title: Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis.
abstract: Observational epidemiological studies have associated plasma lipid concentrations with risk for coronary heart disease (CHD), but these studies cannot distinguish cause from mere correlation. Human genetic studies, when considered with the results of randomized controlled trials of medications, can potentially shed light on whether lipid biomarkers are causal for diseases. Genetic analyses and randomized trials suggest that low-density lipoprotein is causal for CHD, whereas high-density lipoprotein is not. Surprisingly, human genetic evidence suggests that lipoprotein(a) and triglyceride-rich lipoproteins causally contribute to CHD. Gene variants leading to higher levels of plasma apolipoprotein B-containing lipoproteins [low-density lipoprotein, triglyceride-rich lipoproteins, or lipoprotein(a)] consistently increase risk for CHD. For triglyceride-rich lipoproteins, the most compelling evidence revolves around lipoprotein lipase and its endogenous facilitator (APOA5 [apolipoprotein A-V]) and inhibitory proteins (APOC3 [apolipoprotein C-III], ANGPTL4 [angiopoietin like 4]). Combined, these genetic results anticipate that, beyond low-density lipoprotein, pharmacological lowering of triglyceride-rich lipoproteins or lipoprotein(a) will reduce risk for CHD, but this remains to be proven through randomized controlled trials.
authors.affiliation: From the Department of Medicine, Harvard Medical School, Boston, MA (K.M., S.K.); Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (K.M.); Broad Institute of MIT and Harvard, Cambridge, MA (K.M., S.K.); and Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.K.).
authors.forename: Kiran
authors.initials: K
authors.lastname: Musunuru
authors.affiliation: From the Department of Medicine, Harvard Medical School, Boston, MA (K.M., S.K.); Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (K.M.); Broad Institute of MIT and Harvard, Cambridge, MA (K.M., S.K.); and Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.K.). skathiresan@partners.org.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000097:blood / Q000235:genetics; D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D003324:Coronary Artery Disease / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D050171:Dyslipidemias / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000235:genetics*; D017270:Lipoprotein(a) / Q000097:blood / Q000235:genetics; D010641:Phenotype; D011322:Primary Prevention / Q000379:methods; D011379:Prognosis; D018570:Risk Assessment; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005819:Genetic Markers; D000960:Hypolipidemic Agents; D017270:Lipoprotein(a); D014280:Triglycerides; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human
keywords: atherosclerosis; coronary disease; genetics; lipoproteins; triglycerides