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Genetic determinants of the metabolic syndrome

Abstract

The metabolic syndrome is a commonly encountered clinical phenotype presenting as concurrent metabolic abnormalities, including central obesity, dysglycemia, dyslipidemia, and hypertension. Several definitions exist, and it is debated whether or not the clustered risk factors impart a higher cardiovascular risk than the simple sum of the individual components. Nevertheless, the concept of a metabolic syndrome has proven helpful in emphasizing the importance of obesity, insulin resistance and related traits in relation to cardiovascular disease risk. Furthermore, the metabolic syndrome as defined by the National Cholesterol Education Program appears to have a component of heritability, which suggests a genetic basis. Indeed, patients with certain rare single-gene disorders express clusters of abnormalities commonly seen in the metabolic syndrome. Moreover, studies indicate that common genetic variants are associated with the development of this syndrome, although the associations are quite weak and replication of findings has been poor. As with most complex traits, it is premature to propose molecular genetic testing for diagnosis, treatment or both. Unresolved issues include the roles of gene–environment interactions, ethnicity, and sex. In this review, we look at the currently available evidence for common genes that predispose to the development of the metabolic syndrome.

Key Points

  • The metabolic syndrome is a common phenotype that imparts increased risk of cardiovascular disease and diabetes

  • A single clinically operative definition of the metabolic syndrome is not yet available, but is evolving

  • The metabolic syndrome is defined by cut-off points applied to abdominal obesity, blood pressure, blood glucose, and plasma triglyceride and HDL-cholesterol concentrations

  • Genetic studies on the metabolic syndrome have been attempted and a genetic contribution appears to exist

  • No consistent or replicated genetic test is currently available that can be used clinically in the diagnosis, treatment, or both of the metabolic syndrome

  • Environmental factors and complex gene–environment interactions also play an important part in metabolic syndrome expression

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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 and Development Challenge Fund (Project #0507) and by Genome Canada.

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Correspondence to Robert A Hegele.

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Pollex, R., Hegele, R. Genetic determinants of the metabolic syndrome. Nat Rev Cardiol 3, 482–489 (2006). https://doi.org/10.1038/ncpcardio0638

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