Elsevier

The Lancet

Volume 385, Issue 9984, 6–12 June 2015, Pages 2264-2271
The Lancet

Articles
Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials

https://doi.org/10.1016/S0140-6736(14)61730-XGet rights and content

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.

Introduction

The risk of developing coronary heart disease depends on several factors that are related both to lifestyle and genetics. Heritable factors account for as much as 30–60% of the variation in risk,1, 2 and large-scale studies have identified genetic variants associated with coronary heart disease at stringent levels of statistical significance.3, 4 Previous studies have shown that an assessment of genetic risk burden based on several loci can identify individuals at increased risk for incident coronary heart disease in population-based epidemiological cohorts.5, 6, 7, 8, 9, 10, 11, 12 Additionally, whereas some individual variants have been assessed in isolated studies for an association with recurrent events, an independent association between a multi-locus genetic risk score and recurrent coronary heart disease events has not been clearly shown.13, 14, 15, 16

The clinical benefit from treatments that reduce the likelihood of coronary heart disease events might vary by the degree of risk at baseline. As such, in addition to identifying risk, a genetic risk score consisting of fully studied coronary heart disease risk single-nucleotide polymorphisms (SNPs) might also characterise individuals who will receive the greatest clinical benefit from statin therapy. Such a finding would be of particular interest in the primary prevention setting. Therefore, our study had two main goals: first, to test if a multi-locus genetic risk score based on a combination of 27 loci might predict not only incident coronary heart disease in an epidemiological cohort but also incident or recurrent coronary heart disease events in a clinical trial setting; and second, to assess whether or not the clinical benefit of statin therapy varies by genetic risk score in four randomised controlled trials of statin therapy.

Section snippets

Primary prevention populations

The baseline characteristics of the participants of each study are listed in appendix p 4. In brief, the Malmo Diet and Cancer Study (MDCS)17 is a community-based prospective epidemiological cohort of middle-aged (45–64 years old) individuals from southern Sweden. Genetic samples were available from 27 817 people without documented coronary heart disease at baseline. JUPITER18 was a primary prevention trial that tested rosuvastatin 20 mg daily versus placebo in 17 802 individuals with LDL

Results

Higher genetic risk scores were associated with a raised risk of coronary heart disease, independent of established clinical predictors. Specifically, when evaluating participants in low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk score categories, a gradient of risk for coronary heart disease was evident in the studies (table 2). When the data from the primary prevention cohorts were combined, the multivariable-adjusted hazard ratios (HRs) for incident

Discussion

Large-scale genetic association studies have identified several genetic variants that are individually associated with the risk of coronary heart disease. When combined into a 27-variant risk score, our multivariable-adjusted analyses showed that these variants could identify people at increased risk of coronary heart disease events, including incident coronary heart disease in primary prevention populations and recurrent coronary heart disease events in secondary prevention populations.

References (43)

  • P Deloukas et al.

    Large-scale association analysis identifies new risk loci for coronary artery disease

    Nat Genet

    (2013)
  • SE Humphries et al.

    Candidate gene genotypes, along with conventional risk factor assessment, improve estimation of coronary heart disease risk in healthy UK men

    Clin Chem

    (2007)
  • S Kathiresan et al.

    Polymorphisms associated with cholesterol and risk of cardiovascular events

    N Engl J Med

    (2008)
  • G Thanassoulis et al.

    A genetic risk score is associated with incident cardiovascular disease and coronary artery calcium: the Framingham Heart Study

    Circ Cardiovasc Genet

    (2012)
  • MF Hughes et al.

    Genetic markers enhance coronary risk prediction in men: the MORGAM prospective cohorts

    PLoS One

    (2012)
  • E Tikkanen et al.

    Genetic risk prediction and a 2-stage risk screening strategy for coronary heart disease

    Arterioscler Thromb Vasc Biol

    (2013)
  • A Ganna et al.

    Multilocus genetic risk scores for coronary heart disease prediction

    Arterioscler Thromb Vasc Biol

    (2013)
  • I Buysschaert et al.

    A variant at chromosome 9p21 is associated with recurrent myocardial infarction and cardiac death after acute coronary syndrome: the GRACE Genetics Study

    Eur Heart J

    (2010)
  • E Wauters et al.

    Influence of 23 coronary artery disease variants on recurrent myocardial infarction or cardiac death: the GRACE Genetics Study

    Eur Heart J

    (2013)
  • V Tragante et al.

    The impact of susceptibility loci for coronary artery disease on other vascular domains and recurrence risk

    Eur Heart J

    (2013)
  • G Berglund et al.

    The Malmo Diet and Cancer Study. Design and feasibility

    J Intern Med

    (1993)
  • Cited by (519)

    View all citing articles on Scopus

    Authors contributed equally

    View full text