| 1. |
- Albuquerque, João, et al.
(author)
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Generation and validation of a classification model to diagnose familial hypercholesterolaemia in adults.
- 2023
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In: Atherosclerosis. - 1879-1484. ; 383
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Journal article (peer-reviewed)abstract
- The early diagnosis of familial hypercholesterolaemia is associated with a significant reduction in cardiovascular disease (CVD) risk. While the recent use of statistical and machine learning algorithms has shown promising results in comparison with traditional clinical criteria, when applied to screening of potential FH cases in large cohorts, most studies in this field are developed using a single cohort of patients, which may hamper the application of such algorithms to other populations. In the current study, a logistic regression (LR) based algorithm was developed combining observations from three different national FH cohorts, from Portugal, Brazil and Sweden. Independent samples from these cohorts were then used to test the model, as well as an external dataset from Italy.The area under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves was used to assess the discriminatory ability among the different samples. Comparisons between the LR model and Dutch Lipid Clinic Network (DLCN) clinical criteria were performed by means of McNemar tests, and by the calculation of several operating characteristics.AUROC and AUPRC values were generally higher for all testing sets when compared to the training set. Compared with DLCN criteria, a significantly higher number of correctly classified observations were identified for the Brazilian (p<0.01), Swedish (p<0.01), and Italian testing sets (p<0.01). Higher accuracy (Acc), G mean and F1 score values were also observed for all testing sets.Compared to DLCN criteria, the LR model revealed improved ability to correctly classify observations, and was able to retain a similar number of FH cases, with less false positive retention. Generalization of the LR model was very good across all testing samples, suggesting it can be an effective screening tool if applied to different populations.
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| 2. |
- Calabresi, Laura, et al.
(author)
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A novel homozygous mutation in CETP gene as a cause of CETP deficiency in a caucasian kindred
- 2009
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In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 205:2, s. 506-511
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Journal article (peer-reviewed)abstract
- Objective: To analyze the cholesteryl ester transfer protein (CETP) gene and the plasma HDL phenotype in a Caucasian subject with extremely elevated plasma high density lipoprotein-cholesterol (HDL-C). Methods and results: The proband, a 63-year-old male of Swedish ancestry with elevated HDL-C (208 mg/dl) and apoA-I (and 272 mg/dl), was found to be homozygous for a point mutation in exon 2 of CETP gene (c.109 C > T) resulting in a premature termination codon (R37X). Plasma CETP mass and activity were undetectable. Plasma HDL were characterized by predominance of large HDL with enhanced pre beta-HDL content. The proband's sons, heterozygotes for the mutation, had reduced plasma CETP activity and moderately elevated HDL-C. Serum of CETP deficient subjects showed a normal or enhanced cholesterol efflux capacity via ABCG1/SR-BI; cholesterol efflux via ABCA1 and macrophage cholesterol removal were lower than normal. The proband was healthy and had no atherosclerotic plaques in carotid or femoral arteries. Conclusion: Complete CETP deficiency caused by mutations in CETP gene is exceedingly rare in Caucasians; the description of this single case indicates that CETP deficiency does not predispose to atherosclerosis in the absence of major cardiovascular risk factors. (c) 2009 Elsevier Ireland Ltd. All rights reserved.
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| 3. |
- Gomaraschi, Monica, et al.
(author)
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eNOS Activation by HDL Is Impaired in Genetic CETP Deficiency.
- 2014
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:5
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Journal article (peer-reviewed)abstract
- Mutations in the CETP gene resulting in defective CETP activity have been shown to cause remarkable elevations of plasma HDL-C levels, with the accumulation in plasma of large, buoyant HDL particles enriched in apolipoprotein E. Genetic CETP deficiency thus represents a unique tool to evaluate how structural alterations of HDL impact on HDL atheroprotective functions. Aim of the present study was to assess the ability of HDL obtained from CETP-deficient subjects to protect endothelial cells from the development of endothelial dysfunction. HDL isolated from one homozygous and seven heterozygous carriers of CETP null mutations were evaluated for their ability to down-regulate cytokine-induced cell adhesion molecule expression and to promote NO production in cultured endothelial cells. When compared at the same protein concentration, HDL and HDL3 from carriers proved to be as effective as control HDL and HDL3 in down-regulating cytokine-induced VCAM-1, while carrier HDL2 were more effective than control HDL2 in inhibiting VCAM-1 expression. On the other hand, HDL and HDL fractions from carriers of CETP deficiency were significantly less effective than control HDL and HDL fractions in stimulating NO production, due to a reduced eNOS activating capacity, likely because of a reduced S1P content. In conclusion, the present findings support the notion that genetic CETP deficiency, by affecting HDL particle structure, impacts on HDL vasculoprotective functions. Understanding of these effects might be important for predicting the outcomes of pharmacological CETP inhibition.
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| 4. |
- Kontush, Anatol, et al.
(author)
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Structure of HDL : particle subclasses and molecular components
- 2015
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In: High Density Lipoproteins – from biological understanding to clinical exploitation. - Cham : Springer. - 9783319096643 - 9783319096650 ; , s. 3-51
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Book chapter (peer-reviewed)abstract
- A molecular understanding of high-density lipoprotein (HDL) will allow a more complete grasp of its interactions with key plasma remodelling factors and with cell-surface proteins that mediate HDL assembly and clearance. However, these particles are notoriously heterogeneous in terms of almost every physical, chemical and biological property. Furthermore, HDL particles have not lent themselves to high-resolution structural study through mainstream techniques like nuclear magnetic resonance and X-ray crystallography; investigators have therefore had to use a series of lower resolution methods to derive a general structural understanding of these enigmatic particles. This chapter reviews current knowledge of the composition, structure and heterogeneity of human plasma HDL. The multifaceted composition of the HDL proteome, the multiple major protein isoforms involving translational and posttranslational modifications, the rapidly expanding knowledge of the HDL lipidome, the highly complex world of HDL subclasses and putative models of HDL particle structure are extensively discussed. A brief history of structural studies of both plasma-derived and recombinant forms of HDL is presented with a focus on detailed structural models that have been derived from a range of techniques spanning mass spectrometry to molecular dynamics.
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| 5. |
- Niesor, Eric J., et al.
(author)
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Lipid and Apoprotein Composition of HDL in Partial or Complete CETP Deficiency
- 2012
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In: Current Vascular Pharmacology. - 1570-1611. ; 10:4, s. 422-431
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Journal article (peer-reviewed)abstract
- Hyperalphalipoproteinemia, as observed in patients who are either homozygous or heterozygous for cholesteryl ester transfer protein (CETP) deficiency, has been shown to be associated with striking changes in apolipoprotein size distribution, namely, of high-density lipoprotein (HDL) and HDL-like particles. We compared the effect of varying degrees of CETP activity on the HDL apolipoprotein profile in Caucasian CETP-deficient subjects and following pharmacological decrease in CETP activity, using Size Exclusion Chromatography followed by Reverse Phase Protein Array (SEC RPA). The main HDL-associated apolipoproteins (Apo), i.e. ApoA-I, ApoA-II, ApoC-I, and ApoC-III, co-eluted with the HDL peak. The presence of a HDL-like peak migrating between the ApoB-LDL and ApoA-I-HDL was identified in a Caucasian patient with homozygosity for a point mutation in exon 2 of the CETP gene (c. 109 C > T) resulting in a premature termination codon (R37X) and complete CETP deficiency. This HDL-like peak was not observed either in healthy volunteers treated with the CETP modulator dalcetrapib, patients heterozygous for the same mutation, or in patients heterozygous with G165X mutations. SEC RPA offers the possibility to investigate the distribution of a large number of apolipoproteins simultaneously under non-denaturing separation in normal and dyslipidemic subjects. This is only limited by the availability of antibodies against specific apolipoproteins to be investigated.
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| 6. |
- Pavanello, Chiara, et al.
(author)
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Individuals with familial hypercholesterolemia and cardiovascular events have higher circulating Lp(a) levels.
- 2019
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In: Journal of clinical lipidology. - : Elsevier BV. - 1933-2874. ; 13:5
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Journal article (peer-reviewed)abstract
- Cardiovascular disease (CVD) is a major cause of mortality and morbidity. Increased low-density lipoprotein cholesterol (LDL-C) level is its major risk factor. Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated LDL-C since birth and subsequent premature CVD. There is a heterogeneity in the CVD onset in patients with FH. This is potentially due to the presence of other independent risk factors. Lipoprotein(a) [Lp(a)] is an LDL-like particle and represents a strong risk factor for CVD.Our objective was to understand the contribution of Lp(a) in the susceptibility to CVD in individuals with genetic diagnosis of FH.We measured Lp(a) levels in 2 independent and well-characterized genetic-FH cohorts: the FH-Gothenburg cohort (n=190) and the FH-CEGP Milan cohort (n=160). The genetic diagnosis was performed by targeted next-generation sequencing (FH-Gothenburg and part of the FH-CEGP Milan cohort), or by Sanger sequencing.We show that among individuals with genetic diagnosis of FH, those with previous CVD had higher Lp(a) levels. In addition, analyzing the response to the lipid-lowering therapies, we have also shown that statins had the same LDL-C-lowering effect irrespective of the type of FH-causative mutation. However, when we examined the lipid-lowering effect of proprotein convertase subtilisin/kexin type 9 inhibition by antibodies, we observed a trend in a better reduction of the LDL-C level in carriers of nonsense mutations.In conclusion, our results suggest that Lp(a) contributes to CVD onset in individuals with genetic diagnosis of FH. Our finding supports the importance to identify an efficacious therapy to lower Lp(a) in patients with FH to prevent CVD onset or recurrence.
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| 7. |
- Pedrelli, Matteo, et al.
(author)
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Vasculoprotective Properties of Plasma Lipoproteins from Brown Bears (Ursus arctos)
- 2021
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In: Journal of Lipid Research. - : American Society for Biochemistry and Molecular Biology. - 0022-2275 .- 1539-7262. ; 62
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Journal article (peer-reviewed)abstract
- Plasma cholesterol and triglyceride levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early-stage atherosclerosis development when adult. To explore this apparent paradox, we analysed plasma lipoproteins from the same ten bears in winter (hibernation) and in summer using size exclusion chromatography, ultracentrifugation and electrophoresis. LDL cholesterol binding to arterial proteoglycans, and plasma cholesterol efflux capacity were also evaluated. The data collected and analysed from bears were also compared with those from healthy humans. In bears the cholesterol esters, unesterified cholesterol, triglyceride and phospholipid content of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans, but did not change seasonally in bears. Bear LDL was larger, richer in triglycerides, showed pre-beta electrophoretic mobility and had 5-10 times lower binding to arterial proteoglycans than human LDL. Finally, plasma cholesterol efflux capacity was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL cholesterol for arterial proteoglycans and an elevated cholesterol efflux capacity of bear plasma.
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| 8. |
- Pedrelli, Matteo, et al.
(author)
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Vasculoprotective properties of plasma lipoproteins from brown bears (Ursus arctos)
- 2021
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In: Journal of Lipid Research. - : Elsevier. - 0022-2275 .- 1539-7262. ; 62
-
Journal article (peer-reviewed)abstract
- Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early stage atherosclerosis development when adult. To explore this apparent paradox, we analyzed plasma lipoproteins from the same 10 bears in winter (hibernation) and summer using size exclusion chromatography, ultracentrifugation, and electrophoresis. LDL binding to arterial proteoglycans (PGs) and plasma cholesterol efflux capacity (CEC) were also evaluated. The data collected and analyzed from bears were also compared with those from healthy humans. In bears, the cholesterol ester, unesterified cholesterol, TG, and phospholipid contents of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans but did not change seasonally in bears. Bear LDL was larger, richer in TGs, showed prebeta electrophoretic mobility, and had 5-10 times lower binding to arterial PGs than human LDL. Finally, plasma CEC was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL for arterial PGs and an elevated CEC of bear plasma.
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| 9. |
- Petzold, Axel, et al.
(author)
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Diagnosis and classification of optic neuritis
- 2022
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In: Lancet Neurology. - : ELSEVIER SCIENCE INC. - 1474-4422 .- 1474-4465. ; 21:12, s. 1120-1134
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Research review (peer-reviewed)abstract
- There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.
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| 10. |
- Pina, Ana, et al.
(author)
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Virtual genetic diagnosis for familial hypercholesterolemia powered by machine learning.
- 2020
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In: European journal of preventive cardiology. - : Oxford University Press (OUP). - 2047-4881 .- 2047-4873. ; 27:15, s. 1639-1646
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Journal article (peer-reviewed)abstract
- Familial hypercholesterolemia (FH) is the most common genetic disorder of lipid metabolism. The gold standard for FH diagnosis is genetic testing, available, however, only in selected university hospitals. Clinical scores - for example, the Dutch Lipid Score - are often employed as alternative, more accessible, albeit less accurate FH diagnostic tools. The aim of this study is to obtain a more reliable approach to FH diagnosis by a "virtual" genetic test using machine-learning approaches.We used three machine-learning algorithms (a classification tree (CT), a gradient boosting machine (GBM), a neural network (NN)) to predict the presence of FH-causative genetic mutations in two independent FH cohorts: the FH Gothenburg cohort (split into training data (N=174) and internal test (N=74)) and the FH-CEGP Milan cohort (external test, N=364). By evaluating their area under the receiver operating characteristic (AUROC) curves, we found that the three machine-learning algorithms performed better (AUROC 0.79 (CT), 0.83 (GBM), and 0.83 (NN) on the Gothenburg cohort, and 0.70 (CT), 0.78 (GBM), and 0.76 (NN) on the Milan cohort) than the clinical Dutch Lipid Score (AUROC 0.68 and 0.64 on the Gothenburg and Milan cohorts, respectively) in predicting carriers of FH-causative mutations.In the diagnosis of FH-causative genetic mutations, all three machine-learning approaches we have tested outperform the Dutch Lipid Score, which is the clinical standard. We expect these machine-learning algorithms to provide the tools to implement a virtual genetic test of FH. These tools might prove particularly important for lipid clinics without access to genetic testing.
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