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
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
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.
- National Institutes of Health. National Human Genome Research Institute. Accessed last on 5/30/09.
- Collins FS, Green ED, Guttmacher AE et al. A vision for the future of genomics research. Nature 2003;422:835-47.
R, Weissman D, Schmidt SC et al. A map of human genome sequence
variation containing 1.42 million single nucleotide polymorphisms.
M, Marks AD. Chapter 12. Structure of the nucleic acids. In: Mark's
Basic Medical Biochemistry. A Clinical Approach. 3rd ed. Lieberman M, Marks AD eds. Wolters Kluwer-Lippincott Williams & Wilkins. Philadelphia, PA. 2009:199-215.
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
- 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?
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)?
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?