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LSU Journal Club “Loss-of-Function Mutations in A POC3, Triglycerides, and Coronary Disease”. Scott J. Melton, Pgy 1 July 22, 2014. The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Background.
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LSU Journal Club“Loss-of-Function Mutations in APOC3,Triglycerides, and Coronary Disease” Scott J. Melton, Pgy 1 July 22, 2014 The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute
Background • Plasma TG’s are associated with coronary heart disease • >50% of the variation seen in TG’s is due to genetics • GWAS have identified >150 loci related to plasma lipid that suggest plasma TG-rich lipoproteins influence risk of CHD
Research Questions • 1. To what extent do rare DNA sequence variants contribute to TG levels and risk of CHD? • 2. Are there specific variants associated with lower TG levels and reduced CHD?
Study Design • Meta-analysis of seven population based cohorts • GWAS identified DNA sequence variants were tested for association with plasma TG levels • Race specific vs. multiple race models
Study Design • In a separate cohort, four mutations in APOC3 were then sequenced and tested for association with plasma TG levels • In the Framingham cohort, APOC3 mutations were tested for association with CHD • Levels of plasma APOC3 were tested for association with CHD
Study Design • In a secondary analysis: • In pt’s with angiographic CHD, APOC3 levels were tested for association with total and CV mortality • APOC3 levels and the presence of hepatic fat on CT were also tested for association
Rare Mutations in APOC3 and Plasma Levels of Triglycerides. The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. N Engl J Med 2014;371:22-31
Rare Mutations in APOC3 and Reductions in Plasma Triglyceride Levels. The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. N Engl J Med 2014;371:22-31
Association of Four APOC3 Mutations with Plasma Lipid Levels in Replication Studies. The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. N Engl J Med 2014;371:22-31
Association of APOC3 Loss-of-Function Mutations with Risk of Coronary Heart Disease among 110,970 Participants in 15 Studies. The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. N Engl J Med 2014;371:22-31
Cumulative Probability of Freedom from Coronary Heart Disease (CHD) According to Plasma Level of APOC3 at Baseline in the Framingham Heart Study. The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. N Engl J Med 2014;371:22-31
Conclusions • In 3734 people, several rare variants of APOC3 had an effect on plasma TG levels • Approximately 1:150 carried any one of four protein-altering or splice-site variants • Carriers had • 39% lower TG, 22% higher HDL and 16% lower LDL • Circulating levels of APOC3 were 46% lower • Risk of CHD was 40% lower
Conclusions • APOC3 inhibits lipoprotein lipase • Increases TG-rich lipoproteins leading to increased VLDL’s and chylomicrons • APOC3 also delays clearance of TG-rich lipoprotein remnants • Unlike fibrates and fish oil, reduction in plasma TG’s may be atheroprotective
Limitations • Mechanism of APOC3 atheroprotection:????? • Hepatic steatosis??? • No difference between carriers and non-carriers in this study
Authors • The authors are as follows: Jacy Crosby, M.S., Gina M. Peloso, Ph.D., Paul L. Auer, Ph.D., David R. Crosslin, Ph.D., Nathan O. Stitziel, M.D., Ph.D., Leslie A. Lange, Ph.D., Yingchang Lu, M.D., Ph.D., Zheng-zheng Tang, M.S., He Zhang, Ph.D., George Hindy, M.D., Nicholas Masca, Ph.D., Kathleen Stirrups, Ph.D., StavroulaKanoni, Ph.D., Ron Do, Ph.D., Goo Jun, Ph.D., YounaHu, Ph.D., Hyun Min Kang, Ph.D., ChenyiXue, M.S., AnujGoel, M.Sc., Martin Farrall, F.R.C.Path., Stefano Duga, Ph.D., Pier Angelica Merlini, M.D., Rosanna Asselta, Ph.D., DomenicoGirelli, M.D., OlivieroOlivieri, M.D., Nicola Martinelli, M.D., Ph.D., Wu Yin, Ph.D., Dermot Reilly, Ph.D., Elizabeth Speliotes, M.D., Ph.D., Caroline S. Fox, M.D., KristianHveem, M.D., Ph.D., Oddgeir L. Holmen, M.D., MajidNikpay, Ph.D., Deborah N. Farlow, Ph.D., Themistocles L. Assimes, M.D., Ph.D., Nora Franceschini, M.D., M.P.H., Jennifer Robinson, M.D., Kari E. North, Ph.D., Lisa W. Martin, M.D., Mark DePristo, Ph.D., Namrata Gupta, Ph.D., Stefan A. Escher, Ph.D., Jan-H.kan Jansson, M.D., Natalie Van Zuydam, Ph.D., Colin N.A. Palmer, Ph.D., Nicholas Wareham, M.B., B.S., Ph.D., Werner Koch, M.D., Thomas Meitinger, M.D., Annette Peters, M.D.,WolfgangLieb, M.D., RaimundErbel, M.D., Inke R. Konig, Ph.D., JochenKruppa, M.Sc., FranziskaDegenhardt, M.D., OmriGottesman, M.D., Erwin P. Bottinger, M.D., Christopher J. O’Donnell, M.D., Bruce M. Psaty, M.D., Ph.D., Christie M. Ballantyne, M.D., Goncalo Abecasis,Ph.D., Jose M. Ordovas, Ph.D., OlleMelander, M.D., Ph.D., Hugh Watkins, F.R.C.P., MarjuOrho-Melander, Ph.D., Diego Ardissino,M.D., Ruth J.F. Loos, Ph.D., Ruth McPherson, M.D., Ph.D., Cristen J. Willer, Ph.D., Jeanette Erdmann, Ph.D., Alistair S. Hall, F.R.C.P.,Nilesh J. Samani, F.R.C.P., PanosDeloukas, Ph.D., HeribertSchunkert, M.D., James G. Wilson, M.D., Charles Kooperberg, Ph.D., StephenS. Rich, Ph.D., Russell P. Tracy, Ph.D., Dan-Yu Lin, Ph.D., David Altshuler, M.D., Ph.D., Stacey Gabriel, Ph.D., Deborah A. Nickerson, Ph.D.,Gail P. Jarvik, M.D., Ph.D., L. Adrienne Cupples, Ph.D., Alex P. Reiner, M.D., Eric Boerwinkle, Ph.D., and SekarKathiresan, M.D.
