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  • Review Article
  • Published:

Utility of genetic determinants of lipids and cardiovascular events in assessing risk

Nature Reviews Cardiology volume 8, pages 207–221 (2011)Cite this article

Subjects

Abstract

The prevention of coronary heart disease (CHD) is a major public-health goal, but disease architecture is such that a larger proportion of clinical events occur among the average majority than among the high-risk minority—the prevention paradox. Genetic findings over the past few years have resulted in the reopening of the old debate on whether an individualized or a population-based approach to prevention is preferable. Genetic testing is an attractive tool for CHD risk prediction because it is a low-cost, high-fidelity technology with multiplex capability. Moreover, by contrast with nongenetic markers, genotype is invariant and determined from conception, which eliminates biological variability and makes prediction from early life possible. Mindful of the prevention paradox, this Review examines the potential applications and challenges of using genetic information for predicting CHD, focusing on lipid risk factors and drawing on experience in the evaluation of nongenetic risk factors as screening tests for CHD. Many of the issues we discuss hold true for any late-onset common disease with modifiable risk factors and proven preventative strategies.

Key Points

  • In the past 5 years, the technique of genome-wide association analysis has begun to uncover numerous regions of the genome containing variants that influence blood-lipid levels and risk of coronary heart disease (CHD)

  • Common identified single nucleotide polymorphisms associated with CHD are dispersed across different chromosomes, have modest influence on disease risk, are additive in effect, and explain a small proportion of the observed heritability

  • Challenges in using this type of genetic information to predict individual risk of CHD exist

  • Genome-wide association studies are beginning to provide invaluable new information on causal pathways, which should inform and accelerate the design and development of new treatments

  • Emerging technological advances, including rapid, cost-effective sequencing of whole genomes, are set to further advance understanding of human disease, with prospect of developing better diagnostics and therapies

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Figure 1: Scenarios for genetic screening of a population in which the hypothetical lifetime risk of CHD is 50%.
Figure 2: Relationship between cholesterol level and CHD risk in the general population.
Figure 3: Depiction of the frequency distribution of carriage of the number of alleles conferring susceptibility to CHD.

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Acknowledgements

A. D. Hingorani and S. E. Humphries contributed equally to this article. M. V. Holmes is funded by a Population Health Scientist Fellowship from the Medical Research Council (G0802432). The British Heart Foundation supports P. J Talmud (RG/08/008), A. D. Hingorani (FS 05/125), and S. E Humphries (PG/07/133/24,260). This work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centers funding scheme.

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Authors and Affiliations

  1. Department of Epidemiology and Public Health, Genetic Epidemiology Group, University College London, 1–19 Torrington Place, WC1E 6BT, London, UK

    Michael V. Holmes & Aroon D. Hingorani

  2. Department of Medicine, Center for Cardiovascular Genetics, The Rayne Building, University College London, 5 University Street, WC1E 6JF, London, UK

    Seamus Harrison, Philippa J. Talmud & Steve E. Humphries

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All authors contributed to discussion of content for the article, researched data to include in the manuscript, reviewed and edited the manuscript before submission, and revised the manuscript in response to the peer-reviewers' comments. M. V. Holmes, S. Harrison, A. D. Hingorani and S. E Humphries were also involved in writing the manuscript.

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A. Hingorani is a member of the Editorial Board of the Drug and Therapeutics Bulletin (International Society of Drug Bulletins). He has acted as a consultant to London Genetics and to GlaxoSmithKline. He has received honoraria for speaking at educational meetings but has donated these in large part to various medical charities. The other authors declare no competing interests.

Supplementary information

Supplementary Table 1

Loci and genes for lipids, HDL-C, LDL-C and cholesterol identified by genome wide association studies to date (DOC 533 kb)

Supplementary Table 2

Loci and genes for myocardial infarction and/or coronary artery disease identified by genome wide association studies to date (DOC 79 kb)

Supplementary Box 1

Tools for assessing predictive utility of gene markers (DOC 40 kb)

Supplementary Information

Derivation of values for Table 7 (DOC 43 kb)

Supplementary Glossary of terms (DOC 41 kb)

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Holmes, M., Harrison, S., Talmud, P. et al. Utility of genetic determinants of lipids and cardiovascular events in assessing risk. Nat Rev Cardiol 8, 207–221 (2011). https://doi.org/10.1038/nrcardio.2011.6

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