REVIEW / SYNTHE ` SE Genetics of the metabolic syndrome Margarita Tera ´n-Garcı´a and Claude Bouchard Abstract: The concept of a metabolic syndrome (MetS), a cluster of pre-clinical metabolic alterations commonly associ- ated with obesity, is the object of much debate. Genetic studies have the potential to contribute to some of the key ques- tions, including the true nature of the cluster of pre-clinical features and whether it is associated with human genetic variation. This review summarizes the evidence for the presence of familial aggregation for the individual components of MetS and their heritability levels. It also provides an overview of the studies that have dealt with candidate genes for MetS. Potential leads from genome-wide linkage scans are also discussed. The assumption is made that obesity, ectopic fat deposition and abnormal adipose tissue metabolism are responsible for alterations in lipid metabolism, which in turn generates the commonly observed pre-clinical shifts in glucose tolerance, lipids and lipoprotein profile, blood pressure, in- flammatory markers, endothelial function, and a prothrombotic state. Progress in the understanding of the genetic basis of MetS should occur as soon as a consensus is reached on the true nature of MetS, its components and diagnostic criteria. Key words: metabolic syndrome, genetics, genetic epidemiology. Re ´sume ´: Le concept du syndrome me ´tabolique (MetS), de ´termine ´ par un ensemble de troubles pre ´cliniques ge ´ne ´ralement associe ´s a ` l’obe ´site ´, suscite bien des de ´bats. Les e ´tudes sur l’he ´re ´dite ´ peuvent re ´pondre a ` des questions de premier plan tel- les que les caracte ´ristiques fondamentales des troubles pre ´cliniques et leurs associations a ` la variabilite ´ ge ´ne ´tique chez l’humain. Cet article-synthe `se pre ´sente des preuves de la pre ´sence d’agre ´gation familiale des constituants du MetS et leur niveau d’he ´ritabilite ´ et donne un aperc ¸u des ge `nes candidats a ` la base du MetS. Nous analysons aussi les pistes potentielles issues des criblages ge ´nomiques. Nous proposons le postulat suivant : l’obe ´site ´, les de ´po ˆts ectopiques de gras et le trouble du me ´tabolisme du tissu adipeux sont la cause d’anomalies du me ´tabolisme lipidique, entraı ˆnant comme conse ´quence des observations courantes du de ´placement pre ´clinique de la courbe de tole ´rance au glucose et des modifications des profils li- pidiques et lipoprote ´iques, de la pression sanguine, des marqueurs de l’inflammation, de la fonction des endothe ´liums et de l’e ´tat prothrombotique. Notre connaissance des bases ge ´ne ´tiques du MetS avancera de `s qu’on s’entendra sur les caracte ´- ristiques fondamentales du MetS et ses constituants et sur les crite `res de diagnostic. Mots cle ´s : syndrome me ´tabolique, ge ´ne ´tique, l’e ´pide ´miologie ge ´ne ´tique. [Traduit par la Re ´daction] Introduction There is an ongoing debate regarding the nature of meta- bolic syndrome (MetS) and whether it exists at all. This de- bate is largely fueled by two differing schools of thought, one promoting an ‘‘insulin–glucocentric’’, the other a ‘‘cardio–lipocentric’’ approach to the MetS concept. Is MetS a separate entity? Does it add anything to the collection of individual factors that are typically used in its clinical defi- nition? Should the concept be abandoned? Syndrome, from the Greek, means ‘‘concurrence’’. A syn- drome is therefore a cluster of co-occurring symptoms, usu- ally three or more (Jablonski 1991). The term MetS was likely adopted originally in the spirit that over time its na- ture and usefulness would be clarified, that a more precise designation would replace it, or that it would be abandoned. None of this has materialized yet, but a commonly held view among many leaders in the area is that MetS is neither a true syndrome nor a disease as such. This review focuses on the genetics of MetS. How can we address the genetic determinants of MetS while its ex- istence and definition is still a matter of debate? We will assume that the most common definitions of MetS have some validity and will not discuss the merit of the basic concept or its usefulness. We assume that there are multi- ple presentations of MetS, and that it depends on the inter- active effects of many genes and environmental factors, including physical inactivity and poor diet (Bouchard 1995). Historical notes Numerous scientists and laboratories have contributed to the early phases of the evolution of the MetS concept. It is Received 10 August 2006. Accepted 14 November 2006. Published on the NRC Research Press Web site at http://apnm.nrc.ca on 7 February 2007. M. Tera ´n-Garcı ´a and C. Bouchard. 1 Human Genomics Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, USA. 1 Corresponding author (e-mail: bouchac@pbrc.edu). 89 Appl. Physiol. Nutr. Metab. 32: 89–114 (2007) doi:10.1139/H06-102 # 2007 NRC Canada