ArticlesGenetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials
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.
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Authors contributed equally