Biomedicines

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Dear Colleagues,

In 1965, Fredrickson and Lees established the most widely used system to classify hyperlipidemic phenotypes, defining all of them as “familial”, which implied the idea of a Mendelian inheritance of genetic variants with a great phenotypic effect. However, the identification of rare variants in candidate genes led in many cases to explaining the most severe forms, although not the more common and less severe forms. In the case of hypercholesterolemia, variants in classic genes only explain a proportion that does not usually exceed 50% in clinical setting. Genome-wide association studies have identified the existence of common genetic variants at various loci associated with plasma cholesterol level, which could explain the most common forms of hypercholesterolemia through processes such as the accumulation in an individual, or gene–gene and gene–environment interactions.

In this Special Issue, we aim to collect recent advances in the genetic determinants of plasma cholesterol levels, especially related to the development of hyper- and hypocholesterolemia, which includes the identification of new genes, the identification of polygenic forms through scoring systems and their possible application in genetic diagnosis, and the possible existence of complex forms due to gene–gene and gene–environment interactions.

Dr. Jesus M. Martin-Campos
Guest Editor

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Keywords

cholesterol
familial hypercholesterolemia
primary hypocholesterolemia
hypobetalipoproteinemia
genetic risk scores
genetic diagnosis
cardiovascular risk
low-density lipoprotein
genome-wide association studies (GWAS)
gene interactions

Published Papers (2 papers)

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Research

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15 pages, 2662 KiB

Open AccessArticle

Plasminogen Deficiency Significantly Reduces Vascular Wall Disease in a Murine Model of Type IIa Hypercholesterolemia

by Takayuki Iwaki, Tomohiro Arakawa, Mayra J. Sandoval-Cooper, Denise L. Smith, Deborah Donahue, Victoria A. Ploplis, Kazuo Umemura and Francis J. Castellino

Biomedicines 2021, 9(12), 1832; https://doi.org/10.3390/biomedicines9121832 - 4 Dec 2021

Cited by 6 | Viewed by 2059

Abstract

The fibrinolytic system has been implicated in the genesis and progression of atherosclerosis. It has been reported that a plasminogen (Pg) deficiency (Plg^−/−) exacerbates the progression of atherosclerosis in Apoe^−/− mice. However, the manner in which Plg functions in a low-density lipoprotein-cholesterol (LDL-C)-driven model has not been evaluated. To characterize the effect of Pg in an LDL-C-driven model, mice with a triple deficiency of the LDL-receptor (LDLr), along with the active component (apobec1) of the apolipoprotein B editosome complex, and Pg (L^−/−/A^−/−/Plg^−/−), were generated. Atherosclerotic plaque formation was severely retarded in the absence of Pg. In vitro studies demonstrated that LDL uptake by macrophages was enhanced by plasmin (Pm), whereas circulating levels of LDL were enhanced, relative to L^−/−/A^−/− mice, and VLDL synthesis was suppressed. These results indicated that clearance of lipoproteins in the absence of LDLr may be regulated by Pg/Pm. Conclusions: The results from this study indicate that Pg exacerbates atherosclerosis in an LDL-C model of atherosclerosis and also plays a role in lipoprotein modification and clearance. Therefore, controlling the Pg system on macrophages to prevent foam cell formation would be a novel therapeutic approach. Full article

(This article belongs to the Special Issue Advances in the Genetics of Plasma Cholesterol Levels)

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Review

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23 pages, 6702 KiB

Open AccessReview

Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability

by Jesús Maria Martín-Campos

Biomedicines 2021, 9(11), 1728; https://doi.org/10.3390/biomedicines9111728 - 19 Nov 2021

Viewed by 2707

Abstract

Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c. This paper discusses other possibilities for unexplained dyslipidemias associated with LDL-c, such as mosaicism, maternal effect, and induced epigenetic changes. Future studies should consider gene–gene and gene–environment interactions and the development of integrated information about disease-driving networks, including phenotypes, genotypes, transcription, proteins, metabolites, and epigenetics. Full article

(This article belongs to the Special Issue Advances in the Genetics of Plasma Cholesterol Levels)

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