title: Genetic bases of hypertriglyceridemic phenotypes.
abstract: OBJECTIVE
  Hypertriglyceridemia (HTG) is a common diagnosis. Although secondary factors are important for clinical expression, susceptibility to HTG has a strong genetic component, which we review here.
  
  
  RESULTS
  Severe HTG in a few families follows Mendelian - typically autosomal recessive - inheritance of rare loss-of-function mutations in genes such as LPL, APOC2, APOA5, LMF1, and GPIHBP1. In contrast, common complex HTG results from the cumulative influence of small-effect variants (single nucleotide polymorphisms) in genes such as APOA5, GCKR, LPL, and APOB. Intensive resequencing of these four genes has also shown accumulated heterozygous rare variants in HTG patients. Together, more than 20% of the susceptibility to HTG is now accounted for by common and rare variants. Further, classical Fredrickson HTG phenotypes, which were once considered to be distinct based on biochemical features, have a shared genetic architecture.
  
  
  CONCLUSIONS
  Compared to other complex traits, genetic variants account for a high proportion of HTG diagnoses. By tallying the number of HTG risk alleles, it is possible to discriminate between individuals with HTG and normolipidemia, particularly in those with extreme scores. Future directions include finding the missing genetic component and determining whether genetic profiling can help with diagnosis or personalized treatment advice.
authors.affiliation: Departments of Biochemistry and Medicine, Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Johansen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D006953:Hyperlipoproteinemia Type IV / Q000235:genetics* / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000172:deficiency / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics; D018110:Receptors, Lipoprotein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001054:Apolipoproteins A; D002352:Carrier Proteins; C485100:GCKR protein, human; C523701:GPIHBP1 protein, human; C546366:LMF1 protein, human; D008565:Membrane Proteins; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D008071:Lipoprotein Lipase