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Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. By doing so, pharmacogenomics aims to develop rational means to optimise drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of "personalized medicine"; in which drugs and drug combinations are optimized for each individual's unique genetic makeup.

Pharmacogenomics is the whole genome application of pharmacogenetics, which examines the single gene interactions with drugs.

Pharmacogenomic Testing

Pharmacogenomics is being used for all critical illnesses like cancer, cardio vascular disorders, HIV, tuberculosis, asthma, and diabetes.

In cancer treatment, pharmacogenomics tests are used to identify which patient will have toxicity from commonly used cancer drugs and identify which patient will not respond to these drugs. Pharmacogenomics is also as companion diagnostics, meaning that tests are bundled with drugs. Two examples are the KRAS test with cetuximab and the EGFR test with Gefitinib.

In cardio vascular disorders, the main concern is response to drugs including warfarin, clopidogrel, beta blockers, and statins.

Ethnicity

The genotype of a person can affect how they respond to a drug. Additionally, the ethnicity of an individual can affect drug response. The relevant effects of ethnicity on drug response are not great enough to act as a classification system to predict drug response, however. There are too many inconsistencies in pharmacokinetics among and within ethnic groups to apply ethnicity to genetic influence on drugs.

Observable Ethnic Differences

People typically associate differences of ethnicity with differences of appearance. The outward appearance of someone does not directly correlate with how they react to a drug, however. The genes that code for appearance aren’t directly linked to drug response genes, many of which are liver enzymes, so people who look different can respond similarly to the same drug. Conversely, people who look similar or who are from the same ethnic group can respond very differently to the same drug. The basis of applying pharmacogenomics to ethnicity is the idea that like appearance, people of the same ethnic group would respond similarly to the same drug treatment.

Haplotype Mapping

One method used to compare genes across ethnicities is to compare the haplotypes of different ethnic groups from a haplotype database, such as the HapMap Project. The allele variants for the tested Single Nucleotide Polymorphisms (SNPs) are compared to analyze how similar, or different, the genes are between different ethnic groups. This testing method does not analyze actual responses, however, and thus can only provide predictive data on ethnic-drug interactions . Additionally, haplotype databases may be limited in the number of participating ethnic populations; the HapMap Project only has data from Nigerians, Japanese, Chinese, and Americans with Northwestern European descent .

Genetic Polymorphisms between Ethnicities

People of different ethnic groups have differences in alleles and in frequencies of certain SNPs. Comparisons of drug metabolizing genes between ethnic groups may denote a similar or altered response to a drug.

People with differences in drug response genes would be assumed to respond differently to the same drug. Differences are commonly found between individuals and ethnic groups for genes of the CYP450 class of enzymes, which metabolize drugs. For example, Caucasians have 9% to 15% frequency of the CYP268*3 allele which is associated with a decreased metabolism of the chemotherapy drug paclitaxel, compared to Japanese who have a less than 1% frequency of that allele. Conversely, East Asians have an 8% frequency of CYP2C19*3 allele, which is associated with reduced metabolism of several drug classes including thienopyridines, proton pump inhibitors, antidepressants, antibiotics, and steroid hormones whereas Caucasians and Africans have a less than 1% frequency of that allele . The differences in these enzymes that would result in reduced metabolism meaning that the drug would have a longer duration of action and have higher risk of toxicity. People with the genes that reduce metabolism would be more likely to have side effects, thereby encouraging personalized drug therapies.

There are significant similarities in notable genes across ethnicities as well. People of different ethnic backgrounds have similarities especially with genes related to neurochemistry. These similarities indicate that there would be comparable drug responses among each of these ethnic groups. For example, Mexican-Americans, Caucasians, Africans, Han Chinese, and Japanese share 83 of 215 SNPs of an ATP binding cassette binding gene related to antidepressant response . In contrast to the differences in drug response genes, these similarities allow for the standardization of drug treatment. Issues of ethnic differences won't apply as much for these drugs that interact with these shared genes, so pharmacogenomic testing may not even be needed.

Genetic Polymorphisms within Ethnicities

There are notable differences between individuals of the same ethnicities. Members of the same ethnic group follow some genetic patterns, but there are a number of other genes that differ significantly.

For example, Vietnamese have a number of CYP2A6 and CYP2B6 gene variants, involved in HIV drug metabolism, that are more frequent than in other Asians. These differences translate to higher plasma concentrations of the drugs and increased frequency of side effects . Additionally, the CYP2C19*3 allele, related to loss of some drug metabolizing function, is 2 to 3 times more frequent in Japanese and Koreans than in Chinese. Members of the same ethnic group can have very different genes and thus may respond differently to the same drugs, thereby necessitating pharmacogenomic testing.

Intra-ethnic genetic variations are as common and significant as inter-ethnic genetic variations. Ethnic groups provide some genetic patterns, but people are still different enough from each other that ethnicity cannot accurately describe someone's drug response profile. Individual differences of genotype ultimately determine a person's response to medication over other classifications.

Drug Responses

People of different ethnicities may have different genes, but the actual response doesn’t always correlate to these genetic variations.

Genetic similarities indicate that there would be comparable responses to drugs in two separate populations, but members of different ethnic groups with the same genotype can exhibit different phenotypes. For example, olanzapine and perphenazine are especially effective in individuals of African descent, while the drugs have little effect in individuals of European descent with the same genotype for the Regulator of G protein signaling 4 gene .

Similarly, genetic differences indicate that there would be a difference in drug response, but this correlation doesn't always occur either. For example, African-Americans have much higher frequencies of certain alleles related to responding to risperidone than American whites, but there is no significant difference in how the drug acts in either population.

These apparent paradoxes in how genes and drugs interact are due to the complexity of genetic responses. Multiple genes interact to affect how a drug acts upon the body and how it is metabolized. A genome wide screening to analyze the interactions of noteworthy genes is needed to properly predict how drugs will affect someone. Applying ethnic background to such screening, however, is not effective, because ethnicity does not significantly affect a population's genome to affect drug treatment.

See also

• Genomics
  • Chemogenomics
  • Structural genomics
  • Pharmacogenetics
  • Toxicogenomics
  • Clinomics
  • p450
• Pharmaceutical company
• Population groups in biomedicine

External links

• Genomics @ FDA FDA's resource on genomics
• [9] Pharmacogenetics and Genomics magazine (previously Pharmacogenetics)
• [10] The Pharmacogenomics Journal, ISSN: 1470-269X
• [11] Pharmacogenomics Journal, (ISSN 1462-2416) Impact factor: 3.623
• Nature pharmacogenomics gateway
• PharmGKB The Pharmacogenetics and Pharmacogenomics Knowledge Base, an online free tool for Pharmacogenomics research
• NCBI Primer on Pharmacogenomics, a quick introduction to the promise of customised drugs.
• Pharmacogenomics: Drugs Designed for You, an accessible and comprehensive look at pharmacogenomics research, from the University of Utah's Genetic Science Learning Center
• A Drug to Call One's Own : Will medicine finally get personal? - Scientific American Magazine (August 2005)
• PGxNews.Org - Daily updates about advances in Pharmacogenomics and Personalized Medicine
• FDA List of Genomic Biomarkers Predictive of Drug Interactions in August 1, 2008