In 2003 the Human Genome Project was completed and the mapping of the entire human DNA was made available to the public.1  As a result, the National Institutes of Health's (NIH) National Human Genome Research Institute shared its vision for human research for the purposes of improving health.2  Within this vision was the goal to use genomic-based approaches for the prediction of drug response.2  The motivation behind this particular goal is the genetic variations that exist between individuals.  Some of these genetic variations are subtle and are largely neutral in their manifestation.  However some genetic variations can be observed when a stimulus from the environment (such as a medication) is introduced and elicits a response that is exaggerated or a deviation from the norm.  One of the most common genetic polymorphisms (variations) described in the literature and now being recognized in clinical practice is single nucleotide polymorphisms (SNP; often pronounced, "Snips").  These polymorphisms can directly influence a patient's response to drug therapy.  There are over 1 million SNPs in the human genome that occur at a frequency of 1% or greater in the general population.3  

What is a SNP and how does it result in changes in drug response?
In order for a SNP to make sense it is important for clinicians to understand the basic sequence of DNA.  As a reminder, DNA is literally a long list of nucleotides aligned in a specific order.4  The nucleotides that make up the DNA sequence include the purines (adenine (A), guanine (G)) and pyrimidines (cytosine (C), thymine (T)) and are paired with each other within the double helix so that G is paired with C and A is paired with T via hydrogen bonding.  These base pairs also form codons which consist of a series of 3 individual nucleotides.  The combination of these 3 nucleotide sequences is important for a number of functions.  One function is to influence the activity of other regulatory proteins such as those involved in the process of gene transcription and translation for a protein.  Another common function is to determine which amino acid to place next in the sequence during the process of making a new protein (such as an enzyme or transporter).  In order for proteins to be made and function properly, the appropriate sequence of amino acids must be put together during the gene translation process. Therefore, all of these cellular functions are influenced by the sequence of the individual nucleotides in the DNA.  If any one of the individual nucleotides were substituted for a different nucleotide, the ability of genes to be transcribed from the DNA or functional proteins to be produced during gene translation could be significantly impaired.  This change in a single nucleotide is a SNP.3 

The location of the SNP influences the expression or "phenotype" seen in a patient.  A SNP in the coding region of the DNA (cSNP) may or may not result in amino acid substitutions in the protein being formed.  If an amino acid substitution occurs, the protein created may have a different shape or tertiary structure and thus significantly influence that protein's ability to exert its biologic effect.  If the SNP occurs in the promoter or enhancer region of the DNA, gene regulation may be altered resulting in a change in the amount of protein made and/or its expected biologic effect.  Pharmacology Weekly has published several newsletters describing examples of SNPs that can impact the drug response seen in clinical practice.5-8  Unfortunately, SNPs can occur with many proteins involved in drug transport, metabolism and receptors that ultimately  influence both the pharmacokinetic and pharmacodynamic properties of a number of medications.

References:

1. National Institutes of Health.  National Human Genome Research Institute.  Accessed last on 5/30/09.  
2. Collins FS, Green ED, Guttmacher AE et al.  A vision for the future of genomics research.  Nature  2003;422:835-47.  
3. Sachidanandam R, Weissman D, Schmidt SC et al.  A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms.  Nature  2001;409:928-33.  
4. Lieberman M, Marks AD.  Chapter 12.  Structure of the nucleic acids. In: Mark's Basic Medical Biochemistry. A Clinical Approach.  3^rd ed.  Lieberman M, Marks AD eds.  Wolters Kluwer-Lippincott Williams & Wilkins.  Philadelphia, PA.  2009:199-215.
5. Busti AJ, Herrington J, Lehew DS, Nuzum DS, Daves BJ, McKeever GC.  How is warfarin (Coumadin, Jantoven) use in clinical practice influenced by known genetic polymorphisms to CYP450 2C9 and when is testing needed, if at all?
6. Busti AJ, Margolis DM, Lehew DS, Nuzum DS, Daves BJ, McKeever GC.  How does a patient's genetics predispose them to abacavir (Ziagen®) induced hypersensitivity reaction that prevents future use of the drug for the treatment of HIV infection?
7. Busti AJ, Herrington J, Murillo JR, Nuzum DS, Daves BJ, McKeever GC.  How do genetic polymorphisms to UGT1A1*28 increase the risk for life-threatening neutropenia when receiving irinotecan (Camptosar)?
8. Busti AJ, Lehew DS, Nuzum DS, Daves BJ, McKeever GC.  How do oral contraceptives (birth control pills) increase the risk of clots or venous thromboembolisms (DVTs and pulmonary embolisms) in patients with the genetic polymorphism, Factor V Leiden?

• Pharmacogenetics: CYP1A2 Genetic Polymorphisms Reference Table
• Pharmacogenetics: CYP2C9 Genetic Polymorphisms Reference Table
• Pharmacogenetics: CYP2C19 Genetic Polymorphisms Reference Table
• Pharmacogenetics: CYP2D6 Genetic Polymorphisms Reference Table
• Pharmacogenetics: CYP3A4 Genetic Polymorphisms Reference Table
  

Single Nucleotide Genetic Polymorphism, SNP, Human Genome Project, Genetic Variations, DNA, Pharmacogenetics