Drugs and DNA: The Promise of Pharmacogenetics

Tags: ,

 

By: Inga Muser
Supervisor: Dr. Daniel Mueller

Considering the structure of DNA was only determined in 1953, the blinding speed at which the field of genetics is expanding is truly remarkable. From gene therapies for cancer to HPV vaccines, the potential for genetic research to improve medical treatment is almost immeasurable.

DNA makes a fascinating target for various therapies, and for good reason. The tiny double helical strands contain the code for all of the proteins which make us who we are, and while altering this code may be the aim of some labs, improving patient treatment outcomes without directly altering their DNA may provide a more practical immediate approach. That’s the goal of the relatively new research field of pharmacogenetics–using the genotype of a patient to tell us what medications might work best for them. It’s personalized medicine on a whole new level, and it’s rapidly becoming a reality.
Pharmacogenetics doesn’t focus on treatment of mutations or chromosomal disorders which lead to illness, rather it uses information from natural gene variations between individuals. Each gene codes for one protein, and is composed of a sugar backbone holding a string of nucleotides (A, T, C, or G) in a particular sequence, much like a string of letters forms a particular word. These sequences can be quite long, and sometimes one letter (or nucleotide) can be replaced by a different letter in a different person. These are known at single nucleotide polymorphisms (SNPs, pronounced “snips”), which means exactly that–differences in a single nucleotide within the gene sequence (e.g. a T in one person may be replaced by a G in another). In order to be considered a SNP, the variation has to occur commonly within a population (>1%). Most commonly, there are only two versions of the variation in a particular gene, making two alleles.

Pharmacogenetics studies the way these variations cause patients to respond differently to medications, and uses it to determine which medication is best for each individual. Someone with the dominant allele of a gene vs. a patient with the recessive allele may experience less of a certain side effect, or a different side effect completely. A good example of this is seen in patients taking antipsychotic medication. Some SNPs (like the HTR2C rs1414334 C allele) have been significantly associated with weight gain due to antipsychotics. Conversely, the -759T allele variant has been associated with the opposite effect.1

Implementing pharmacogenetics programs into clinics is a way of individualizing a treatment plan, and ultimately better outcomes, lower costs, and greater patient compliance. Research continues to broaden the fields where this type of program is applicable; recent studies suggest potential benefit for patients taking warfarin,2 hematopoietic stem cell outcome in children,3 leukemia patients,4 kidney transplant recipients,5 and many more.

Despite the obvious advantages to a personalized approach to medicine, the implementation of pharmacogenetics practice has been less than extraordinary due to a variety of hurdles. Nevertheless, implemented programs have been met with considerable success and positive patient feedback. One of the recent successes has been with antiplatelet therapy at the University of Maryland. Polymorphisms in the CYP2C19 gene (most commonly CYP2C19*2, CYP2C19*3, and CYP2C19*17), can severely impair the functioning of Plavix, a common anticoagulant.6,7 15-20% of the Asian population and 3-5% of Caucasians are classified as “poor metabolizers” as they have no CYP2C19 function8,9 due to polymorphisms in the gene. Patients carrying an abnormal variant should also avoid benzodiazapines (e.g. Valium) due to impaired metabolic capacities.10

The University of Maryland has implemented a Personalized Anti-platelet Pharmacogenetics Program (also known as PAP3) for cardiac catheterization patients, whereby patients are offered CYP2C19 genetic testing. The results are returned within five hours along with prescribing recommendations for anti-platelet therapy. Of all the patients which took part in the first ten months of the program, 32% were identified as poor metabolizers and 63% of these patients were prescribed an alternative anti-platelet therapy.11 The program has been met with considerable success, although it has also uncovered a wide gap in standardized protocols for pharmacogenetics programs which would allow other clinics to implement programs of their own.

While the promise and potential of this field is growing quickly with its complementing body of research, practical application has been sluggish at best. Nevertheless, as the evidence of positive patient outcomes grows, so does the potential of personalized medicine, and it may not be long before this medicine of the future becomes a reality of the present.

References:

1. Ma X, Maimaitirexiati T, Zhang R, et al. HTR2C polymorphisms, olanzapine-induced weight gain and antipsychotic-induced metabolic syndrome in schizophrenia patients: a meta-analysis. International Journal of Psychiatry Clinical Practice. 2014; 18(4):229.
2. Nutescu EA, Drozda K, Bress AP, et al. Feasibility of implementing a comprehensive warfarin pharmacogenetics service. Pharmacotherapy. 2013; 33(11):1156-1164.
3. Franca R, Stocco G, Favretto D, et al. Role of Pharmacogenetics in Hematopoietic Stem Cell Transplantation Outcome in Children. International Journal of Molecular Sciences. 2015; 16(8):18601-18627.
4. Simeon V, Todoerti K, Rocca FL, et al. Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine. International Journal of Molecular Sciences. 2015; 16(8):17514-17534.
5. Provenzani A, Santeusanio A, Mathis E, et al. Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients. World Journal of Gastroenterology. 2013; 19(48):9156.
6. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. New England Journal of Medicine. 2009; 7(8):354-362.
7. Frére C, Cuisset T, Gaborit B, et al. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost. 2009; 7(8):1409-1411.
8. Bertilsson L. Geographical/Interracial Differences in Polymorphic Drug Oxidation. Clinical Pharmacokinetics. 1995; 29(3):192-209.
9. Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Pharmacokinetics. 2002; 41(12):913-958.
10. Tennant F. Opioid regimens in patients with chronic pain with multiple cytochrome P450 defects. Journal of Opioid Manag. 2015; 11(3):237-242.
11. Shuldiner AR, Palmer K, Pakyz RE et al. Implementation of Pharmacogenetics: The University of Maryland Personalized Anti-Platelet Pharmacogenetics Program. American Journal of Medical Genetics Part C: Seminars in Medical Genetics2014; 166(1):76-84.