title: Functional validation of new pathways in lipoprotein metabolism identified by human genetics.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute for Translational Medicine and Therapeutics and Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bauer
authors.forename: Ioannis M
authors.initials: IM
authors.lastname: Stylianou
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055106:Genome-Wide Association Study; D006801:Humans; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism*; D023421:Models, Animal; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C479896:ANGPTL3 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D008074:Lipoproteins; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B