Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.
BACKGROUND
Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy.


METHODS
A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis.


RESULTS
When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT.


CONCLUSIONS
A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy.


BACKGROUND
National Institutes of Health.
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
J L
JL
Mega
Cardiovascular Division, Department of Medicine and Division of Statistical Genomics, Washington University School of Medicine, Saint Louis, MO.
N O
NO
Stitziel
Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT; Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
J G
JG
Smith
Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine and Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
D I
DI
Chasman
William Harvey Research Institute, Queen Mary University of London and Barts NIHR CV Biomedical Research Institute, London, United Kingdom.
M
M
Caulfield
Quest Diagnostics, Alameda, CA.
J J
JJ
Devlin
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
F
F
Nordio
Pfizer Research Laboratory, Groton, CT.
C
C
Hyde
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
C P
CP
Cannon
Department of Nutrition, Harvard School of Public Health and Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA.
F
F
Sacks
International Centre for Circulatory Health, National Heart & Lung Institute, Imperial College London, United Kingdom.
N
N
Poulter
International Centre for Circulatory Health, National Heart & Lung Institute, Imperial College London, United Kingdom.
P
P
Sever
Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine and Cardiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
P M
PM
Ridker
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
E
E
Braunwald
Department of Clinical Sciences, Faculty of Medicine, Lund University and Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
O
O
Melander
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT; Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
S
S
Kathiresan
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
M S
MS
Sabatine
D003327:Coronary Disease / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D061366:Numbers Needed To Treat; D011322:Primary Prevention; D012008:Recurrence; D018570:Risk Assessment; D055502:Secondary Prevention; D016896:Treatment Outcome
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors