An Overview of the Genomics of Metabolic Syndrome

Metabolic syndrome (MetS) is a widely recognized concept generally defined as a clustering of risk factors including hypertension, insulin resistance, and obesity. This clustering of risk factors then leads to an increased risk for diabetes and cardiovascular disease (CVD; Ford, Li, & Zhao, 2010). It is estimated that in the United States, MetS affects more than 34% of the population and contributes to a threefold increase in cardiovascular-related deaths (Ford et al., 2010). Still, diagnostic criteria of MetS differ among experts and organizations (American Association of Clinical Endocrinologists [AACE]; National Cholesterol Education Program Adult Treatment Panel III [ATPIII]; World Health Organization [WHO]), and this difference leads to a lack of consensus in the clinical utility of the diagnosis (Simmons et al., 2010). In 2009, an effort was made by many expert organizations to standardize the diagnosis of this complex disorder by using a harmonizing definition (Table 1; Alberti et al., 2009). Diagnosis of MetS using the harmonizing definition is contingent on meeting a threshold value in at least three of the following five factors: waist circumference, triglycerides, high-density lipoprotein-cholesterol, blood pressure, and glucose (Alberti et al., 2009). Table 1 Harmonizing Definition of Metabolic Syndrome (MetS) Even with a harmonizing definition, the global prevalence of MetS can be difficult to estimate because it can affect patients by gender groupings differently. For example, in India, the prevalence of MetS for men is approximately 8%, whereas for women it is estimated at 46% (Cameron, Shaw, & Zimmet, 2004). In Iran, 30% of men and 55% of women met the diagnostic criteria for MetS (Azimi-Nezhad et al., 2012). Some of these differences are clearly due to gender, but racial and ethnic differences may also play a role. When the U.S. population is divided by both gender and ethnicity, adult African American women have a 38.8% prevalence of MetS, and African American men have 25.3% prevalence, whereas their Caucasian counterparts have a prevalence of 31.5% and 37.2%, respectively (Roger et al., 2011). Risk factors associated with the development of MetS are similar to those associated with hypertension, diabetes, renal disease, and obesity, with variables such as lifestyle, gender, ethnicity, and genomic precursors playing important roles in the development of MetS. Because MetS is the combination of the effects of more than one risk factor, pinpointing a causative genotype has been difficult. Genomic and molecular methodologies including linkage analysis, genome-wide association (GWA) studies, epigenetics, and proteomics have all been used to attempt to unravel this genetic puzzle (Table 2). The results of these studies have shown that MetS is a polygenetic (under the control of more than one gene) condition with varying influence from multiple environmental factors. Therefore the inheritance of a single specific risk allele may be less important than the additive effects of many alleles, some of which may be “high risk,” some which may be “moderate risk,” and others of which may be “low risk.” However, the current understanding of the disease shows that certain risk alleles that have relevance for the individual components of the disease may also have an overlapping value in the overall risk for the development of MetS. This review will examine the possible contributions of cardiovascular, obesity, and diabetes genomic risk factors to the development of MetS as reported in the literature. Table 2 Definitions of Common Methodologies Used in the Study of Metabolic Syndrome