Genetic determinants of plasma triglycerides.
Plasma triglyceride (TG) concentration is reemerging as an important cardiovascular disease risk factor. More complete understanding of the genes and variants that modulate plasma TG should enable development of markers for risk prediction, diagnosis, prognosis, and response to therapies and might help specify new directions for therapeutic interventions. Recent genome-wide association studies (GWAS) have identified both known and novel loci associated with plasma TG concentration. However, genetic variation at these loci explains only ∼10% of overall TG variation within the population. As the GWAS approach may be reaching its limit for discovering genetic determinants of TG, alternative genetic strategies, such as rare variant sequencing studies and evaluation of animal models, may provide complementary information to flesh out knowledge of clinically and biologically important pathways in TG metabolism. Herein, we review genes recently implicated in TG metabolism and describe how some of these genes likely modulate plasma TG concentration. We also discuss lessons regarding plasma TG metabolism learned from various genomic and genetic experimental approaches. Treatment of patients with moderate to severe hypertriglyceridemia with existing therapies is often challenging; thus, gene products and pathways found in recent genetic research studies provide hope for development of more effective clinical strategies.
Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 5K8, Canada.
Christopher T
CT
Johansen
Sekar
S
Kathiresan
Robert A
RA
Hegele
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III / Q000235:genetics; D001054:Apolipoproteins A / Q000235:genetics; D001055:Apolipoproteins B / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics; D044943:Fatty Acid Desaturases / Q000235:genetics; D005260:Female; D058607:Fibric Acids / Q000627:therapeutic use; D055106:Genome-Wide Association Study; D006801:Humans; D015228:Hypertriglyceridemia / Q000188:drug therapy / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D052439:Lipid Metabolism Disorders / Q000208:ethnology; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009525:Niacin / Q000627:therapeutic use; D049294:Phospholipid Transfer Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000037:antagonists & inhibitors; D018110:Receptors, Lipoprotein; D012306:Risk; D014280:Triglycerides / Q000097:blood* / Q000235:genetics*; D051720:Upstream Stimulatory Factors / Q000235:genetics; D044465:White People
C479896:ANGPTL3 protein, human; C437704:APOA5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A; D001055:Apolipoproteins B; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D058607:Fibric Acids; C485100:GCKR protein, human; C523701:GPIHBP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C546366:LMF1 protein, human; C116385:MLXIPL protein, human; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D018110:Receptors, Lipoprotein; C493170:TRIB1 protein, human; D014280:Triglycerides; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; D009525:Niacin; D044943:Fatty Acid Desaturases; D017346:Protein Serine-Threonine Kinases; D008071:Lipoprotein Lipase