condition known as familial hypobetalipoproteinemia type 2 (FHBL2) that represents a unique human model of ANGPTL3 deficiency. Finally, we will examine the lipid-lowering potential of pharmacological inhibition of ANGPTL3 based on the results of clinical trials employing Evinacumab, the first approved fully humanized monoclonal antibody against ANGPTL3. The future perspectives for ANGPTL3 inhibition will also be revised
Contribution of mutations in low density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) genes to familial combined hyperlipidemia (FCHL): A reappraisal by using a resequencing approach
No full textBackground:Defective low-density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) alleles havebeen implicated in familial combined hyperlipidemia (FCHL). However, their contribution might havebeen influenced by diagnostic criteria. This study was aimed to reassess the frequency of rare andcommon variants inLDLRandLPLin FCHL individuals classified with stringent criteria.Methods: LDLRandLPLwere resequenced in 208 FHCL and 171 controls. Variants were classified as loss-(LOF) or gain-of-function (GOF) based uponin silicoprediction, familial segregation and availablefunctional data.Results:Eight LOF variants were detected inLDLR, 6 of which were missense and 2 were predicted todisrupt normal splicing; all were present at heterozygous state. They were found in 10 FCHL but not incontrols, thus indicating that 4.8% of FCHL individuals should be reclassified as FH. LDL-C (positive) andBMI (negative) were the strongest predictors ofLDLRmutations with LDL-C 181 mg/dl being the bestthreshold for diagnosing the presence of dysfunctionalLDLRalleles. The cumulative prevalence of def-initeLPLdefective alleles (1 rare and 2 common heterozygous missense variants) was comparable be-tween FCHL and controls (10.1% vs. 10.5%). Conversely, theLPLGOF variant p.Ser474* showed a lowerfrequency in FCHL than in controls (13.5% vs. 24.0%, p1⁄40.008). Overall, LOFLPLvariants did not show aTG-modulating effect.Conclusions:Ourfindings indicate that, in well characterized FCHL individuals, variants inLDLRandLPLprovide a small contribution to this dyslipidemia, thus limiting the need for such genetic testing.©2015 Elsevier Ireland Ltd. All rights reserve
Spectrum of mutations and long-term clinical outcomes in genetic chylomicronemia syndromes
Full text linkOBJECTIVE: Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are the prototypes of monogenic and polygenic conditions underlying genetically based severe hypertriglyceridemia. These conditions have been only partially investigated so that a systematic comparison of their characteristics remains incomplete. We aim to compare genetic profiles and clinical outcomes in FCS and MCS. Approach and Results: Thirty-two patients with severe hypertriglyceridemia (triglyceride >1000 mg/dL despite lipid-lowering treatments with or without history of acute pancreatitis) were enrolled. Rare and common variants were screened using a panel of 18 triglyceride-raising genes, including the canonical LPL, APOC2, APOA5, GP1HBP1, and LMF1. Clinical information was collected retrospectively for a median period of 44 months. Across the study population, 37.5% were classified as FCS due to the presence of biallelic, rare mutations and 59.4% as MCS due to homozygosity for nonpathogenic or heterozygosity for pathogenic variants in canonical genes, as well as for rare and low frequency variants in noncanonical genes. As compared with MCS, FCS patients showed a lower age of hypertriglyceridemia onset, higher levels of on-treatment triglycerides, and 3-fold higher incidence rate of acute pancreatitis. CONCLUSIONS: Our data indicate that the genetic architecture and natural history of FCS and MCS are different. FCS expressed the most severe clinical phenotype as determined by resistance to triglyceride-lowering medications and higher incidence of acute pancreatitis episodes. The most common genetic abnormality underlying FCS was represented by biallelic mutations in LPL while APOA5 variants, in combination with high rare polygenic burden, were the most frequent genotype of M
PNPLA3 I148M gene variant is not associated with metabolic syndrome and cardiometabolic risk in non-alcoholic fatty liver disease
No full textAnalysis of Children and Adolescents with Familial Hypercholesterolemia
No full textObjective To evaluate the effectiveness of criteria based on child-parent assessment in predicting familial hypercholesterolemia
(FH)-causative mutations in unselected children with hypercholesterolemia.
Study design LDLR, APOB, and PCSK9 genes were sequenced in 78 children and adolescents (mean age 8.4 ± 3.7
years) with clinically diagnosed FH. The presence of polygenic hypercholesterolemia was further evaluated by genotyping
6 low-density lipoprotein cholesterol (LDL-C)-raising single-nucleotide polymorphisms.
Results Thirty-nine children (50.0%) were found to carry LDLR mutant alleles but none with APOB or PCSK9
mutant alleles. Overall, 27 different LDLR mutations were identified, and 2 were novel. Children carrying mutations
showed higher LDL-C (215.2 ± 52.7 mg/dL vs 181.0 ± 44.6 mg/dL, P < .001) and apolipoprotein B levels
(131.6 ± 38.3 mg/dL vs 100.3 ± 30.0 mg/dL, P < .004), compared with noncarriers. A LDL-C of ~190 mg/dL was the
optimal value to discriminate children with and without LDLR mutations. When different diagnostic criteria were
compared, those proposed by the European Atherosclerosis Society showed a reasonable balance between sensitivity
and specificity in the identification of LDLR mutations. In children without mutation, the FH phenotype was
not caused by the aggregation of LDL-C raising single-nucleotide polymorphisms.
Conclusions In unselected children with hypercholesterolemia, LDL-C levels >190 mg/dL and a positive family history
of hypercholesterolemia appeared to be the most reliable criteria for detecting FH. As 50% of children with suspected
FH did not carry FH-causing mutations, genetic testing should be considere
Nonalcoholic fatty liver disease (NAFLD), but not its susceptibility gene variants, influences the decrease of kidney function in overweight/obese children
Full text linkNonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of kidney disease in adults and children. However, it is uncertain whether this association is influenced by major NAFLD susceptibility genes. In a sample of 230 overweight/obese children, 105 with NAFLD (hepatic fat fraction ≥5% by magnetic resonance imaging) and 125 without NAFLD, rs738409 in PNPLA3, rs58542926 in TM6SF2, rs1260326 in GCKR, and rs641738 in MBOAT7 were genotyped. Abnormal kidney function was defined as estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 and/or the presence of microalbuminuria (24 h urinary albumin excretion between 30 and 300 mg). In comparison with children without NAFLD, those with NAFLD showed increased prevalence of reduced eGFR (13.3% vs. 1.6%; p < 0.001) and microalbuminuria (8.6% vs. 3.4%, p = 0.025). TM6SF2, GCKR, and MBOAT7 risk alleles did not show any impact on kidney function, while the PNPLA3 G allele was associated with lower eGFR, but only in children with NAFLD (p = 0.003). After adjustment for confounders, NAFLD (OR, 4.7; 95% CI, 1.5-14.8; padj = 0.007), but not the PNPLA3 gene variant, emerged as the main independent predictor of renal dysfunction. Overall, our findings suggest that NAFLD remains the main determinant of decline in kidney function in overweight/obese children, while the PNPLA3 rs738409 prosteatogenic variant has a small impact, if an
The role of lipid metabolism in shaping the expansion and the function of regulatory T cells
Full text linkMetabolic inflammation, defined as a chronic low-grade inflammation, is implicated in numerous metabolic diseases. In recent years, the role of regulatory T cells (Tregs) as key controllers of metabolic inflammation has emerged, but our comprehension on how different metabolic pathways influence Treg functions needs a deeper understanding. Here we focus on how circulating and intracellular lipid metabolism, in particular cholesterol metabolism, regulates Treg homeostasis, expansion, and functions. Cholesterol is carried through the bloodstream by circulating lipoproteins (chylomicrons, very low-density lipoproteins, low-density lipoproteins). Tregs are equipped with a wide array of metabolic sensors able to perceive and respond to changes in the lipid environment through the activation of different intracellular pathways thus conferring to these cells a crucial metabolic and functional plasticity. Nevertheless, altered cholesterol transport, as observed in genetic dyslipidemias and atherosclerosis, impairs Treg proliferation and function through defective cellular metabolism. The intracellular pathway devoted to the cholesterol synthesis is the mevalonate pathway and several studies have shown that this pathway is essential for Treg stability and suppressive activity. High cholesterol concentrations in the extracellular environment may induce massive accumulation of cholesterol inside the cell thus impairing nutrients sensors and inhibiting the mevalonate pathway. This review summarizes the current knowledge regarding the role of circulating and cellular cholesterol metabolism in the regulation of Treg metabolism and functions. In particular, we will discuss how different pathological conditions affecting cholesterol transport may affect cellular metabolism in Tregs
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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