Genes, Lifestyle, and Coronary Artery Disease Amit V. Khera, MD MSc May 30, 2017 Acknowledgements Kathiresan Lab (Broad) Malmö Diet and Cancer Study Connor Emdin, DPhil Isabel Drake, PhD Pradeep Natarajan, MD Olle Melander, MD, PhD Alexander Bick, BS Marju Orho-Melander, PhD Sekar Kathiresan, MD BioImage Study Usman Baber, MD Atherosclerosis Risk in Communities Roxana Mehran, MD Eric Boerwinkle, PhD Daniel Rader, MD Valentin Fuster, MD Women’s Genome Health Study Broad Genomics Platform Daniel Chasman, PhD Namrata Gupta, PhD Nancy Cook, PhD Stacey Gabriel, PhD Paul Ridker, MD Myocardial infarction risk determined by interplay of genetic and lifestyle factors JAMA (1951) Family 27% 14% History Cases Controls N=100 N=146 Clinical interpretation of genetic testing for heart attack risk 100 patients with myocardial infarction Monogenic LDL cholesterol Triglyceride clearance Lipoprotein(a) A monogenic risk pathway mutation identified in 5% of individuals presenting with myocardial infarction 100 patients with Monogenic myocardial infarction Risk LDL cholesterol 3.2-fold LDLR, APOB Triglyceride clearance 2.3-fold LPL, APOA5 Lipoprotein(a) 2.8-fold LPA Clinical interpretation of genetic testing for heart attack risk 100 patients with myocardial infarction Monogenic LDL Cholesterol Triglyceride Clearance Lipoprotein(a) Polygenic Polygenic Risk Score >50 genetic variants associated with myocardial infarction Cases Controls N=60K N=120K Kathiresan Nature Genetics (2009) Samani Nature Genetics (2011) Deloukas Nature Genetics (2013) Nikpay Nature Genetics (2015) u Nature Reviews| Genetics Manuscript number NRG-15-099Kathiresan29|11|16 Author notes Pleasecheck thesefigr escarefully and return any comments/amendmentsthat you might haveto meassoon aspossible. In particular, wewouldulikeyou to check thefollowing: • Dothefigr esconveytheintended message? • Areall thelabelsaccurateand intheright place? • Areall thearrowsintheright place? • Areanychemical structurescorrect? • Haveshapesanducolouursbeenused consistentlyand accuratelythroughout thefigr es? • Haveanyof thefigr esbeenpreviouslypublished,or havetheybeensupplied byacolleague(s) whoisnot anamed author onthearticle? To mark up any corrections, pleaseusethecommenting toolsin thePDF, or print and draw by hand, rather than directly editing thePDFs. Genetic variants associated with myocardial infarction highlight multiple underlying pathways Fig1 Vasodilation LDLcholesterol Triglyceride-rich n ammation Cellularproliferation Vasculartone athwayremainsuncertain andlipoprotein(a) lipoproteins andvascular andnitricoxide remodelling signalling • SORT1 • LPL • IL6R • COL4A1–COL4A2 • GUCY1A3 • PPAP2B • CYP17A1–CNNM2– • PCSK9 • TRIB1 • CXCL12 • MIA3 • EDNRA • WDR12 NT5C2KIAA1462 • APOB • APOA5/A4/ • SH2B3 • REST–NOA1 • NOS3 • VAMP5–VAMP8– • ATP2B1 • ABCG5– C3/A1 • ZC3HC1 • FURIN–FES GGCX • HHIPL1 ABCG8 • ANGPTL4 • 9p21 • ZEB2 • MFGE8–ABHD2 • LPA • PDGFD • AK097927 SMG6–SRRRASD1– • LIPA • SWAP70 • MRAS SMCR3–PEMT • LDLR • KSR2 • SLC22A4–SLC22A5 • UBE2Z–GIP– • APOE • ADAMTS7 • ANKS1A ATP5G1–SNF8 • BCAS3 • PHACTR1 • PMAIP1–MC4R • FLT1 • TCF21 ZNF507 • SMAD3 • KCNK5 • SLC5A3–MRPS6– • PLG KCNE2 • HDAC9 POM121L9P– • ABO ADORA2A • SVEP1 Kathiresan Nature Genetics (2009) NatureReviews|Genetics Samani Nature Genetics (2011) Deloukas Nature Genetics (2013) Nikpay Nature Genetics (2015) Khera & Kathiresan | Nature Reviews Genetics | 2017 Polygenic risk score: Measure of inherited risk for coronary disease Polygenic Risk Score Polygenic risk score: Divide population into genetic risk groups (low, intermediate, high) Bottom 20% Top 20% INTERMEDIATE LOW HIGH Polygenic Risk Score