Functional validation of new pathways in lipoprotein metabolism identified by human genetics
Abstract
PURPOSE OF REVIEW: Recent genome-wide association studies (GWAS) have identified approximately 100 genomic loci that are associated with plasma lipid traits, two-thirds of which had never been previously associated with lipoprotein metabolism. Identification of the causal genes and variants, functional validation of these genes and biological pathways, and elucidation of molecular mechanisms is required and poses a daunting task. RECENT FINDINGS: Human genetics have been used to recently 'validate' genes, such as LIPG, SCARB1 and ANGPTL3, which were previously implicated in lipoprotein metabolism through classical wet bench approaches. Additionally, many novel genes have been identified as associated with plasma lipid traits by GWAS, though only relatively few have been functionally validated through targeted sequencing and genetic manipulation in cells and animals. These types of studies have defined new roles in lipid metabolism for the novel lipid genes SORT1 and TRIB1. These examples demonstrate the ways in which human genetics can validate candidate genes, as well as provide a novel discovery that requires functional validation at the bench, and point towards a more complete understanding of the molecular physiology of lipoprotein metabolism. SUMMARY: This review summarizes recent developments in the use of human genetics to validate candidate genes in lipoprotein metabolism as well as in the functional validation of novel GWAS loci associated with plasma lipid traits.
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Few GWAS-significant associations have been confirmed as the true risk variant through molecular, biochemical, or biophysical work.
“Very few of the thousands of GWAS significant associations have been shown using molecular genetics, biochemistry or biophysics to be the actual risk variant38, 109.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [109]
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- Authors
- Bauer, R. C., Stylianou, I. M., & Rader, D. J.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Rader, Daniel J
- Venue
- Current Opinion in Lipidology
- Published
- 2011-04
- Volume
- 22
- Issue
- 2
- Pages
- 123-128
- ISSN
- 0957-9672 (ISSN-L)
- OpenAlex
- W2318829551
- Cited by
- 36
- References
- 38
- Citations by year
- 2026: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 4 · 2014: 1 · 2013: 5 · 2012: 12
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Opinion in Lipidology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- lipoprotein metabolism, genome-wide association study, functional validation, candidate genes, endothelial lipase, scavenger receptor class B type I, ANGPTL3, SORT1, TRIB1, lipid metabolism genes
- MeSH terms
- Angiopoietin-like Proteins, Angiopoietin-Like Protein 3, Animals, Humans, Lipoproteins, Signal Transduction, Models, Animal, Angiopoietins, Scavenger Receptors, Class B, Genome-Wide Association Study
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