Metabolic syndrome is one of the world’s fastest growing health problems. It is a major risk factor for both type 2 diabetes 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, and a decrease in HDL cholesterol).[i]  Effective prevention or treatment of metabolic syndrome significantly reduces the risk for developing these serious complications.

Historically, medical treatment of metabolic syndrome  has been reactive, initiated as a response to the onset of disease symptoms.   And because we didn’t fully understand the genetic and environmental factors involved, our treatment efforts often been imprecise, unpredictable and ineffective.

Personalized medicine is changing this paradigm; it is defined as the pro-active tailoring of medical treatment to the individual characteristics of each patient during all stages of care, including prevention, diagnosis, treatment, and follow up[ii]

Genomic Testing and Personalized Medicine

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 studies to survey genes or regions for genetic variants that contribute to increased susceptibilities to complex human diseases, such as Metabolic Syndrome.

One of the early hopes of the genomic project was to pinpoint specific genes that caused common diseases. Scientists now think the answer is more complex, with many diseases the result of multiple genes interacting.

These technological 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 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  polymerase chain reaction (PCR)  technology, as well as the use of mass spectrometry   Mass spectroscopic methods are being used in conjunction with proteomic, genomic, and informatic techniques to identify and measure multiple analytes in a highly parallel fashion. These methods provide insight into how cells regulate gene expression in response to their environment; particularly relevant to our discussion of the metabolic syndrome.

These advances have paved the way for the rise of Personalized Medicine., This approach relies on understanding how a person’s unique molecular and genetic profile makes them susceptible to certain diseases. While personalized medicine is the antithesis of the “one size fits all” treatment protocols available for treating disease, it can, at the same time be considered as parallel to the traditional approach in the treatment of disease but using more precise tools.

Personalized medicine is also about[iii]

  • Risk Assessment: genetic testing to reveal predisposition to disease.
  • Prevention: Behavioral/lifestyle/Treatment intervention to prevent disease
  • Detection:. Early detection of disease at the molecular level
  • Diagnosis: Accurate disease diagnosis enabling effective disease strategy
  • Treatment: Improved outcomes through targeted treatments and reduced side effects
  • Management: Active monitoring of treatment response and disease progression.

The Benefits of Personalized Medicine[iv]

Personalized medicine is already transforming the practice of medicine. It is allowing health care providers to:

  • Shift the emphasis in medicine to prevention and prediction of disease rather than reaction to it;
  • Focus on susceptibility to disease, improve disease detection, preempt disease progression;
  • Ability to make more informed medical decisions; earlier disease interventions than was possible in the past;
  • Customize disease-prevention strategies;
  • Prescribe more effective drugs and avoid prescribing drugs with predictable side effects;
  • Have a higher probability of desired outcomes thanks to better targeted therapies;
  • Reduce the time, cost, and failure rate of pharmaceutical clinical trials, and
  • Eliminate trial-and-error inefficiencies that inflate health care costs and undermine patient care

Knowledge of how an individual’s genome influences their likelihood of developing (or not developing) a broad range of medical conditions promotes directed wellness and disease prevention: for example,  if a person’s genomic information indicates a higher-than-average risk of developing metabolic syndrome, that person may choose a lifestyle, or sometimes be prescribed medications, to better regulate the aspects of health and wellness over which he or she has control. The person may benefit in the long run

Applications to Metabolic Syndrome

Candidate Genes

Rapid progress has already been made in identifying the “Candidate genes” associated with Metabolic Syndrome:[v]  (Candidate genes are those genes whose variances are associated with phenotyically defined disease states)

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 γ; 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 has resulted in the institution of earlier and more effective  preventive measures.

Metabolic syndrome is not an equal opportunity disease; for example, there is a higher prevalence in men than women.  Prevalence also varies substantially among ethnic groups, with the highest rate noted in Mexican-American women. These differences persist even after adjusting for contributing factors, such as age, body mass index, socioeconomic status, and lack of physical activity. 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.[vi]  Due to the increasing prevalence of obesity, the prevalence of metabolic syndrome continues to increase.

Variant Susceptibility

Indeed, how do we explain differences among ethnic groups and individuals in the incidence and manifestations of the Metabolic Syndrome?

Two hypotheses have been proposed to explain the variations of susceptibility among individuals, and among groups, to the metabolic syndrome and variations in its associated phenotypes[vii].

According to the thrifty genotype hypothesis proposed by Neel in 1962, energy conserving genotypes selected by a harsh environment  are associated with a survival disadvantage when there is an abundance of food.

The thrifty phenotype hypothesis was introduced by Hales and Barker in 1992. 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; but not beneficial with increased food intake.

However, there is an important caveat:

While multiple genetic targets are involved in the pathogenesis and progression of the metabolic syndrome, the human genome has not changed markedly in the last decade; yet the prevalence of the 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.  Indeed, obesity is a key etiological factor, related to 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 insights 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[viii].

Only with a full understanding of gene-gene, gene-nutrient and gene-nutrient-environment interactions can the molecular basis of the metabolic syndrome be solved and subsequent type 2 diabetes and CVD[ix].

Companion Diagnostics

New gene-based and other molecular diagnostic laboratory tests can also be used to determine the benefits and harms for an individual of taking certain medications. These tests are known as companion diagnostics. Information on an individual’s drug metabolism, for example, can yield information on who might benefit most from a drug and those at risk for atypical adverse reactions. Tests can also inform the optimal dose or treatment frequency needed to achieve a desired therapeutic effect in an individual patient.

Opportunities and Challenges for the Clinical Laboratory 

  • Since personalized medicine can define the risk of developing metabolic syndrome, the challenge will be for laboratories to work with physicians to integrate traditional diagnostic testing into specific risk assessment profiles. These individualized test profiles will be key in supporting personalized prevention and diagnosis efforts
  • Personalized medicine often begins with the primary care physician. In addition to ordering traditional diagnostic tests, primary care physicians will be ordering genomic-based tests that they are far less familiar with. Laboratories can add value to the physician’s practice through education to these physicians.
  • By providing interpretations of genomic test results, laboratory professionals will strengthen their role of consultant, influencing the management of patients and related clinical outcomes, and reinforcing their role as a key part part of the healthcare delivery team.
  • New offerings will likely affect every function of the lab, including staffing, processing, equipment purchases, results reporting, billing, validation and continuous education and training.


Metabolic syndrome is a consequence of multiple gene–environment interactions. The gradual increase in prevalence of overweight and obesity as well as obesity related metabolic syndrome in the industrialized world is clearly not caused by changes in the genetic make up of the human species. This increase indicates the importance of environmental influences, such as low levels of physical activity and availability of calorie-rich diets. However, identification of susceptibility genes of metabolic syndrome and their functional variants as well as the associated pathophysiological mechanisms are of utmost importance, because it enables investigators to design preventive strategies and targeted treatments.  The development of genomic based personalized medicine is providing effective  prevention and treatment strategies, but research continues into the role of candidate genes, and the application of pharmacogenomics (which uses an individual’s genome to provide a more informed and tailored drug prescription)[xi]

[i] H Roche, C Phillips, M Gibney.  The Metabolic Syndrome- The Crossroads of Diet and Genetics. Proc Nutr Soc. 2005 Aug;64(3):371-7. Physician 2006

[ii] FDA: U.S. Food and Drug Administration.  Personalized Medicine: FDA’s Unique Role and Responsibilities in Personalized Medicine.

[iii] The Age of Personalized Medicine. Personalized Medicine Coalition (PMC). “What Is Personalized Medicine”. 2011

[iv] The Jackson Laboratory: Genetics and Your Health/ Personalized medicine and You 2014

[v] Q.Song, S. Wang, A Zafari. Genetics of the Metabolic Syndrome.  Turner-White.  Hospital Physician. 2006

[vi] Q.Song, S. Wang, A Zafari. Genetics of the Metabolic Syndrome.  Turner-White.  Hospital Physician. 2006

[vii] Q.Song, S. Wang, A Zafari. Genetics of the Metabolic Syndrome.  Turner-White.  Hospital Physician. 2006

[viii] New Clues To The Genetic Origins of Obesity.  Beth Israel Deaconess Medical Center.  Press Release. BIDMC News. Aug. 2015.

[ix] H Roche, C Phillips, M Gibney.  The Metabolic Syndrome- The Crossroads of Diet and Genetics. Proc Nutr Soc. 2005 Aug;64(3):371-7.

[x] Q.Song, S. Wang, A Zafari. Genetics of the Metabolic Syndrome.  Turner-White.  Hospital Physician. 2006

[xi] FDA: U.S. Food and Drug Administration.  Consumer Updates: Personalized Medicine Will Fit you Like a Glove.

Originally posted by AAFP-PT POL Insights.

About The Author

Irwin is Quality Advisor for COLA Resources, Inc (CRI®). where he provides a wide range of technical assistance to laboratories across the country. He previously held the position of Executive Director at Community Response, a community-based organization that provides HIV/AIDS support services in metropolitan Chicago. Prior to that position he was the Laboratory Manager of Crittenden Memorial Hospital, West Memphis, AR. He holds a Bachelor of Science degree from Brooklyn College, a Medical Technology degree from Good Samaritan School of Medical Technology, a Master of Science degree from Colorado State University, and a Master of Business Administration degree from the University of Memphis.

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