Pharmacogenomics: A clinical tool for personalized medicine

Pharmacogenomics (PGx), also known as pharmacogenetics, is the study of how an individual’s genetic makeup influences response to different drugs or medications. Individuals with the same disease will respond differently to the same drug prescription. We also often hear people say that a particular drug does not work too well for them or that the drug has no effect. Similarly, it is common to hear of adverse effects of drugs on some individuals (Figure 1). This is now explained by science – individuals process different drugs differently.

Figure 1: Schematic representation of individuals with varied drug responses to the same drug prescription.

In addition to age, gender, and weight, genetic factors play an important role in drug response. Pharmacogenomics studies have revealed the relationship between genetic variation and drug responses. The genetic variants such as SNPs, Indels, and CNVs in the genes encoding for enzymes lead to changes in the function or abundance of proteins, leading to the gain of function or loss of function phenotypes implicating varied responses to drugs. Based on the functional status of the allele and its impact on enzyme activity, individuals will be categorized as rapid, normal, intermediate, or poor metabolizers for a specific gene/drug pair (1).

Drug Metabolism:

The metabolism of drugs is a process of altering the molecules chemically after they enter the body. Most drugs have lipophilic centers and are converted to hydrophilic centers during biotransformation, which increases their water solubility to allow elimination in urine or bile (2). The cytochrome P450 (CYP) families of enzymes are major players in the metabolism of many drugs; it is estimated that 1/3rd of all drugs are metabolized by CYP3A and 1/4th of all drugs are metabolized by CYP2D6 enzymes (3). Although more than 50 CYP enzymes are reported, 6 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) metabolize 90 percent of drugs, where CYP3A4 and CYP2D6 are most significant enzymes (4).

The History of Pharmacogenetics:

The term Pharmacogenetics (PGx) was coined by Friedrich Vogel in 1959 (5). The history of PGx dates back more than 2000 years when Pythagoras described a trait now known as favism and advised against the consumption of fava beans. Later, scientists discovered deficiency of G6PD leads to the development of red blood cell hemolysis or acute hemolytic anemia in some individuals upon eating fava beans, indicating the important observation made by Pythagoras on non-tolerating of fava beans in certain individuals is prominent in a subset of the population (5, 6).

Furthermore, PGx gained importance about 60 years ago with the discovery that the metabolism of the muscle relaxant succinylcholine and a deficient N-acetylation of isoniazid (antituberculosis drug) has a genetic component (7,8). Looking at the succinylcholine history, doctors sometimes encountered patients in whom the paralyzing effects of succinylcholine lasted considerably longer than normal, putting the patients in prolonged apnea. Later Werner Kalow showed that the prolonged apnea was caused by the presence of a variant in BCHE (9).

Drug Metabolizers and Transporters:

Multiple drugs and genes under many therapeutic areas are reported in the literature on their role in drug response. Drug metabolizers like CYP2C9 for non-steroidal anti-inflammatory drugs (NSAIDs), CYP2D6 for Opiods, CYP2B6 for Sertraline, CYP2C19 for Tricyclic antidepressants (TCAs), and many more drugs are reported in individuals with multiple metabolizer phenotype based on the allelic variation in these genes (10). For example, CYP2C9 *3/*3 is a poor metabolizer of NSAIDs, CYP2D6 *4/*4 is a poor metabolizer for Opiods, CYP2C19 *2/*17 is an intermediate metabolizer for TCAs (Figure 2a).

Similarly, drug transporters such as SLCO1B1 for Statins, which facilitates the hepatic uptake of all statins, and ABCG2 for Rosuvastatin, which modulates the absorption and disposition of rosuvastatin, are well cited in the guidelines. For example, SLCO1B1 *5/*5 shows poor function phenotype for statins, where it carries two no-function alleles (Figure 2b) and carries one ABCG2 c.421 C/A variant shows decreased function phenotype for Rosuvastatin (11). The therapeutic area covered under Pharmacogenetics is expanding as more scientific evidence gets accumulated. Therapy areas such as cardiovascular, oncology, psychiatry, neurology, transplantation, and many more benefit patients both in cost savings and by improving the quality of health (12, 13).

Figure 2: Phenotype for drug-metabolizing enzymes and transporters.

Guidelines for Drug Dosing:

Although the PGx testing showed a promising outcome in preventing adverse drug reactions, multiple drug selection, multiple hospital visits, and cost savings, not much of this knowledge has been translated into clinical practice (6). The reasons for being lack of guidelines for dosing recommendation, lack of awareness in real-world clinical settings, and limited evidence of clinical validity have delayed PGx progress to clinical settings. However, upon accumulation of guidelines, scientific statements from consortiums like the Clinical Pharmacogenetics Implementation Consortium (CPIC), The Pharmacogenomics Knowledge Base (PharmGKB), PharmVar, AHA, and approvals in the FDA for testing specific gene and drug combinations lead to the development of more clinical PGx tests. Further, the growing body of evidence is helping to integrate PGx testing into daily clinical practice (10, 14, 15).

CPIC is an international consortium established in 2009 with the objective of clinical implementation of pharmacogenetic tests by creating, curating, and posting freely available, peer-reviewed, evidence-based, updatable, and detailed gene-drug clinical practice guidelines for the benefit of patient care. CPIC is a close partner of PharmGKB, an interactive tool and knowledge database to investigate how genes affect drug response (16). CPIC has published guidelines for nearly 100 drugs and covers up to 20 genes with dosing recommendations for different phenotypes. CPIC provides recommendations for the level A and B drug/gene combinations, where these pairs have sufficient research evidence for at least one prescribing action to be recommended. Levels C and D are not considered to have adequate evidence or actionability to have prescribing recommendations (10). Similarly, levels 1 and 2 are considered as high evidence drug/gene pairs in PharmGKB.

Advantages of Pharmacogenetics Test:

The PGx test has multiple advantages on specific gene/drug pairs, which indicates,

• Whether the medication will be effective for an individual
• Whether an individual needs different doses than standard
• Whether an individual needs alternative therapy
• Whether an individual is at risk for serious side effects or adverse drug reactions due to altered metabolism of the medication

Methodology: 

The PGx test can be performed using multiple technology platforms to identify the variants in the gene of interest. Platforms such as Sanger sequencing, Real-time PCR, Genotyping arrays, Next generation sequencing (NGS) are utilized in the research and clinical setting for variant detection (Figure 3). Each platform has its own advantages, hence the objective for the testing must be clear before opting for the test.

Figure 3: Different methodology for PGx testing.

For example, if variants of interest are restricted to single or 2 variants in a gene, it’s always better to go with Sanger sequencing, which saves both time and cost. On the other hand, the most robust and advanced technology, like NGS, can opt for the multi-gene analysis, which is rapid, saves time, and provides comprehensive analysis for multiple drug/gene pairs in a shorter time, which will always be beneficial for the patient from the clinical point of view. Many genes like CYP2C19, CYP2C9, CYP2D6, DPYD, etc. are reported with multiple certain function variants and haplotypes (2 or more SNPs in a single allele) in the genes, indicating the whole gene analysis for accurate diplotype (represent two-star alleles) calling and to categorize precise phenotype.

Direct-to-consumer PGx Test:

Though PGx tests are more suitable and appropriate for clinical settings, few companies offering direct-to-consumer (DTC) health packages include PGx as one of the screening components to provide a complete wellness package. Consumers willing to take DTC tests as a proactive step are encouraged, however, they must be cautious and ensure they consult the clinician and follow the directions of the physician before taking or changing any medication based on such DTC reports.

PGx Testing at MedGenome:

Being a global leader in the genomic industry, many PGx tests are offered by MedGenome. Single gene to multiple gene/drug pair tests are performed using various technology platforms. For example, Clopidogrel-CYP2C19, 5- Fluorouracil-DPYD, Tacrolimus-CYP3A5, and multi gene/drug pair tests like Curegen advanced, which reports up to 100 drugs and checks 20 genes are offered. Multiple therapy areas are covered in MedGenome PGx tests to provide a comprehensive analysis of various drugs and genes (Figure 4).

Figure 4: Therapy areas covered under pharmacogenetics test at MedGenome.

Conclusion: 

Pharmacogenomics is a combination of pharmacology and genetics, which is used effectively to profile an individual’s DNA to prescribe suitable drugs with appropriate dosages. Pharmacogenetic testing informs us there is a better way to prescribe medicine than a hit-and-miss strategy. PGx is a clinical tool for personalized medicine, which must be utilized in primary to tertiary clinical settings by clinicians to i) combat adverse drug reactions, ii) avoid multiple visits to hospitals by patients for non-responsive therapy, iii) to reduce the financial burden, and iv) to improve the quality of patient health. Enhancing the knowledge of clinicians by continuous education on the advantages of PGx testing at clinics and awareness programs for the public may boost the utility of testing and, in parallel, it helps holistically on true well-being.

References: 

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