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Metabolic syndrome: from epidemiology to systems biology

Nature Reviews Genetics volume 9, pages 819–830 (2008)Cite this article

Key Points

  • Metabolic syndrome (MetSyn) is a group of metabolic conditions that occur together and promote the development of type 2 diabetes and cardiovascular disease. These include abdominal obesity, insulin resistance, low levels of high-density lipoprotein (HDL), elevated levels of triglycerides, elevated blood pressure, and a pro-inflammatory, pro-thrombotic milieu.

  • MetSyn traits are determined by the interaction of environmental factors, particularly excess calorific intake and a sedentary lifestyle, and genetic factors.

  • Genome-wide association studies have revealed a number of novel genes contributing to MetSyn traits. These include genes affecting obesity, lipoprotein levels, type 2 diabetes, and fasting glucose levels.

  • As yet, only a small fraction of the genetic component of MetSyn traits can be explained by known genes and loci. It is clear that the overall genetic architecture of MetSyn traits must be complex, involving hundreds of genes, with both common and rare variants.

  • Two somewhat unexplored areas that are important in MetSyn are sex differences and maternal nutrition.

  • Studies in rodent models have elucidated some fundamental mechanisms contributing to MetSyn and its relationship to diabetes and cardiovascular disease. These include abnormalities in fuel partitioning and mitochondrial function, inflammation related to obesity, and endoplasmic reticulum stress.

  • It seems unlikely that the complex molecular networks that underlie MetSyn can be fully addressed by traditional genetic and biochemical approaches. Recent studies suggest that systems-based approaches, that look beyond individual components, may be able to model gene–gene and gene–environment interactions in MetSyn.

  • One systems-based approach that is proving particularly useful is the integration of common DNA variation, global expression array analysis and clinical phenotypes. When applied to genetically randomized populations, it has the potential to model causal interactions as well as gene co-expression networks.

Abstract

Metabolic syndrome (MetSyn) is a group of metabolic conditions that occur together and promote the development of cardiovascular disease (CVD) and diabetes. Recent genome-wide association studies have identified several novel susceptibility genes for MetSyn traits, and studies in rodent models have provided important molecular insights. However, as yet, only a small fraction of the genetic component is known. Systems-based approaches that integrate genomic, molecular and physiological data are complementing traditional genetic and biochemical approaches to more fully address the complexity of MetSyn.

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Figure 1: Approaches to identify gene variations that contribute to MetSyn.
Figure 2: Integration of DNA variation, gene expression and clinical phenotypes for analysis of complex traits.

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Acknowledgements

We thank our colleagues for valuable discussion, C. Farber and A. Ghazalpour for help with figures, and R. Chen for secretarial assistance.

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Authors and Affiliations

  1. Department of Medicine and Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, 90095, California, USA

    Aldons J. Lusis

  2. Department of Human Genetics, University of California, Los Angeles, 90095, California, USA

    Aldons J. Lusis & Karen Reue

  3. Department of Biochemistry, University of Wisconsin–Madison, Madison, 53706, Wisconsin, USA

    Alan D. Attie

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  1. Aldons J. Lusis
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Correspondence to Aldons J. Lusis.

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FURTHER INFORMATION

Attie laboratory diabetes database

Genomics of Lipid Associated Disorders Database

Complex Trait Consortium

The GeneNetwork

The Jackson Laboratory, Mouse Phenome Database

Glossary

Insulin resistance

A condition in which normal amounts of insulin are inadequate to produce a normal response from muscle, fat, liver or other cells. Such insulin resistance can result in elevated glucose levels in the blood owing to decreased uptake by cells, as well as effects on glycogen storage and lipid metabolism.

Dyslipidaemia

An abnormal or atypical pattern of lipoproteins in the blood. Examples include low levels of high-density lipoprotein cholesterol (hypoalphalipoproteinaemia), or elevated levels of triglyceride (hypertriglyceridaemia) or cholesterol (hypercholesterolaemia).

Genome-wide association study

(GWA study). An examination of common genetic variation across the genome designed to identify associations with traits such as common diseases. Typically, several hundred thousand SNPs are interrogated using microarray technologies.

High-density lipoprotein

(HDL). One of five classes of lipoproteins in the blood that transport cholesterol and triglycerides between tissues. HDL levels are inversely correlated with cardiovascular disease and thus are hypothesized to be protective, perhaps by removing cholesterol from atheroma.

Heritability

An estimate of the proportion of genetic variation in a population that is attributable to genetic variation among individuals.

Linkage analysis

Analysis of the segregation patterns of alleles or loci in families or experimental crosses. Such analysis is commonly used to map genetic traits by testing whether a trait co-segregates with genetic markers whose chromosomal locations are known.

Quantitative trait locus

(QTL). A genetic locus that influences complex and usually continuous traits, such as blood pressure or cholesterol levels. QTLs are identified using linkage analysis.

Linkage disequilibrium

(LD). In population genetics, LD is the nonrandom association of alleles. For example, alleles of SNPs that reside near one another on a chromosome often occur in nonrandom combinations owing to infrequent recombination. LD is useful in genome-wide association studies as it reduces the number of SNPs that must be interrogated to determine genotypes across the genome. Conversely, strong LD can complicate the identification of functional variants. LD should not be confused with genetic linkage, which occurs when genetic loci or alleles are inherited jointly, usually because they reside on the same chromosome.

Visceral fat

Fat that is located inside the peritoneal cavity, between internal organs, as opposed to subcutaneous fat, which is found under the skin, or intramuscular fat, which is interspersed in skeletal muscle.

Correlation

In statistics, a measure of the strength and direction of a linear relationship between two variables. Usually measured as a correlation coefficient.

Epigenetics

Changes in gene expression that are stable through cell division but do not involve changes in the underlying DNA sequence. The most common example is cellular differentiation, but it is clear that environmental factors, such as maternal nutrition, can influence epigenetic programming.

Ceramide

A family of lipid molecules composed of sphingosine and a fatty acid. In addition to being structural components of lipid bilayers, it is now clear that ceramides can act as signalling molecules.

Oxidative phosphorylation

A metabolic pathway that uses oxidation of nutrients to generate ATP. The electron transport chain in mitochondria is the site of oxidative phosphorylation in eukaryotes.

Haploinsufficiency

A condition in a diploid organism in which a single functional copy of a gene results in a phenotype, such as a disease.

Genetically randomized population

A population in which genotypes are randomized owing to the random assortment of alleles during gametogenesis.

Conditional probability

The probability of an event, A, given the occurrence of some other event, B.

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Lusis, A., Attie, A. & Reue, K. Metabolic syndrome: from epidemiology to systems biology. Nat Rev Genet 9, 819–830 (2008). https://doi.org/10.1038/nrg2468

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