Summary 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. Findings 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. Interpretation 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. Funding National Institutes of Health.
Association of the Trp719Arg Polymorphism in Kinesin-Like Protein 6 With Myocardial Infarction and Coronary Heart Disease in 2 Prospective Trials: The CARE and WOSCOPS Trials Olga A. Iakoubova, ...Carmen H. Tong, Charles M. Rowland, Todd G. Kirchgessner, Bradford A. Young, Andre R. Arellano, Dov Shiffman, Marc S. Sabatine, Hannia Campos, Christopher J. Packard, Marc A. Pfeffer, Thomas J. White, Eugene Braunwald, James Shepherd, James J. Devlin, Frank M. Sacks The Trp719Arg polymorphism in KIF6 was associated with recurrent myocardial infarction in the CARE (Cholesterol And Recurrent Events) trial and with primary CHD in the WOSCOPS (West of Scotland Coronary Prevention Study) trial. In placebo-treated patients, carriers of the KIF6 719Arg allele (59.4% of the CARE trial cohort) had an adjusted hazard ratio of 1.50 (95% confidence interval CI 1.05 to 2.15) in the CARE trial and an adjusted odds ratio of 1.55 (95% CI 1.14 to 2.09) in the WOSCOPS trial. Among carriers of the KIF6 719Arg risk allele, the absolute risk reduction by pravastatin was 4.89% (95% CI 1.81% to 7.97%) in the CARE trial and 5.49% (95% CI 3.52% to 7.46%) in the WOSCOPS trial
Abstract Background The National Comprehensive Cancer Network recommends that women who carry gene variants that confer substantial risk for breast cancer consider risk-reduction strategies, that is, ...enhanced surveillance (breast magnetic resonance imaging and mammography) or prophylactic surgery. Pathogenic variants can be detected in women with a family history of breast or ovarian cancer syndromes by multigene panel testing. Objectives To investigate whether using a seven-gene test to identify women who should consider risk-reduction strategies could cost-effectively increase life expectancy. Methods We estimated effectiveness and lifetime costs from a payer perspective for two strategies in two hypothetical cohorts of women (40-year-old and 50-year-old cohorts) who meet the National Comprehensive Cancer Network–defined family history criteria for multigene testing. The two strategies were the usual test strategy for variants in BRCA1 and BRCA2 and the seven-gene test strategy for variants in BRCA1 , BRCA2 , TP53 , PTEN , CDH1 , STK11 , and PALB2 . Women found to have a pathogenic variant were assumed to undergo either prophylactic surgery or enhanced surveillance. Results The incremental cost-effectiveness ratio for the seven-gene test strategy compared with the BRCA1/2 test strategy was $42,067 per life-year gained or $69,920 per quality-adjusted life-year gained for the 50-year-old cohort and $23,734 per life-year gained or $48,328 per quality-adjusted life-year gained for the 40-year-old cohort. In probabilistic sensitivity analysis, the seven-gene test strategy cost less than $100,000 per life-year gained in 95.7% of the trials for the 50-year-old cohort. Conclusions Testing seven breast cancer–associated genes, followed by risk-reduction management, could cost-effectively improve life expectancy for women at risk of hereditary breast cancer.
Evidence from multiple large prospective studies suggests that a common polymorphism that encodes an arginine (Arg)–to–tryptophan substitution at position 719 in the KIF6 gene is associated with ...coronary heart disease (CHD) and reduction in coronary events from statin therapy. Carriers of the 719Arg allele were at greater risk for primary and secondary CHD events, and statin therapy significantly reduced coronary events in 719Arg carriers but not in noncarriers. The number needed to treat to prevent a single CHD event ranged from 10 to 20 for 719Arg carriers, compared to >80 for noncarriers in the Cholesterol and Recurrent Events (CARE) study, the West of Scotland Coronary Prevention Study (WOSCOPS), the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT–TIMI22) study. In conclusion, assessment of 719Arg carrier status holds promise for stratification of coronary event risk and for selection of optimal therapy in primary and secondary CHD prevention.
A Kinesin Family Member 6 Variant Is Associated With Coronary Heart Disease in the Women’s Health Study Dov Shiffman, Daniel I. Chasman, Robert Y. L. Zee, Olga A. Iakoubova, Judy Z. Louie, James J. ...Devlin, Paul M. Ridker The 719Arg allele of KIF6 was previously found to be associated with risk of coronary heart disease (CHD) in the ARIC (Atherosclerosis Risk In Communities), CARE (Cholesterol And Recurrent Events), and WOSCOPS (West of Scotland Coronary Prevention Study) trials. In Caucasian participants of the WHS (Women’s Health Study), carriers of the 719Arg allele had increased risk of CHD (adjusted hazard ratio HR = 1.24 95% confidence interval (CI) 1.04 to 1.46, p = 0.013) and myocardial infarction (adjusted HR = 1.34 95% CI 1.02 to 1.75, p = 0.034) but not ischemic stroke.
The lack of significant association of apoB with CVD in this study, and the correspondingly modest effect of apoB adjustment on the association of LDL-P with CVD, may reflect the fact that apoB is a ...measure of all very low-density lipoprotein, intermediate-density lipoprotein, and LDL particles, and of these, LDL was predominantly associated with CVD in this study. ...among subjects who were not classified into 1 of the 4 statin benefit groups, lipoprotein subfractions were independently associated with CVD.
Polymorphism in KIF6 Gene and Benefit From Statins After Acute Coronary Syndromes: Results from the PROVE IT-TIMI 22 Study Olga A. Iakoubova, Marc S. Sabatine, Charles M. Rowland, Carmen H. Tong, ...Joseph J. Catanese, Koustubh Ranade, Katy L. Simonsen, Todd G. Kirchgessner, Christopher P. Cannon, James J. Devlin, Eugene Braunwald Benefit from intensive statin therapy was significantly greater in KIF6 719Arg carriers (adjusted hazard ratio HR 0.59, 95% confidence interval CI 0.45 to 0.77) than in noncarriers (adjusted HR 0.94, 95% CI 0.70 to 1.27; adjusted p = 0.018 for interaction between 719Arg carrier status and treatment). Absolute risk reduction was 10.0% in carriers versus 0.8% in noncarriers. The benefit of intensive therapy in carriers was significant as early as day 30 of therapy; in contrast, no significant benefit was observed in noncarriers.
A previous genetic analysis of the Cholesterol and Recurrent Events (CARE) trial found that carriers of the 719Arg allele of the kinesin family member 6 gene ( KIF6 ) (rs20455), but not noncarriers, ...received significant event reduction from pravastatin therapy. However, that previous analysis of CARE included only Caucasian patients and was limited to the myocardial infarction components of the primary end point. Therefore, the aim of this study was to investigate whether pravastatin therapy reduced primary end point events in KIF6 719Arg carriers and noncarriers, separately, in the combined ethnic groups of CARE. The effect of pravastatin therapy on primary end point events (fatal coronary event or nonfatal myocardial infarction) was investigated in Cox regression models that adjusted for population structure using either self-reported ethnicity or the principal components of genetic heterogeneity. After adjustment for age, gender, and self-reported ethnicity, pravastatin therapy reduced events in carriers of KIF6 719Arg (hazard ratio HR 0.63, 95% confidence interval CI 0.49 to 0.83) but not in noncarriers (HR 1.01, 95% CI 0.69 to 1.45) (p for interaction = 0.049). After adjustment for age, gender, traditional risk factors, and principal components, pravastatin therapy reduced events in carriers of 719Arg (HR 0.64, 95% CI 0.49 to 0.85) but not in noncarriers (HR 0.90, 95% CI 0.62 to 1.32) (p for interaction = 0.14). In conclusion, in an analysis that included CARE patients of all ethnic groups, pravastatin therapy significantly and substantially reduced primary end point events in carriers of the KIF6 719Arg allele but not in noncarriers.
Abstract Background Aspirin use for the primary prevention of cardiovascular disease (CVD) is controversial because of the need to balance the risk of major bleeding events caused by aspirin with the ...benefit of CVD events prevented by aspirin. The United States Preventive Services Task Force (USPSTF) proposed guidelines that use CVD risk thresholds, based on the Framingham Risk Score, to identify patients likely to benefit from aspirin use. Genetic information could be used to modify this CVD risk assessment; for example, 2 variants of the LPA gene, which encodes apolipoprotein(a), are associated with increased risk of CVD. Objectives To estimate the incremental cost-effectiveness of using genetic test results for 2 LPA variants to derive modified Framingham Risk Score estimates and to use these estimates to identify patients likely to benefit from aspirin use according to USPSTF guidelines for aspirin use in the primary prevention of CVD. Methods A cost-effectiveness model of 1 million patients representative of the US population was developed based on the association of 2 LPA variants (rs3798220 and rs10455872) with CVD. The cost of testing was estimated for patients whose 10-year CVD risk would exceed the USPSTF treatment threshold if they were to test positive for the LPA variants. Patient utility estimates for myocardial infarction and stroke, and cost estimates (using a 3.5% annual discount rate) for myocardial infarction, stroke, and gastrointestinal bleeding events were based on published estimates. Results Recommending aspirin to patients whose CVD risk surpassed the risk threshold when LPA information was included in their risk assessment would prevent an estimated 65 CVD events over 10 years. At a genetic test cost of $150, the incremental cost-utility of testing for LPA variants is estimated at $24,942 per quality-adjusted life-year. Conclusions LPA genotyping in the context of the aspirin use guidelines for primary prevention of CVD could be cost-effective.
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