2523079777a9e75e7186a449da876254 264723.pdf d123dc6f2e6a00f9edb411e00009c85ec6d69781 264723.pdf 5d50cf455b187922b4511f86a4a01f19859c69ed6a3377631bf2cca2859fd73f 264723.pdf Title: Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability Subject: 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. Keywords: plasma cholesterol levels; autosomal dominant hypercholesterolemia; genetic risk scores; mosaicism; maternal effect; epigenetics Author: Jesús Maria Martín-Campos Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Nov 19 14:23:11 2021 CET ModDate: Fri Nov 19 14:26:31 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 23 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 6862884 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- INTHKG+VnURWPalladioL Type 1 Custom yes yes no 10 0 YFBKEN+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 RJVGVE+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 OKNHGC+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 LPYGPS+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 EBFBTV+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 36 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 58 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 62 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 66 0 TCAESR+CMSY10 Type 1 Builtin yes yes no 92 0 RILWGI+EURM10 Type 1 Builtin yes yes no 112 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 03:22:34 CEST RepresentationInformation: 264723.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 11:59:21 CEST Size: 6862884 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 589 FreeObjects: 5 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Cholesterol Metabolism Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: The Endogenous Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: The Exogenous Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Genetic Determinants of Plasma LDL Cholesterol Levels in the Pregenomic Era Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Children: Item: Title: Monogenic Forms of Hypercholesterolemia Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Monogenic Forms of Hypocholesterolemia Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Genetics of LDL Cholesterol in the Big-Data Era Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: Genes Related to LDL Cholesterol Metabolism Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Apolipoproteins and Lipoprotein Receptors Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Transporters Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Enzymes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Transcription Factors and Transcriptional Modulators Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Other Genes Related to LDL-c Metabolism Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Genes Not Related to LDL Cholesterol Metabolism Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Polygenicity and Polygenic Risk Scores Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Other Causes of High Plasma LDL Cholesterol Levels Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Children: Item: Title: Somatic Mutations/Mosaicism Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Maternal Effect Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Epigenetic Modifications Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: The Future: The Era of System Genetics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Info: Title: Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability Author: Jesús Maria Martín-Campos Subject: 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. 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Link Rect: 59, 135, 95, 145 Annotation: Subtype: Link Rect: 294, 100, 331, 111 Annotation: Subtype: Link Rect: 337, 100, 374, 111 Annotation: Subtype: Link Rect: 301, 65, 338, 76 Annotation: Subtype: Link Rect: 344, 65, 380, 76 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 467, 709, 505, 720 Annotation: Subtype: Link Rect: 95, 687, 133, 697 Annotation: Subtype: Link Rect: 235, 653, 273, 663 Annotation: Subtype: Link Rect: 283, 617, 321, 628 Annotation: Subtype: Link Rect: 374, 583, 411, 594 Annotation: Subtype: Link Rect: 500, 560, 538, 571 Annotation: Subtype: Link Rect: 148, 526, 185, 536 Annotation: Subtype: Link Rect: 333, 502, 371, 513 Annotation: Subtype: Link Rect: 236, 479, 274, 490 Annotation: Subtype: Link Rect: 131, 446, 169, 456 Annotation: Subtype: Link Rect: 417, 410, 454, 421 Annotation: Subtype: Link Rect: 427, 376, 465, 387 Annotation: Subtype: Link Rect: 364, 353, 402, 364 Annotation: Subtype: Link Rect: 239, 330, 276, 341 Annotation: Subtype: Link 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97, 640 Annotation: Subtype: Link Rect: 59, 595, 97, 605 Annotation: Subtype: Link Rect: 59, 561, 97, 571 Annotation: Subtype: Link Rect: 136, 538, 173, 548 Annotation: Subtype: Link Rect: 195, 515, 232, 525 Annotation: Subtype: Link Rect: 132, 491, 170, 502 Annotation: Subtype: Link Rect: 157, 457, 194, 467 Annotation: Subtype: Link Rect: 407, 445, 444, 456 Annotation: Subtype: Link Rect: 391, 422, 429, 433 Annotation: Subtype: Link Rect: 435, 422, 471, 433 Annotation: Subtype: Link Rect: 59, 400, 97, 410 Annotation: Subtype: Link Rect: 103, 400, 139, 410 Annotation: Subtype: Link Rect: 145, 365, 182, 375 Annotation: Subtype: Link Rect: 188, 365, 224, 375 Annotation: Subtype: Link Rect: 238, 341, 276, 352 Annotation: Subtype: Link Rect: 281, 307, 318, 318 Annotation: Subtype: Link Rect: 317, 284, 354, 295 Annotation: Subtype: Link Rect: 245, 249, 282, 260 Annotation: Subtype: Link Rect: 95, 227, 133, 237 Annotation: Subtype: Link Rect: 519, 203, 557, 214 Annotation: Subtype: Link Rect: 266, 180, 304, 191 Annotation: Subtype: Link Rect: 190, 157, 228, 168 Annotation: Subtype: Link Rect: 253, 135, 291, 145 Annotation: Subtype: Link Rect: 109, 100, 146, 111 Annotation: Subtype: Link Rect: 408, 65, 446, 76 Page: Sequence: 22 Annotations: Annotation: Subtype: Link Rect: 104, 710, 141, 720 Annotation: Subtype: Link Rect: 499, 686, 536, 697 Annotation: Subtype: Link Rect: 288, 652, 325, 663 Annotation: Subtype: Link Rect: 520, 629, 557, 640 Annotation: Subtype: Link Rect: 104, 595, 142, 605 Annotation: Subtype: Link Rect: 430, 571, 468, 582 Annotation: Subtype: Link Rect: 442, 537, 480, 548 Annotation: Subtype: Link Rect: 310, 514, 347, 525 Annotation: Subtype: Link Rect: 423, 491, 460, 502 Annotation: Subtype: Link Rect: 131, 457, 169, 467 Annotation: Subtype: Link Rect: 59, 411, 97, 421 Annotation: Subtype: Link Rect: 166, 377, 204, 387 Annotation: Subtype: Link Rect: 375, 353, 412, 364 Annotation: Subtype: Link Rect: 108, 331, 146, 341 Annotation: Subtype: Link Rect: 503, 307, 541, 318 Annotation: Subtype: Link Rect: 183, 273, 221, 283 Annotation: Subtype: Link Rect: 225, 226, 263, 237 Annotation: Subtype: Link Rect: 286, 204, 324, 214 Annotation: Subtype: Link Rect: 330, 204, 366, 214 Annotation: Subtype: Link Rect: 440, 180, 478, 191 Annotation: Subtype: Link Rect: 484, 180, 520, 191 Annotation: Subtype: Link Rect: 371, 157, 408, 168 Annotation: Subtype: Link Rect: 506, 134, 543, 145 Annotation: Subtype: Link Rect: 520, 100, 557, 111 Annotation: Subtype: Link Rect: 310, 65, 348, 76 Page: Sequence: 23 Annotations: Annotation: Subtype: Link Rect: 302, 721, 340, 732 Annotation: Subtype: Link Rect: 183, 687, 221, 697 Annotation: Subtype: Link Rect: 176, 653, 214, 663 Annotation: Subtype: Link Rect: 192, 618, 230, 628 Annotation: Subtype: Link Rect: 261, 594, 298, 605 Annotation: Subtype: Link Rect: 520, 571, 557, 582 Annotation: Subtype: Link Rect: 431, 538, 469, 548 Annotation: Subtype: Link Rect: 95, 515, 132, 525 Annotation: Subtype: Link Rect: 161, 491, 199, 502 Annotation: Subtype: Link Rect: 215, 457, 252, 467 Annotation: Subtype: Link Rect: 104, 423, 141, 433 Annotation: Subtype: Link Rect: 444, 399, 481, 410 Annotation: Subtype: Link Rect: 199, 365, 236, 375 Annotation: Subtype: Link Rect: 82, 331, 119, 341 Annotation: Subtype: Link Rect: 494, 307, 532, 318 Annotation: Subtype: Link Rect: 484, 272, 522, 283 Annotation: Subtype: Link Rect: 253, 238, 290, 249 Annotation: Subtype: Link Rect: 297, 238, 333, 249 Annotation: Subtype: Link Rect: 519, 226, 557, 237 Annotation: Subtype: Link Rect: 59, 215, 95, 226 Annotation: Subtype: Link Rect: 246, 192, 284, 203 Annotation: Subtype: Link Rect: 290, 192, 326, 203 Checksum: cd12e2ee Type: CRC32 Checksum: 2523079777a9e75e7186a449da876254 Type: MD5 Checksum: d123dc6f2e6a00f9edb411e00009c85ec6d69781 Type: SHA-1