Pharmacogenomics

Pharmacogenomics is the study of the genetic factors that determine how a person will respond to a drug. The term comes from the words "pharmacology" and "genomics," and is therefore the cross-roads of pharmaceuticals and genetics. It is a rapidly growing field in human genetics.

Scientists think that the same genetic differences that make each person unique (such as appearance, behavior) may also be the same factors that determine whether or not a drug will work against our diseases and whether it will produce side effects. The aim of pharmacogenomics is to tailor the treatment to the patient. Pharmacogenomics is opening the doors to assessing a person's genetic background, and using that information to make informed treatment decisions, including the odds that the treatment will be effective from the start.

Pharmacogenomics is expected to bring many benefits to patients and the health care industry, increase the number of new drugs and reduce the costs associated with drug development.

Pharmacogenomics today

Currently, most of the research done in pharmacogenomics studies is on the cytochrome P450 (CYP) family of liver enzymes. This is because CYP enzymes are responsible for breaking down more than 30 different classes of drugs. DNA variation in genes that code for these enzymes can affect their ability to break down certain drugs. Clinical trials researchers use genetic tests for variations in cytochrome P450 genes to screen and monitor patients. Less active or inactive forms of CYP enzymes that cannot break down and eliminate drugs from the body can cause overdoses in patients.

Two theoretical models

Scientists are focusing on mapping out the genomic differences between different phenotype-expressing groups. This is the central focus of both the genotype-to-phenotype (G2P) and the phenotype-to-genotype (P2G) approaches. These are the two theoretical models being used in pharmacogenomics today - genotype being human genetic variation (a man has an XY chromosome and a woman has an XX chromosome, this is a genotypic variation), and phenotype being human individual/ group variation (one is male and the other is female) .

G2P

The G2P approach consists of tracking down sets of genes that are thought to be important in regulating the response to drugs. Variation in the DNA sequences of those genes is then catalogued so that the different phenotypes associated with this variation can be identified. This approach is beneficial when studying effects whose molecular mechanisms are well understood. For example, the G2P approach is useful for studying gene families known to be important for pharmacokinetics - the study of how drugs are absorbed, distributed and cleared from the body. G2P is also recognized as useful to pharmacodynamics - the study of how drugs achieve their therapeutic effect.

P2G

The P2G approach is the reverse. It consists of tracking down phenotypic variations in drug responses. This leads to the identification of genes that could explain these variations. The genotypic variation is then compared to the phenotypic variation, so that its clinical usefulness can be confirmed. The P2G approach is sometimes considered advantageous when studying pharmacogenomic effects whose significant phenotypical variations to drug response can be easily observed and measured.

Genotyping technology

The mapping out of genotype-phenotype interactions is done mainly through single nucleotide polymorphism genotyping. Single nucleotide polymorphisms (SNPs - pronounced "snips") are naturally occurring variations of single nucleotides at set positions in a population's genome. For SNPs to be used to predict a person's drug response, a person's DNA must be examined (sequenced) for the presence of specific SNPs. The human genome is made up of strings of nucleotides that can be:

• A - adenine,
• C - cytosine,
• T - thymine, or
• G - guamine.

As an example, at a SNP location, 70% of all human chromosomes may have an A at a certain location, while the remaining 30% have a G. This genotypic difference can cause a phenotypic difference in hair colour, height, or drug response, depending on the gene.

Detection of differences can also be done through haplotype characterization (the characterization of SNPs that are usually genetically linked and transmitted together). This characterization is considered better in detecting polygenic associations, but the process is more complex and costs more than SNP characterization.

SNPs have certain technical properties that make detection of gene variations possible through numerous high-throughput (see below) approaches. Also, the great amount of sequence information from the Human Genotype Project has enabled organizations to look for SNP variation in the human population. The SNP Consortium, a group of pharmaceutical and technological companies, academic institutions and a medical research charity, has identified and mapped 300,000 SNPs and provides information on almost 900,000 mapped SNPs in the human genome.

Traditional gene sequencing technology is very slow and expensive. This has been a barrier to the widespread use of SNPs as a diagnostic tool. DNA microarrays (or DNA chips) are an evolving technology that may make it possible for doctors to examine their patients for specific SNPs quickly and affordably. A single microarray can now be used to screen 100,000 SNPs found in a patient's genome in a few hours. As DNA microarray technology evolves, SNP screening in the doctor's office to determine a patient's response to a drug - before a drug is prescribed - will likely become common.

Measuring techniques

Several techniques have been developed to measure the genotypes of SNPs, called high-throughput (HT) genotyping technology. A common feature of HT genotyping is the use of the polymerase chain reaction (PCR). PCR is a laboratory method used to make many copies of a DNA fragment in minutes using an enzyme called polymerase.

Some other potential benefits and barriers

In addition to developing more accurate methods of determining the proper drug dosages, pharmacogenomics is expected to contribute to advanced screening for disease. Knowing your genetic code will let you to make lifestyle and environmental changes at an early age so you can avoid or lessen the severity of a genetic disease. Better vaccines made of genetic material - either DNA or RNA - are also expected to activate the immune system but will not be able to cause infections.

The complexity of finding gene variations that affect drug response may slow progress in pharmacogenomics. Because SNPs occur every 100 to 300 bases along the three-billion-base human genome, millions of SNPs need to be identified and analyzed to determine any involvement in drug response. We also have limited knowledge of which genes are involved in each drug response.

Looking at the social-ethical aspects

The issues of large-scale genotyping of populations, which the wider use of pharmacogenomics-based drug discovery and medicine will require, are complex. They also affect all of society, not just the pharmaceutical industry, regulatory bodies and patients. Scientists, industry and academia have analyzed and discussed many of these issues. Their views currently form the basis for the start of discussion covering the wider ethical, political, social and technological aspects of the use of pharmacogenomics.

Pharmacogenomics in the future

Pharmacogenomics is not yet a major field of study in Canada. However, the need to reduce adverse drug reactions and costs for the health care system may encourage pharmacogenomic research programs by both private enterprises and government. The reduction of drug development time and the need to get more new drugs on the market are also making pharmaceutical companies increase pharmacogenomics use in their clinical research programs.