Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability
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 detec...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/11/1728 |
| _version_ | 1797511099385380864 |
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| author | Jesús Maria Martín-Campos |
| author_facet | Jesús Maria Martín-Campos |
| author_sort | Jesús Maria Martín-Campos |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T05:41:37Z |
| format | Article |
| id | doaj.art-c4c241a5112a4a1790b22baefbe64060 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T05:41:37Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-c4c241a5112a4a1790b22baefbe640602023-11-22T22:32:34ZengMDPI AGBiomedicines2227-90592021-11-01911172810.3390/biomedicines9111728Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” HeritabilityJesús Maria Martín-Campos0Stroke Pharmacogenomics and Genetics Group, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau (IR-HSCSP)–Biomedical Research Institute Sant Pau (IIB-Sant Pau), C/Sant Quintí 77-79, 08041 Barcelona, SpainChanges 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.https://www.mdpi.com/2227-9059/9/11/1728plasma cholesterol levelsautosomal dominant hypercholesterolemiagenetic risk scoresmosaicismmaternal effectepigenetics |
| spellingShingle | Jesús Maria Martín-Campos Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability Biomedicines plasma cholesterol levels autosomal dominant hypercholesterolemia genetic risk scores mosaicism maternal effect epigenetics |
| title | Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability |
| title_full | Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability |
| title_fullStr | Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability |
| title_full_unstemmed | Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability |
| title_short | Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability |
| title_sort | genetic determinants of plasma low density lipoprotein cholesterol levels monogenicity polygenicity and missing heritability |
| topic | plasma cholesterol levels autosomal dominant hypercholesterolemia genetic risk scores mosaicism maternal effect epigenetics |
| url | https://www.mdpi.com/2227-9059/9/11/1728 |
| work_keys_str_mv | AT jesusmariamartincampos geneticdeterminantsofplasmalowdensitylipoproteincholesterollevelsmonogenicitypolygenicityandmissingheritability |