A mechanism-based operational definition and classification of hypercholesterolemia

Civeira, Fernando; Arca, Marcello; Cenarro, Ana; Hegele, Robert A.

doi:10.1016/j.jacl.2022.09.006

Cited by 34 publications

(20 citation statements)

References 68 publications

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“…Our study has several limitations: (1) The identified variants in APOE gene are rare mutations, and therefore, they explain a small percentage of hyperlipidemias in our population. (2) DBL is a highly fluctuating phenotype, due to changes in body weight, changes in diet, alcohol consumption, etc This phenotype variability makes diagnosis difficult and therefore, the association between the presence of some APOE variants and the presence of DBL may not always be unequivocal.…”

Section: Discussionmentioning

confidence: 92%

“…Subjects were divided according to their lipid phenotype as follows: 1673 patients were diagnosed with isolated hypercholesterolemia (isolated HC) if triglycerides (TG) <150 mg/dL and LDL cholesterol ≥130 mg/dL or apoB ≥120 mg/dL; 1646 were diagnosed of combined hyperlipidemia (CHLP) when TG ≥150 mg/dL and non-HDL cholesterol (HDLc) ≥160 mg/dL or apoB ≥120 mg/dL; 129 patients with isolated hypertriglyceridemia (isolated HTG) when ≥150 mg/dL and non-HDLc <160 mg/dL and apoB <120 mg/dL; and 219 subjects were considered normolipidemic (TG <150 mg/dL and LDL cholesterol <130 mg/dL and apoB <120 mg/dL). 1 Dysbetalipoproteinemia (DBL) was considered when non-HDLc/apoB≥1.7 plus TG/(apoB) ≥1.35, in mg/dL. 12 There were 210 subjects with DBL criteria, all included in the combined hyperlipidemia group.…”

Section: Methodsmentioning

confidence: 99%

“…Traditionally, this genetic component has been assigned as monogenic, polygenic, and complex or multifactorial, depending on whether the phenotype is mainly due to a major and rare gene defect with Mendelian transmission, to a combination of multiple common risk alleles with minor effects, or if is the result of the interaction of the genetic variation in multiple genes with environmental factors, such as overweight or obesity, respectively. 1 Although the genes responsible of many genetic diseases causing hyperlipidemia have already been described, 2 there are still many individuals with the suspicion of genetic defects but without the genetic cause known.…”

mentioning

confidence: 99%

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Contribution of APOE Genetic Variants to Dyslipidemia

Bea

Larrea-Sebal

Marco-Benedí

et al. 2023

ATVB

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BACKGROUND: apo (apolipoprotein) E has crucial role in lipid metabolism. The genetic variation in APOE gene is associated with monogenic disorders and contributes to polygenic hypercholesterolemia and to interindividual variability in cholesterol. APOE rare variants may be involved in the phenotype of genetic hyperlipidemias. METHODS: Exon 4 of APOE were sequenced in all consecutive unrelated subjects with primary hyperlipidemia from a Lipid Unit (n=3667) and 822 random subjects from the Aragon Workers Health Study. Binding affinity of VLDL (very low-density lipoprotein) to LDL receptor of pathogenic predicted apoE variants was analyzed in vitro. Lipoprotein particle number, size, and composition were studied by nuclear magnetic resonance. RESULTS: In addition to common polymorphisms giving rise to APOE2 and APOE4, 14 gene variants were found in exon 4 of APOE in 65 subjects. p.(Leu167del) in 8 patients with isolated hypercholesterolemia and in 8 patients with combined hyperlipidemia. Subjects with p.(Arg121Trp), p.(Gly145Asp), p.(Arg154Ser), p.(Arg163Cys), p.(Arg165Trp), and p.(Arg168His) variants met dysbetalipoproteinemia lipid criteria and were confirmed by nuclear magnetic resonance. VLDL affinity for the LDL receptor of p.(Arg163Cys) and p.(Arg165Trp) heterozygous carriers had intermedium affinity between APOE2/2 and APOE3/3. p.(Gly145Asp) and p.(Pro220Leu) variants had higher affinity than APOE3/3. CONCLUSIONS: APOE genetic variation contributes to the development of combined hyperlipidemia, usually dysbetalipoproteinemia, and familial hypercholesterolemia. The lipid phenotype in heterozygous for dysbetalipoproteinemia-associated mutations is milder than the homozygous APOE2/2-associated phenotype. Subjects with dysbetalipoproteinemia and absence of APOE2/2 are good candidates for the study of pathogenic variants in APOE . However, more investigation is required to elucidate the significance of rarer variants of apoE.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Contribution of APOE Genetic Variants to Dyslipidemia

Bea

Larrea-Sebal

Marco-Benedí

et al. 2023

ATVB

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“…Not all severe hypercholesterolemias are FH [ 8 ]. FH is a genetic disease in which a clear dominant inheritance should be observed within affected families.…”

Section: Genetics and Molecular Basismentioning

confidence: 99%

Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

Taranto

Fortunato

2023

IJMS

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Genetics of Familial Hypercholesterolemia (FH) is ascribable to pathogenic variants in genes encoding proteins leading to an impaired LDL uptake by the LDL receptor (LDLR). Two forms of the disease are possible, heterozygous (HeFH) and homozygous (HoFH), caused by one or two pathogenic variants, respectively, in the three main genes that are responsible for the autosomal dominant disease: LDLR, APOB and PCSK9 genes. The HeFH is the most common genetic disease in humans, being the prevalence about 1:300. Variants in the LDLRAP1 gene causes FH with a recessive inheritance and a specific APOE variant was described as causative of FH, contributing to increase FH genetic heterogeneity. In addition, variants in genes causing other dyslipidemias showing phenotypes overlapping with FH may mimic FH in patients without causative variants (FH-phenocopies; ABCG5, ABCG8, CYP27A1 and LIPA genes) or act as phenotype modifiers in patients with a pathogenic variant in a causative gene. The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. This review aims to report the updates on the genetic and molecular bases of FH with their implication for molecular diagnosis.

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“…both genetic and environmental factors. 3,4 Currently, diagnosis of hypercholesterolemia is based on the serum levels of TC and LDL-C.…”

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confidence: 99%

Identification of multiple plasma lipids as diagnostic biomarkers of hypercholesterolemia and the underlying mechanisms based on pseudo‐targeted lipidomics

Zhao,

Tang,

Cao

et al. 2024

Rapid Comm Mass Spectrometry

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RationaleHypercholesterolemia is an important risk factor for cardiovascular diseases and death. This study performed pseudo‐targeted lipidomics to identify differentially expressed plasma lipids in hypercholesterolemia, to provide a scientific basis for the diagnosis and pathogenesis of hypercholesterolemia.MethodsPseudo‐targeted lipidomic analyses of plasma lipids from 20 patients with hypercholesterolemia and 20 normal control subjects were performed using liquid chromatography–mass spectrometry. Differentially expressed lipids were identified by principal component analysis and orthogonal partial least squares discriminant analysis. Receiver operating characteristic curves were used to identify differentially expressed lipids with high diagnostic value. The Kyoto Encyclopedia of Genes and Genomes pathway database was used to identify enriched metabolic pathways.ResultsWe identified 13 differentially expressed lipids in hypercholesterolemia using variable importance of projection > 1 and p < 0.05 as threshold parameters. The levels of eight sphingomyelins and cholesterol sulfate were higher and those of three triacylglycerols and lysophosphatidylcholine were reduced in hypercholesterolemia. Seven differentially expressed plasma lipids showed high diagnostic value for hypercholesterolemia. Functional enrichment analyses showed that pathways related to necroptosis, sphingolipid signaling, sphingolipid metabolism, and steroid hormone biosynthesis were enriched.ConclusionsThis pseudo‐targeted lipidomics study demonstrated that multiple sphingomyelins and cholesterol sulfate were differentially expressed in the plasma of patients with hypercholesterolemia. We also identified seven plasma lipids, including six sphingomyelins and cholesterol sulfate, with high diagnostic value.

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A mechanism-based operational definition and classification of hypercholesterolemia

Cited by 34 publications

References 68 publications

Contribution of APOE Genetic Variants to Dyslipidemia

Contribution of APOE Genetic Variants to Dyslipidemia

Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

Identification of multiple plasma lipids as diagnostic biomarkers of hypercholesterolemia and the underlying mechanisms based on pseudo‐targeted lipidomics

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