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Genetic determinants of plasma lipoproteins

Nature Clinical Practice Cardiovascular Medicine volume 4, pages 600–609 (2007)Cite this article

Abstract

The search for common genetic determinants of plasma lipoproteins began in the early 1980s. Despite some exceptions, these efforts have not yet yielded a set of biological markers that can be used in clinical practice. By contrast, successes in defining the molecular basis of rare single-gene disorders, such as familial hypoalphalipoproteinemia, have shown the value of experimental designs that focus on genomic analysis of individuals within the tails of Gaussian distributions of quantitative lipoprotein traits. For example, this strategy showed that a small but relevant proportion of individuals within the <5% tail of plasma HDL-cholesterol distribution have mutations in genes that cause familial hypoalphalipoproteinemia. The value of clinical testing for genomic variants as an adjunct to a biochemical measurement of plasma lipoproteins, however, is at best questionable. A more direct impact of genetic studies is that definitions of 'common' and 'large genetic effects' have become more tempered, reflecting perhaps the biological reality that plasma lipoproteins are probably determined by the aggregate of numerous modest and occasional large genetic effects in addition to environmental factors. Here, we review recent progress on genomic variants and cholesterol metabolism, and discuss the impact these genetic studies will have on clinical cardiology.

Key Points

  • Differences in plasma lipoprotein concentrations throughout a population reflect the different environmental and genetic factors affecting each individual

  • The contribution that a single genetic variable might be expected to have on lipoprotein concentration has been down-sized over the past decade

  • A recent strategy used to identify genes associated with plasma lipoproteins is 'missense-accumulation' analysis—the identification of rare alleles with large effects at extremes of quantitative traits

  • Although genetic research has proven useful in some settings, the clinical utility of 'across the board' genetic screening remains somewhat unsettled at present

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Figure 1: 'Missense-accumulation' analysis.

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Acknowledgements

Support has been provided by the Jacob J Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics, a Career Investigator award from the Heart and Stroke Foundation of Ontario, and operating grants from the Canadian Institutes for Health Research, the Heart and Stroke Foundation of Ontario, the Ontario Research Fund and by Genome Canada through the Ontario Genomics Institute.

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Authors and Affiliations

  1. RL Pollex is a Research Assistant in the Vascular Biology Group and RA Hegele is Director of the Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, ON, Canada.,

    Rebecca L Pollex & Robert A Hegele

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Correspondence to Robert A Hegele.

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Pollex, R., Hegele, R. Genetic determinants of plasma lipoproteins. Nat Rev Cardiol 4, 600–609 (2007). https://doi.org/10.1038/ncpcardio1005

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