Personalized Medicine: It’s in Our Genes

Vol. 12 •Issue 11 • Page 16

Personalized Medicine: It’s in Our Genes

Approximately 95 percent of our genomic DNA sequence is shared with chimpanzees.1 While this may sound alarming, it confirms the hypothesis that we, as individuals, are not solely the product of our genes. Rather, we are a product of our genes and their interactions with the surrounding environment through complex biochemical systems. Unraveling these biological systems along with the identification of the human genome sequence has led to a better understanding of human disease processes and the beginning of more specific or targeted drug therapies.

In the clinical laboratory, molecular diagnostics has become a routine testing discipline with applications for diagnostic, prognostic and predictive testing. These applications continue to be developed for addressing the more complex yet common diseases. However, an intriguing aspect of clinical medicine and our ability to diagnose disease more accurately is often how diagnosis-based therapy fails (Table 1).

Response to Therapy

Therapeutic response is highly variable between individuals and can be associated with serious adverse reactions (ADRs).2 ADRs rank as one of the leading causes of morbidity and mortality in the developed world.3 Not only does this interindividual variability affect patient care, but the cost to the health care system can also be significantly altered by pharmacologic therapies if there are a large number of nonresponders or ADRs.

Can we approach response to therapy in a similar fashion as we would a diagnostic test for a complex disease? That is, are there alterations in our genome that could predict whether an individual would respond to or have minimal ADRs to a specific therapy? In addition, would it be possible to use this same type of information to provide optimal drug dosage? It is estimated that 20 percent to 95 percent of these variable responses can be explained by a genetic predisposition for drug response and not a predisposition for disease. The application of molecular diagnostic technologies to address drug response through genomics has become known as pharmacogenomics (PGx). The overall goal of PGx is to increase favorable drug responses and decrease adverse responses in an individual patient.4 This requires the ability to detect minor alterations or differences in our DNA, known as polymorphisms, that may be associated with these adverse responses.


Polymorphisms are gene sequences that occur in at least one percent of the population. There are approximately 10 million single nucleotide polymorphisms (SNPs or one base changes) that are scattered throughout our genome. With respect to PGx, the majority of these SNPs are found in drug metabolizing enzymes, receptors, transport proteins and drug targets (Table 2). The overall expression, function and stability of these proteins can be determined by a particular SNP that may be present in the gene sequence.

Numerous technologies are available for detecting SNPs on a routine basis. Typically, DNA is extracted from a whole blood specimen, then interrogated using various methodologies. The INVADER® technology (Third Wave Technologies, Madison, WI) is an enzymatic method for detecting polymorphisms and does not require amplification of gene sequences. Alternatively, the polymerase chain reaction (PCR) is most commonly used to amplify specific regions of genes, which are then analyzed using restriction enzymes, DNA sequencing or probe hybridization reactions. Assay throughput can vary from low (gel-based) to high (microchip array or automated sequencing) depending on the platform used. As PGx becomes more mainstream, the molecular diagnostics laboratory will be able to provide testing with analytical performance characteristics suitable for routine use.

SNPs or other genetic variations can result in loss or gain of drug metabolizing enzyme activity. This functional difference in enzyme activity can have profound effects on the drug dosage and obtained therapeutic levels.5 In addition to quantitative differences in enzyme activity, SNPs can also lead to functional differences in receptor proteins as with the b2-adrenergic receptor in asthma patients. Certain receptor polymorphisms are associated with a lack of response to the commonly prescribed medication, albuterol.6

Dr. Tsongalis is director, Molecular Pathology, Department of Pathology and Laboratory Medicine, Hartford (CT) Hospital.

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