1,721,001 research outputs found
INDIVIDUAZIONE DELLA CAUSA GENETICA RESPONSABILE DELLA IPOCOLESTEROLEMIA NELLE FAMIGLIE DI CAMPODIMELE (LT).
Full text linkIl progetto di studio riguarda l’individuazione della causa genetica responsabile della ipocolesterolemia nelle famiglie del comune di Campodimele(LT). Queste famiglie, caratterizzate da un’alta frequenza di individui con bassi livelli di colesterolo totale ed LDL, erano state individuate nel corso di una indagine epidemiologica dedicata ai fattori di rischio dell’aterosclerosi.Il disegno dello studio include lo screening dei geni candidati e il confronto delle caratteristiche cliniche e metaboliche tra indiviui portatori e non portatori. Nella comunità di Campodimele è stata riscontrata la mutazione S17X nel gene ANGPTL3 in tutti i probandi., inoltre sono state individuate due ulteriori mutazioni sullo stesso gene (FsE96del e FsS122. GLi omozigoti per la mutazione S17X non hanno concentrazioni rilevabile di proteina Angptl3 nel siero e una marcata riduzione di tutti il lipidi plasmatici. Gli eterozigoti mostrano una riduzione del 42% dei livelli di Angptl3 rispetto ai non-carriers ma solo una riduzione significativa del colesterolo totale e High density lipoprotein cholesterol. L'ipolipidemia familiare combinata segrega con tratto recessivo
Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis
No full textAngiopoietin-like 3 (ANGPTL3) regulates lipoprotein metabolism by modulating extracellular lipases. Loss-of function mutations in ANGPTL3 gene cause familial combined hypolipidemia (FHBL2). The mode of inheritance and hepatic and vascular consequences of FHBL2 have not been fully elucidated. To get further insights on these aspects, we reevaluated the clinical and the biochemical characteristics of all reported cases of FHBL2. One hundred fifteen FHBL2 individuals carrying 13 different mutations in the ANGPTL3 gene (14 homozygotes, 8 compound heterozygotes, and 93 heterozygotes) and 402 controls were considered. Carriers of two mutant alleles had undetectable plasma levels of ANGPTL3 protein, whereas heterozygotes showed a reduction ranging from 34% to 88%, according to genotype. Compared with controls, homozygotes as well as heterozygotes showed a significant reduction of all plasma lipoproteins, while no difference in lipoprotein(a) [Lp(a)] levels was detected between groups. The prevalence of fatty liver was not different in FHBL2 subjects compared with controls. Notably, diabetes mellitus and cardiovascular disease were absent among homozygotes. FHBL2 trait is inherited in a codominant manner, and the lipid-lowering effect of two ANGPTL3 mutant alleles was more than four times larger than that of one mutant allele. No changes in Lp(a) were detected in FHBL2. Furthermore, our analysis confirmed that FHBL2 is not associated with adverse clinical sequelae. The possibility that FHBL2 confers lower risk of diabetes and cardiovascular disease warrants more detailed investigation
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
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
Analysis 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
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
Genetic variants in adipose triglyceride lipase influence lipid levels in familial combined hyperlipidemia
No full textOBJECTIVE:
Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.
METHODS:
Four SNPs within the PNPLA2 gene (rs7925131, rs7942159, rs66460720 and the nonsynonymous P481L) were selected based on previous association with decreased plasma levels of free fatty acids (FFA) and total triglycerides (TG) and their high frequency (MAF>0.25). These SNPs were genotyped in 214 FCHL individuals from 83 families and in 103 controls and the corresponding haplotypes were reconstructed.
RESULTS:
No association between individual SNPs and the FCHL trait was observed. However, two PNPLA2 haplotypes were associated with lower risk of FCHL (P<0.004 after Bonferroni's correction). Compared to the others, these haplotypes were related to lower TG (118.9 ± 66.8 vs. 197.1 ± 114.7 mg/dl; P=0.001) and higher HDL-C (62.3 ± 15.8 vs. 51.0 ± 15.0 mg/dl; P<0.005). In a subgroup of studied subjects (n=63) protective haplotypes were also associated with lower FFA levels (0.33 ± 0.11 vs. 0.46 ± 0.18 mEq/L; P<0.05). These effects were independent from age, BMI and HOMA(IR).
CONCLUSION:
These data demonstrate that variants within PNPLA2 may modulate the TG component of FCHL trait, thus implicating PNPLA2 as modifier gene in this lipid disorder. They also suggest a potential role of PNPLA2 in the metabolism of TG-rich lipoprotein
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
Genetically determined deficiency of ANGPTL3 does not alter HDL ability to preserve endothelial homeostasis
No full text: Individuals with loss-of-function mutations in the ANGPTL3 gene express a rare lipid phenotype called Familial Combined Hypolipidemia (FHBL2). FHBL2 individuals show reduced plasma concentrations of total cholesterol and triglycerides as well as of lipoprotein particles, including HDL. This feature is particularly remarkable in homozygotes in whom ANGPTL3 in blood is completely absent. ANGPTL3 acts as a circulating inhibitor of LPL and EL and it is thought that EL hyperactivity is the cause of plasma HDL reduction in FHBL2. Nevertheless, the consequences of ANGTPL3 deficiency on HDL functionality have been poorly explored. In this report, HDL isolated from homozygous and heterozygous FHBL2 individuals were evaluated for their ability to preserve endothelial homeostasis as compared to control HDL. It was found that only the complete absence of ANGPTL3 alters HDL subclass distribution, as homozygous, but not heterozygous, carriers have reduced content of large and increased content of small HDL with no alterations in HDL2 and HDL3 size. The plasma content of preβ-HDL was reduced in carriers and showed a positive correlation with plasma ANGPTL3 levels. Changes in composition did not however alter the functionality of FHBL2 HDL, as particles isolated from carriers retained their capacity to promote NO production and to inhibit VCAM-1 expression in endothelial cells. Furthermore, no significant changes in circulating levels of soluble ICAM-1 and E-selectin were detected in carriers. These results indicate that changes in HDL composition associated with the partial or complete absence of ANGPTL3 did not alter some of the potentially anti-atherogenic functions of these lipoproteins
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