Paul M Ridker

Harvard University, Cambridge, Massachusetts, United States

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Publications (837)10549.55 Total impact

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    ABSTRACT: Fibrinogen, coagulation factor VII (FVII), factor VIII (FVIII), and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities and additional variation may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n=2) and rare (n=10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identify new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information to understanding individual variation in hemostasis pathways. Copyright © 2015 American Society of Hematology.
    Blood 06/2015; DOI:10.1182/blood-2015-02-624551 · 10.43 Impact Factor
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    ABSTRACT: Nonfasting triglycerides are similar or superior to fasting triglycerides at predicting cardiovascular events. However, diagnostic cut points are based on fasting triglycerides. We examined the optimal cut point for increased nonfasting triglycerides. We obtained baseline nonfasting (<8 h since last meal) samples from 6391 participants in the Women's Health Study who were followed prospectively for ≤17 years. The optimal diagnostic threshold for nonfasting triglycerides, determined by logistic regression models by use of c-statistics and the Youden index (sum of sensitivity and specificity minus 1), was used to calculate hazard ratios (HRs) for incident cardiovascular events. Performance was compared to thresholds recommended by the American Heart Association (AHA) and European guidelines. The optimal threshold was 175 mg/dL (1.98 mmol/L), with a c-statistic of 0.656, statistically better than the AHA cut point of 200 mg/dL (c-statistic 0.628). For nonfasting triglycerides above and below 175 mg/dL, after adjusting for age, hypertension, smoking, hormone use, and menopausal status, the HR for cardiovascular events was 1.88 (95% CI 1.52-2.33, P < 0.001), and for triglycerides measured at 0-4 and 4-8 h since the last meal, 2.05 (1.54- 2.74) and 1.68 (1.21-2.32), respectively. We validated performance of this optimal cut point by use of 10-fold cross-validation and bootstrapping of multivariable models that included standard risk factors plus total and HDL cholesterol, diabetes, body mass index, and C-reactive protein. In this study of middle-aged and older apparently healthy women, we identified a diagnostic threshold for nonfasting hypertriglyceridemia of 175 mg/dL (1.98 mmol/L), with the potential to more accurately identify cases than the currently recommended AHA cut point. © 2015 American Association for Clinical Chemistry.
    Clinical Chemistry 06/2015; DOI:10.1373/clinchem.2015.241752 · 7.77 Impact Factor
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    ABSTRACT: b>Background: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI). Methods: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49 066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17 672/31 394 with/without periodontitis); 68 761 participants with BMI and genotype data; and 57 871 participants (18 881/38 990 with/without periodontitis) with data on BMI and periodontitis. Results: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data. Conclusions: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.
    International Journal of Epidemiology 06/2015; DOI:10.1093/ije/dyv075 · 9.20 Impact Factor
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    ABSTRACT: C-reactive protein has been evaluated as a risk factor for breast cancer in epidemiologic studies. However, results from prospective studies are inconsistent. We evaluated the association using pre-diagnostic blood samples in a case-control study nested within the Nurses' Health Study (NHS) and the full cohort of the Women's Health Study (WHS). 943 cases in the NHS and 1919 cases in the WHS contributed to the analysis. Conditional logistic regression and Cox proportional hazards model were used in the NHS and WHS, respectively. We pooled our results with prior prospective studies using random effect meta-analysis. In the NHS, higher CRP levels were associated with a suggestively increased risk of breast cancer (quintile 5 vs. 1: relative risk [RR] = 1.27, 95% confidence interval [CI] = 0.93, 1.73; Ptrend = 0.02); results did not vary significantly by tumor invasiveness or hormone receptor status. However, no association was observed in the WHS for overall risk (quintile 5 vs. 1: RR = 0.89, 95%CI = 0.76, 1.06; Ptrend = 0.38) or by tumor invasiveness or hormone receptor status. The meta-analysis (including 5371 cases from 11 studies) showed a modestly increased risk among women in the highest vs. lowest categories of CRP (RR = 1.26, 95%CI = 1.07, 1.49). Existing data from prospective studies suggest that CRP, a non-specific marker of inflammation, is modestly positively associated with breast cancer risk. Our findings provide support to the concept that inflammation can influence breast cancer development. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 05/2015; DOI:10.1158/1055-9965.EPI-15-0187 · 4.32 Impact Factor
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    ABSTRACT: Natriuretic peptides are positively associated with incident cardiovascular disease (CVD), but data in women, particularly with regard to improvements in risk prediction, are sparse. We measured the N-terminal prohormone form of B-type natriuretic peptide (NT-proBNP) in 480 cases of incident CVD (myocardial infarction, stroke, and cardiovascular death) and a reference subcohort of 564 women from the Women's Health Study who were followed for a median of 12.0 (interquartile range 7.6 to 13.4) years. Median (interquartile range) NT-proBNP concentrations were greater in women who developed CVD (81 ng/l [50 to 147]) than those who did not (64 ng/l [38 to 117]; p <0.0001). For women in the highest compared to the lowest quartile, NT-proBNP was 65% greater after adjusting for established cardiovascular risk factors and kidney function (adjusted hazard ratio [aHR] 1.65, 95% confidence interval [CI] 1.03 to 2.64, p trend = 0.03). When analyzed as a continuous variable, the aHR per 1 - SD difference in Ln(NT-proBNP) was 1.22 (1.03 to 1.44; p = 0.02). The per 1 - SD change in Ln(NT-proBNP) appeared stronger for cardiovascular death (aHR 1.43, 95% CI 1.05 to 1.94, p = 0.02) and stroke (aHR 1.24, 95% CI 1.03 to 1.50, p = 0.03) than myocardial infarction (aHR 1.09, 95% CI 0.87 to 1.37, p = 0.44). When added to traditional risk co-variables, NT-proBNP did not significantly improve the C-statistic (0.751 to 0.757; p = 0.09) or net reclassification into <5%, 5 to <7.5%, and ≥7.5% 10-year CVD risk categories (0.014; p = 0.18). In conclusion, in this prospective study of initially healthy women, NT-proBNP concentrations showed statistically significant association with incident CVD that was independent of traditional cardiovascular risk factors but did not substantially improve measures of CVD risk prediction. Copyright © 2015 Elsevier Inc. All rights reserved.
    The American Journal of Cardiology 05/2015; DOI:10.1016/j.amjcard.2015.05.014 · 3.43 Impact Factor
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    ABSTRACT: Enzymatically glycosylated proteins partake in multiple biological processes, including glucose transport and inflammation. We hypothesized that a novel biomarker (GlycA) of N-acetyl methyl groups originating mainly from N-acetylglucosamine moieties of acute-phase glycoproteins is related to incident type 2 diabetes mellitus and compared it with high-sensitivity C-reactive protein. In 26 508 initially healthy women free of diabetes mellitus, baseline GlycA and high-sensitivity C-reactive protein were quantified by nuclear magnetic resonance spectroscopy and immunoturbidimetry, respectively. During median follow-up of 17.2 years, 2087 type 2 diabetes mellitus cases occurred. In Cox models with adjustment for age, race, smoking, alcohol, activity, menopausal status, hormone use, family history, and body mass index, quartile 4 versus 1 hazard ratios and 95% confidence intervals were 2.67 (2.26-3.14) for GlycA and 3.93 (3.24-4.77) for high-sensitivity C-reactive protein; both P trend <0.0001. Associations for GlycA and high-sensitivity C-reactive protein were attenuated after additionally adjusting for lipids: 1.65 (1.39-1.95) and 2.83 (2.32-3.44), respectively, both P trend <0.0001, and after mutual adjustment: 1.11 (0.93-1.33; P trend=0.10) and 2.57 (2.09-3.16; P trend<0.0001), respectively. Our finding of an association between a consensus glycan sequence common to a host of acute-phase reactants and incident type 2 diabetes mellitus provides further support for inflammation in the development of type 2 diabetes mellitus. Additional studies exploring the role of enzymatic glycosylation in the prevention of type 2 diabetes mellitus are warranted. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000479. © 2015 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 04/2015; 35(6). DOI:10.1161/ATVBAHA.115.305635 · 5.53 Impact Factor
  • PLoS ONE 04/2015; 10(4):e0120758. DOI:10.1371/journal.pone.0120758 · 3.53 Impact Factor
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    Molecular Psychiatry 04/2015; · 15.15 Impact Factor
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    ABSTRACT: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37.
    Molecular Psychiatry 04/2015; DOI:10.1038/mp.2015.37 · 15.15 Impact Factor
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    ABSTRACT: -Epidemiological findings suggest a relationship between Alzheimer's disease (AD), inflammation and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. -Using summary statistics (p-values and odds ratios) from genome-wide association studies of over 200,000 individuals, we investigated overlap in single nucleotide polymorphisms (SNPs) associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides (TG), high- (HDL) and low-density lipoprotein (LDL) levels. We found up to 50-fold enrichment of AD SNPs for different levels of association with CRP, LDL, HDL and TG SNPs using an FDR threshold < 0.05. By conditioning on polymorphisms associated with the four phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across four independent AD cohorts (total n = 29,054 AD cases and 114,824 healthy controls) and discovered two genome-wide significant variants on chromosome 4 (rs13113697, closest gene HS3ST1, odds ratio (OR) = 1.07, 95% confidence interval (CI) = 1.05-1.11, p = 2.86 x 10(-8)) and chromosome 10 (rs7920721, closest gene ECHDC3, OR = 1.07, 95% CI = 1.04-1.11, p = 3.38 x 10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. -We demonstrate genetic overlap between AD, CRP, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci including two genome-wide significant variants conferring increased risk for Alzheimer's disease.
    Circulation 04/2015; DOI:10.1161/CIRCULATIONAHA.115.015489 · 14.95 Impact Factor
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    ABSTRACT: Prospective data to examine the association of homocysteine with age-related macular degeneration (AMD) are limited. We examined the prospective relation of plasma homocysteine level and AMD in a large cohort of apparently healthy women. We evaluated the relationship between baseline levels of plasma homocysteine and incident AMD among 27,479 female health professionals aged 40 years or older. Main outcome measures were total AMD, defined as self-report documented by medical record evidence of an initial diagnosis after randomization, and visually significant AMD, defined as confirmed incident AMD with visual acuity 20/30 or worse attributable to this condition. During an average 10 years of follow-up, a total of 452 cases of AMD, including 182 cases of visually significant AMD, were documented. Women in the highest versus lowest quartile of plasma homocysteine had modestly, but statistically non-significant, increased risks of total AMD (hazard ratio, HR, 1.24, 95% confidence interval, CI, 0.95-1.63; p for trend 0.07) and visually significant AMD (HR 1.41, 95% CI 0.92-2.17; p for trend 0.052) in age- and treatment-adjusted analyses. These prospective data from a large cohort of apparently healthy women do not support a strong role for homocysteine in AMD occurrence.
    Ophthalmic Epidemiology 04/2015; 22(2):85-93. DOI:10.3109/09286586.2015.1012272 · 1.27 Impact Factor
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    ABSTRACT: Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes. © 2015 World Obesity.
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    ABSTRACT: -Cardiac troponin and B-type natriuretic peptide (BNP) concentrations associate with adverse cardiovascular outcome in primary prevention populations. Whether statin therapy modifies this association is poorly understood. -We measured high-sensitivity cardiac troponin I (hsTnI) in 12,956 and BNP in 11,076 participants without cardiovascular disease in the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial before randomization to rosuvastatin 20 mg per day or placebo. Nearly 92% of participants had detectable circulating hsTnI, and 2.9% of men and 4.1% of women had levels above proposed sex-specific reference limits of 36 and 15 ng/L, respectively. hsTnI concentrations in the highest tertile were associated with a first major cardiovascular event (adjusted Hazard Ratio (aHR) 2.19, 95% CI 1.56-3.06; P-trend<0.001). BNP levels in the highest tertile were also associated a first cardiovascular event (aHR 1.94, 95% CI 1.41-2.68, P-trend<0.001). The risk of all-cause mortality was elevated for the highest vs. the lowest tertiles of hsTnI (aHR 2.61, 95% CI 1.81-3.78; P-trend<0.001) and BNP (aHR 1.45, 95% CI 1.03-2.04; P-trend=0.02). Rosuvastatin was equally effective in preventing a first cardiovascular event across categories of hsTnI (aHR range 0.50-0.60) and BNP (aHR range 0.42-0.67) with no statistically significant evidence of interaction (P-interaction=0.53 and 0.20, respectively). -In a contemporary primary prevention population, baseline cardiac troponin I and BNP were associated with the risk of vascular events and all-cause mortality. The benefits of rosuvastatin were substantial and consistent regardless of baseline hsTnI or BNP concentrations. -www.clinicaltrials.gov. Identifier: NCT 00239681.
    Circulation 03/2015; 131(21). DOI:10.1161/CIRCULATIONAHA.114.014522 · 14.95 Impact Factor
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    ABSTRACT: The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98). In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    European Heart Journal 03/2015; DOI:10.1093/eurheartj/ehv072 · 14.72 Impact Factor
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    ABSTRACT: Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 03/2015; DOI:10.1016/j.ajhg.2015.01.019 · 10.99 Impact Factor
  • Paul M Ridker, Lynda Rose, Nancy R Cook
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    ABSTRACT: Current algorithms for statin allocation in primary prevention use epidemiologic estimates of absolute risk. However, a global risk prediction score has not been used as an enrollment criterion in any randomized trial of statin therapy. Moreover, completed statin trials show greater relative risk reductions for those patients at lower levels of absolute risk. Thus, risk calculators that rely solely on epidemiologic modeling do not ensure that those who will benefit are selected for treatment. We propose a hybrid approach to statin prescription for apparently healthy men and women that strongly endorses pharmacologic treatment for those who have estimated 10-year risks ≥7.5% and for whom trial-based evidence supports statin efficacy in primary prevention. Although individuals could still be treated on the basis of absolute risk alone, the hybrid approach is evidence-based, is easily applied in clinical practice, and may increase the transparency of physician-patient interactions concerning prescription of statin therapy in primary prevention. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
    Journal of the American College of Cardiology 03/2015; 65(9):942-948. DOI:10.1016/j.jacc.2014.12.028 · 15.34 Impact Factor
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    ABSTRACT: 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. 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. 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. 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. National Institutes of Health. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet 03/2015; 385(9984). DOI:10.1016/S0140-6736(14)61730-X · 45.22 Impact Factor

Publication Stats

89k Citations
10,549.55 Total Impact Points

Institutions

  • 1992–2015
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1991–2015
    • Brigham and Women's Hospital
      • • Division of Preventive Medicine
      • • Department of Medicine
      • • Donald W. Reynolds Foundation Cardiovascular Clinical Research Center
      • • Center for Cardiovascular Disease Prevention
      • • Division of Rheumatology, Immunology, and Allergy
      Boston, Massachusetts, United States
  • 1989–2015
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2013
    • University of Exeter
      • Medical School
      Exeter, England, United Kingdom
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 2011–2013
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
    • Erasmus MC
      • Department of Epidemiology
      Rotterdam, South Holland, Netherlands
    • University of Cambridge
      • Department of Public Health and Primary Care
      Cambridge, ENG, United Kingdom
    • Vanderbilt University
      • Division of Cardiovascular Medicine
      Nashville, MI, United States
  • 2012
    • McGill University
      • Department of Epidemiology, Biostatistics and Occupational Health
      Montréal, Quebec, Canada
  • 2010
    • Johns Hopkins University
      • Welch Center for Prevention, Epidemiology, and Clinical Research
      Baltimore, Maryland, United States
    • University of Chicago
      • Department of Obstetrics & Gynecology
      Chicago, Illinois, United States
  • 2001–2010
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • Boston Children's Hospital
      • Department of Laboratory Medicine
      Boston, MA, United States
  • 2009
    • University of Groningen
      Groningen, Groningen, Netherlands
    • Broad Institute of MIT and Harvard
      • Program in Medical and Population Genetics
      Cambridge, Massachusetts, United States
    • Baylor University
      Waco, Texas, United States
  • 2008
    • University of Washington Seattle
      • Department of Epidemiology
      Seattle, WA, United States
  • 2005–2008
    • University of California, San Diego
      • Department of Family and Preventive Medicine
      San Diego, CA, United States
    • University of Toronto
      • Division of Cardiac Surgery
      Toronto, Ontario, Canada
    • Florida Atlantic University
      • Department of Biomedical Science
      Boca Raton, Florida, United States
  • 2007
    • Schepens Eye Research Institute
      Boston, Massachusetts, United States
    • Boston Medical Center
      Boston, Massachusetts, United States
    • Beth Israel Deaconess Medical Center
      • Division of Vascular and Endovascular Surgery
      Boston, Massachusetts, United States
  • 2004–2007
    • George Washington University
      Washington, Washington, D.C., United States
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 2001–2006
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 2003
    • Institut Català de la Salut
      Cerdanyola del Vallès, Catalonia, Spain
    • University of Pittsburgh
      • Department of Epidemiology
      Pittsburgh, Pennsylvania, United States
  • 2002
    • The Vascular Group
      Albany, New York, United States
  • 1999
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States
    • McLean Hospital
      • Alcohol and Drug Abuse Research Center
      Cambridge, Massachusetts, United States
  • 1997
    • Magee-Womens Hospital
      Pittsburgh, Pennsylvania, United States