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  • Review Article
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The genetics of familial combined hyperlipidaemia

Nature Reviews Endocrinology volume 8, pages 352–362 (2012)Cite this article

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Abstract

Almost 40 years after the first description of familial combined hyperlipidaemia (FCHL) as a discrete entity, the genetic and metabolic basis of this prevalent disease has yet to be fully unveiled. In general, two strategies have been applied to elucidate its complex genetic background, the candidate-gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL or its related traits, with a variable degree of scientific evidence. Some genes influence the FCHL phenotype in many pedigrees, whereas others are responsible for the affected state in only one kindred, thereby adding to the genetic and phenotypic heterogeneity of FCHL. This Review outlines the individual genes that have been described in FCHL and how these genes can be incorporated into the current concept of metabolic pathways resulting in FCHL: adipose tissue dysfunction, hepatic fat accumulation and overproduction, disturbed metabolism and delayed clearance of apolipoprotein-B-containing particles. Genes that affect metabolism and clearance of plasma lipoprotein particles have been most thoroughly studied. The adoption of new traits, in addition to the classic plasma lipid traits, could aid in the identification of new genes implicated in other pathways in FCHL. Moreover, systems genetic analysis, which integrates genetic polymorphisms with data on gene expression levels, lipidomics or metabolomics, will attribute functions to genetic variants in addition to revealing new genes.

Key Points

  • The list of familial combined hyperlipidaemia (FCHL) susceptibility genes is expanding and now comprises approximately 35 genes, each with a different level of scientific evidence

  • Genes that affect the metabolism and clearance of plasma lipoprotein particles have been studied in most detail in patients with FCHL

  • The adoption of new metabolic traits will aid in the identification of genes that are more proximal in the metabolic processes that eventually result in elevated plasma lipoprotein levels

  • The FCHL gene pool consists of a mix of genes, ranging from very rare with substantial effect sizes to more common with only a moderate effect on lipid phenotype

  • Linkage and genome-wide association studies are both hypothesis-free, complementary strategies, but not sufficient to unravel the complex genetic background of FCHL

  • Systems genetic analysis, which integrates genetic polymorphisms with the wealth of information emerging from new genomic and proteomic technologies, should reveal new genes and attribute functions to genetic variants

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Figure 1: Key processes in the pathogenesis of familial combined hyperlipidaemia.

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Authors and Affiliations

  1. Department of Internal Medicine and Endocrinology, Maastricht University Medical Centre, P. Debyelaan 25, Maastricht, 6229, HX, The Netherlands

    Martijn C. G. J. Brouwers, Marleen M. J. van Greevenbroek & Coen D. A. Stehouwer

  2. Department of Internal Medicine, Radboud University Nijmegen Medical Centre, 463 AIG, P. O. Box 9101, Nijmegen, 6500 HB, The Netherlands

    Jacqueline de Graaf & Anton F. H. Stalenhoef

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  1. Martijn C. G. J. Brouwers
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  2. Marleen M. J. van Greevenbroek
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M. C. G. J. Brouwers, M. M. J. van Greevenbroek, J. de Graaf and A. F. H. Stalenhoef researched the data and contributed equally to writing the article. All authors provided a substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Anton F. H. Stalenhoef.

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Brouwers, M., van Greevenbroek, M., Stehouwer, C. et al. The genetics of familial combined hyperlipidaemia. Nat Rev Endocrinol 8, 352–362 (2012). https://doi.org/10.1038/nrendo.2012.15

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