Metabolic syndrome is one of the world’s fastest growing health problems. It is a major risk factor for both type 2 diabetes mellitus and cardiovascular diseases (CVD), including heart attack and stroke. The etiology is complex, determined by the interplay of both genetic and environmental factors. It is characterized by the clustering of multiple metabolic abnormalities, including abdominal obesity, insulin resistance, hypertension, impaired glucose tolerance and dyslipidemia (manifested by elevation of total cholesterol, LDL and triglyceride concentrations, as well as a decrease in HDL cholesterol).1 Effective prevention or treatment of metabolic syndrome significantly reduces the risk for developing these serious complications.

In the United States, approximately 25% of the adult population (age 20 and older) and up to 45% of those older than 50 meet the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP/ATP III) diagnostic criteria for metabolic syndrome. Metabolic syndrome is not an equal opportunity disease. For example, there is a higher prevalence in men. Prevalence also varies substantially among ethnic groups, with the highest rate in Mexican-American women.

These differences persist even after adjusting for contributing factors, such as age, body mass index (BMI), smoking and drinking habits, socioeconomic status and physical inactivity, as well as menopausal status among women. These ethnic differences strongly suggest a genetic component in the pathogenesis of metabolic syndrome. For example, it is estimated that genetic factors explain approximately 40% of the variance in body fat and up to 70% of the variance in abdominal obesity.2 Due to the increasing prevalence of obesity, the prevalence of metabolic syndrome continues to increase.

Common genetic variants in a number of genes may increase susceptibility to metabolic syndrome. These genetic variants may act in concert with other gene variants and a number of environmental factors.

The last decade has seen revolutionary advances in human genetics research. Among these, the most relevant include the completion of the human genome project, the identification of large numbers of genetic markers and the understanding of gene linkage disequilibrium. These recent advances allow ­comprehensive and large-scale association studies to survey genes or regions for variants that contribute to genetic susceptibilities to complex human diseases, including metabolic syndrome. The interactions between genetic variants, as well as interactions between genetic variants and environmental factors, play a crucial role in the expression of disease traits.

These advances have also led to the emergence of the molecular diagnostic clinical laboratory. Progress in automated DNA sequencing, sequencing of the human genome, refinements in mass spectrometry and improvement in polymerase chain reaction (PCR) technology have revolutionized molecular biology and genetic testing and its diagnostic applications.

At present, most clinical laboratories that provide molecular diagnostic services do so through the utilization of PCR technology, as well as the use of mass spectrometry. Mass spectroscopic methods are used in conjunction with proteomic, genomic and informatic techniques to identify and measure multiple analytes in a highly parallel fashion. These methods will ultimately provide insight into how cells regulate gene expression in response to their environment, which is particularly relevant to the discussion of the metabolic syndrome.

Variations of Susceptibility

How are differences explained among ethnic groups and individuals in the incidence and manifestations of metabolic syndrome? Two hypotheses have been proposed to explain the variations of susceptibility among individuals and among groups to metabolic syndrome and variations in its associated phenotypes.2

According to the thrifty genotype hypothesis proposed by James Neel in 1962,3 individuals living in a harsh environment with unstable food supply would maximize their probability of survival if they could maximize storage of surplus energy. Genetic selection would thus favor energy-conserving genotypes in such environments. However, the selected genetic variations that were favored during malnutrition would become unfavorable when nutrition improved. This hypothesis assumes that common genetic variants of thrifty genes predispose to metabolic syndrome.

The thrifty phenotype hypothesis was introduced by Nicholas Hales and David J.P. Barker in 1992.4 According to this hypothesis, babies who experienced intrauterine malnutrition may have adapted to poor nutrition by reducing energy expenditure and becoming “thrifty.” These metabolic adaptations are beneficial when individuals are poorly nourished during childhood and adult life; however, with increased food intake, these adaptations are not. Support for this hypothesis comes from the observed associations of low birth weight with later development of insulin resistance and type 2 diabetes in several populations.

Clues as to the Genetic Origins of Obesity

Significant risk factors for the development of metabolic syndrome include being overweight or obese, having a sedentary lifestyle, smoking and eating a diet that is high in fats and processed carbohydrates. Although many cases of metabolic syndrome may be prevented or mitigated through lifestyle and dietary changes, not all risk can be mitigated due to the interplay of genetic and environmental factors.

Recent advances in genetic research provide insight into the genes involved; this will enable the development of more effective prevention and treatment strategies. For example, a research team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and the Massachusetts Institute of Technology (MIT) revealed the mechanistic explanation behind the strongest genetic association with obesity. The findings, published in The New England Journal of Medicine, uncovered a genetic circuit that controls whether our bodies burn or store fat. Manipulating that genetic circuit may offer a new approach for obesity treatments.5

The Candidate Genes

Rapid progress has already been made in identifying the “candidate genes” associated with metabolic syndrome:2

  • Genes causing monogenic obesity: Leptin; Leptin receptor; Melanocortin receptor; and Pro-opiomelanocortin
  • Genes regulating free fatty acid metabolism: Adiponectin; β-Adrenergic receptors; Fatty acid binding protein-2; Lipases; Uncoupling proteins
  • Genes affecting insulin sensitivity: Peroxisome proliferator-activated receptor ?; Glycoprotein PC-1; Insulin receptor substrates; Skeletal muscle glycogen synthase, Calpain-10
  • Genes affecting lipid metabolism: CD36; Apolipoprotein E; 11 β-Hydroxysteroid dehydrogenase Type; Upstream transcription factor
  • Genes related to inflammation: Tumor necrosis factor-α; C-reactive protein

Understanding how these genes work to influence or even turn on or off the risk factors for metabolic syndrome will result in the institution of earlier and more effective preventive measures. However, there is an important caveat: while multiple genetic targets are involved in the pathogenesis and progression of metabolic syndrome, the human genome has not changed markedly in the last decade; yet the prevalence of metabolic syndrome has increased exponentially. This illustrates the importance of gene-environment interactions, such as low levels of physical activity and the availability of calorie-rich diets that play such an important role.

Understanding the biological impact of gene-nutrient interactions will provide additional key insights into the pathogenesis and progression of diet-related polygenic disorders, including metabolic syndrome. Only with a full understanding of gene-gene, gene-nutrient and gene-nutrient-environment interactions can the molecular basis of metabolic syndrome be solved to minimize the adverse health effects of obesity and reduce the risk of metabolic syndrome and subsequent type 2 diabetes and CVD.1

Originally published by ADVANCE for Lab in the Quest for Quality Column

References
1. H Roche, C Phillips, M Gibney. The Metabolic Syndrome- The Crossroads of Diet and Genetics. Proc Nutr Soc. 2005 Aug; 64(3):371-7. http://www.ncbi.nlm.nih.gov/pubmed/16048671
2. Q. Song, S. Wang, A Zafari. Genetics of the Metabolic Syndrome. Turner-White. Hospital Physician. 2006. http://www.turner-white.com/pdf/hp_oct06_genetic.pdf
3. Neel JV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet 1962;14:353-62.
4. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992;35:595-601.
5. New Clues To The Genetic Origins of Obesity. Beth Israel Deaconess Medical Center. Press Release. BIDMC News. Aug. 2015. http://www.eurekalert.org/pub_releases/2015-08/bidm-nct081915.php