Genetics and the prevention of CAD Presented by: Robert Roberts, MD, FRCPC, MACC, FAHA, FRSC Professor and Departmental Chair ISCTR University of Arizona College of Medicine Phoenix Past President and CEO, University of Ottawa Heart Institute Founding Director, Ruddy Canadian Cardiovascular Genetics Centre Scientist Emeritus and Advisor, University of Ottawa Heart Institute No Disclosures
Genetics of Coronary Artery Disease GENETIC PREDISPOSITION 50% of susceptibility to CAD is genetic 10% of CAD occurs before the age of 50, with genetic predisposition being the predominate risk factor in this subgroup Lloyd Jones et al. JAMA 2004;(291)2204-11 Maremberg et al. NEJM. 1994;(330)1041-46
GENETICS OF CORONARY ARTERY DISEASE AND MYOCARDIAL INFARCTION 50 genetic risk variants for CAD of genome-wide significance have been identified and replicated in independent populations Nature Genetics Jan 2013;Vol.45
GENETIC VARIANTS OF CAD Genome Wide Significant p- value 0.00000005 (5x10-8 ) Nature Genetics Jan 2013;Vol.45
CARDIoGRAMplusC4D Discovery Population: 194,527 Replication Population: 15,613 TOTAL : 210,140 Nature Genetics 2013 Jan;45(1):25-33
Common Genetic risk Variants for Coronary Artery Disease 1. Genetic variants for CAD occur commonly. 50% occur in over 50% of the population 30% occur in over 75% of the population 2. Each genetic risk variant exerts minimal risk averaging about 17% relative risk Roberts, Circ Res. 2014 Jun 6;114(12):1890-903
IMPORTANT IMPLICATIONS FOR FUTURE PREVENTION AND THERAPY 35 of the 50 genetic variants predisposing to CAD mediate their risk through UNKNOWN risk factors Roberts, Circ Res. 2014 Jun 6;114(12):1890-903
Percent of Population Distribution of Genetic Risk Variants Associated with CAD Ottawa Heart Genomic Study (n=14,495) Cases Controls Genetic Risk Score (cgrs) based on 21 genetic variants Roberts, Circ Res. 2014 Jun 6;114(12):1890-903
GENETIC RISK OF CORONARY ARTERY DISEASE AND MYOCARDIAL INFARCTION Risk for CAD is proportional to the number of genetic risk variants, rather than the risk of a specific variant Nature Genetics Jan 2013;Vol.45
Prevention of Coronary Artery Disease HYPOTHESIS: The Comprehensive prevention of CAD will require treatment of genetic risk factors in addition to conventional risk factors
CLINICAL APPLICATION OF GENETIC VARIANTS FOR CAD In this study 27 of the known genetic variants for CAD were genotyped and analyzed in a sample size of 48,421 selected from clinical trials
CLINICAL APPLICATION OF GENETIC VARIANTS FOR CAD Population Genotyped Primary prevention clinical trial JUPITER ASCOT Secondary prevention clinical trial CARE PROVE-IT-TIMI 22 Community cohort Malmo diet and cancer study
The 27 Known Genetic Risk Variants for CAD selected for this study
CLINICAL APPLICATION OF GENETIC RISK VARIANTS FOR CAD TO PREDICT CARDIAC EVENTS OBJECTIVE: To determine whether the 27 genetic risk variants, after adjusting for traditional risk factors, would further risk stratify for CAD events
CLINICAL APPLICATION OF GENETIC RISK VARIANTS FOR CAD TO PREDICT CARDIAC EVENTS Traditional risk factors adjusted for in the analysis: Age Sex Smoking Hypertension FAMILY HISTORY HDL and LDL cholesterol Diabetes Race
ESTIMATION OF THE INDIVIDUAL GENETIC RISK SCORE Sum of the number of Risk alleles for CAD inherited by the individual weighted by the log of the odds ratio
GENETIC RISK VARIANTS IMPROVE STRATIFICATION FOR CARDIAC EVENTS
GENETIC RISK VARIANTS FOR CAD ARE INDEPENDENT PREDICTORS OF CARDIAC EVENTS Genetic Stratification of the Jupiter Clinical Trial Genetic Score Odds Ratio Low risk 1.00 Intermediate risk 1.30 High risk 1.70
GENETIC RISK VARIANTS ARE INDEPENDENT PREDICTORS OF CAD EVENTS AND THE RESPONSE TO STATIN THERAPY Genetic Score Reduction in Events (Statins) Low risk 34% Intermediate risk 32% High risk 50%
GENETIC RISK VARIANTS PREDICT RESPONSE TO STATIN THERAPY IN EACH RISK GROUP
GENETIC RISK VARIANTS CAN BE USED TO SELECT CAD CANDIDATES WHO WILL RECEIVE THE GREATEST THERAPEUTIC BENEFIT Genetic Score Prevention of Primary Event (number to treat) Low risk 66 Intermediate risk 42 High risk 25
GENETIC RISK VARIANTS ARE INDEPENDENT PREDICTORS OF CAD EVENTS WITH THERAPEUTIC IMPLICATIONS In the primary prevention trials there was roughly a threefold difference between the low and high genetic risk groups for the number of patients needed to be treated to prevent one CAD event
GENETIC RISK VARIANTS ARE INDEPENDENT PREDICTORS OF CAD EVENTS WITH THERAPEUTIC IMPLICATIONS Genetic Score Prevention of Secondary Event (number of patients to treat) Low risk 57 Intermediate risk 42 High risk 20
GENETIC RISK VARIANTS ARE INDEPENDENT PREDICTORS OF CAD EVENTS AND THE RESPONSE TO STATIN THERAPY 1% absolute risk reduction by statin therapy is associated with a significant gradient when stratified for Genetic Risk: Genetic Risk Group Absolute Risk Reduction High risk group 1.71% Intermediate risk group 0.71% Low risk group 0.29%
GENETIC RISK VARIANTS ARE INDEPENDENT PREDICTORS OF CAD EVENTS AND THE RESPONSE TO STATIN THERAPY Genetic risk variants for CAD predict primary and secondary events independent of traditional risk factors Genetic variants provide further stratification for risk over and above traditional risk factors Genetic risk variants for CAD can identify on an individual basis, those with the greatest response to statin therapy.
Advantage of Genetic Variants over Conventional Biomarkers ONE venipuncture per lifetime since one s DNA does not change over one s lifetime Roberts, Circ Res. 2014 Jun 6;114(12):1890-903
Advantage of Genetic Variants over Conventional Biomarkers Genetic Risk for CAD is the Same at Birth as at Death so can be used to select candidates for Primary Prevention Roberts, Circ Res. 2014 Jun 6;114(12):1890-903
I would like to express my appreciation to all the collaborating Investigators associated with CARDIoGRAMplusC4D
DR. RUTH MCPHERSON S LABORATORY DR. GEORGE WELLS STATISTICAL METHODS CENTRE RUDDY CANADIAN CARDIOVASCULAR GENETICS CENTRE GENETICS GROUP DR. ALEX STEWART S LABORATORY
Acknowledgements Robert Roberts, MD, FRCPC, MACC GRANT SUPPORT The Canadian Institutes of Health Research, CIHR #MOP82810 The Canada Foundation for Innovation, CFI #11966