Skip Navigation LinksHome > Spring 2011 - Volume 41 - Issue > Pharmacogenomics and management of cardiovascular disease
Text sizing:
A
A
A
Nursing:
doi: 10.1097/01.NURSE.0000394517.13969.29
Feature

Pharmacogenomics and management of cardiovascular disease

Howe, Linda A. Phd, CNS, CNE

Free Access
Article Outline
Collapse Box

Author Information

Linda A. Howe is an associate professor in the school of nursing at Clemson (S.C.) University. Adapted and updated from Howe LA. Pharmacogenomics and management of cardiovascular disease. Nurse Pract J. 2009;34(8):28–35.

BEFORE THE COMPLETION of the Human Genome Project in 2003, individual responses to medications were usually called idiosyncrasies. In addition, ethnic differences weren't usually seen as genetic variants, as is the case today. With the identification of single-nucleotide polymorphisms (SNPs, pronounced "snips"), pharmacogenomics and pharmacogenetics (the study of individual genetic variants) have emerged as the newest science to determine genetic variants of populations (see Pharmacogenomics terms). More than 15 million SNPs in the human genome may or may not cause an obvious variant depending on the location on the gene; therefore, the possibility of drug reactions will become individualized. Applying this knowledge is necessary for proper management of numerous cardiovascular disease processes, as is incorporating pharmacogenomics and pharmacogenetics into everyday practice so you can offer optimal treatment for patients.

Back to Top | Article Outline

Research studies

Although the completion of the genome project was groundbreaking, knowledge of genetic differences as it relates to medications has actually been expanding for nearly 100 years. Originally, pharmacology and genetics were separate fields of scientific study, but the two sciences merged into pharmacogenetics when a few variant genes were identified that affected pharmacologic response. Garrold, a British geneticist, outlined individual human responses to certain chemicals in the 1930s. In 1949, Haldane identified individual reactions to certain drugs, such as vitamin D-resistant rickets. From these rather rudimentary discoveries, the science was further advanced in 1956 by Kalow when the discovery of an alteration in plasma cholinesterase (the enzyme that destroys succinylcholine) resulted in longer periods of paralysis from the administration of succinylcholine to electroshock patients, thereby extending the effects from the usual few minutes to over an hour in some cases. Through his careful research, Kalow discovered the likely presence of both heterozygous and homozygous effects of genetic causes of drug responses.1,2

A genetic mutation, which can occur as a single gene, multiple genes, or a chromosomal aberration, has often been connected with the possibility of providing protection against various diseases; for example, carriers of cystic fibrosis mutation (who aren't affected by the disease) are thought to be protected against cholera.3 Other mutations can affect the pharmacokinetics, metabolism, and deactivation of drugs. Depending on the location of the mutation, the expression of the mutation may or may not be observed. Research efforts in the 1960s discovered the process of drug acetylation. Acetylation determines the speed at which a drug is metabolized and rendered inactive. Slow acetylators (also referred to as poor metabolizers) could develop more toxic events associated with a drug; conversely, fast acetylators (fast metabolizers) would have a shorter duration of drug action.4

Further discoveries include the pioneering work of Allison in the sub-Saharan desert, where he identified the connection between sickle cell trait and malarial resistance. This led to the discovery of the G6PD enzyme, which helps metabolize glucose and acts in the oxidative process that occurs inside of tissue cells. G6PD is the most common enzyme deficiency in humans, with a higher incidence in individuals with sub-Saharan ancestry, including Blacks.5 These individuals may have alterations in reactions to many drugs, which can result in hemolysis of red blood cells.

A later discovery by Smith has been influential in antihypertensive therapy. The study focused on debrisoquine, a sympatholytic antihypertensive agent used primarily in current studies to determine enzyme deficiencies. Although Smith and several colleagues ingested high doses of the drug, only he experienced a significant and prolonged drop in BP that resulted in syncope. The metabolites of the drug weren't found in his urine. Further research identified slow and fast acetylators of this drug.6 Slow acetylators, like Smith, have a deficiency in a member of the cytochrome P450 (CYP450) family of enzymes, namely CYP2D6; this decreased the metabolism of debrisoquine and caused the adverse reactions (see Genes/gene products that modify disease or treatment response to selected cardiac-associated drugs).

The CYP450 enzyme system isn't a single enzyme, but a system of 12 families of enzymes. Study of the effects of the CYP450 enzyme systems has yielded many discoveries. Several of the families are known to play a role in the metabolism of drugs; others are responsible for clearing other endogenous and exogenous chemicals. The enzymes are named CYP, followed by the group number, followed by a letter and a number designating the specific enzyme. CYP3A, a group that is responsible for more than 50% of drug metabolism, is associated with many drug-drug and drug-food interactions. CYP3A4 is an enzyme in that group most commonly used in drug metabolism in the CYP3A group. About half of the U.S. population are slow acetylators, putting them at greater risk for toxic reactions, especially with drugs that have a tight therapeutic index, such as digoxin.7,8

Another isoenzyme, CYP2D6, present in at least 10% of the White population, is found in the endoplasmic reticulum and affects the metabolism of about 20% of drugs.2 These patients also can experience fewer drug effects when the enzyme is needed to convert the inactive form of a drug into an active form. Other members of the CYP450 enzyme system are present in the gastrointestinal (GI) tract and are affected by grapefruit juice, charbroiled foods, and cruciferous vegetables. These agents affect the speed at which enzymes metabolize drugs. In the Asian population, deficiency of the CYP2C19 isoenzyme makes this population poor metabolizers of drugs such as amiodarone, an antiarrhythmic. The effect of poor metabolism would raise the blood levels of the drug, putting the patient at risk for adverse effects.2 (See Examples of inducers and inhibitors of CYP450 isoenzymes.)

In addition to CYP450 variants, single gene variants that play a role in drug metabolism pathways can alter a patient's response or increase toxicity at normal dosage ranges. The gene ADRB3 is a beta2 receptor gene that interacts with catecholamines. Several clinical studies have shown that a specific SNP can alter the effectiveness or toxicity of inhaled beta-agonist medications.

CYP2C9 is the enzyme responsible for the metabolism of warfarin, and VKORC1 is associated with vitamin K reductase. In individuals with variants in these two genes, significant alterations in drug metabolism and deactivation can result. Individuals with CYP2C9 variation took a median of 95 days before they achieved a stable and effective dosage regimen, while experiencing a higher incidence of bleeding. Patients presenting with two variant alleles (both CYP2C9 and VKORC1) required a 15% to 30% lower maintenance dose to maintain stable blood levels according to international normalized ratio (INR) standards of care. Another study of both the CYP2C9 and VKORC1 gene variants found that about 35% of the population required altered drug dosing.9

Back to Top | Article Outline

Cardiovascular pharmacologic concerns

Large clinical trials can identify adverse effects and adverse reactions in pharmacology. Results of these trials, however, can't be used to predict the effect a drug may have on an individual patient.10 Cardiovascular pharmacogenetics identified alterations based on genetic mutations over 20 years ago in studies of hydralazine and procainamide. Current research is centering on drug target proteins, such as are found in the renin-angiotensin system enzymes, and the effect on angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). In addition, studies have been conducted on the efficacy of various classes of drugs, including the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) agents.11 Hopefully, research will continue to determine protocols for accurate dosing of cardiovascular drugs to decrease adverse reactions and improve outcomes.

Back to Top | Article Outline

Antihypertensive agents

Table. Genes/gene pr...
Table. Genes/gene pr...
Image Tools

Estimates suggest that about 60 million Americans have hypertension.11 Thiazide diuretics are often recommended as the drug of choice for initial therapy, but genes responsible for renal sodium reabsorption can affect the patient's responsiveness to diuretic therapy. A mutation in a G-protein gene has been found in the Black population, which puts them at risk for a low-renin, salt-sensitive, hypertensive syndrome. This mutation, however, caused a significant difference in clinical outcomes in only 5% of the patients studied.10

An additional mutation in the sodium channel genes can cause Liddle syndrome, a rare and severe salt-sensitive hypertensive syndrome caused by an autosomal dominant gene. Patients often present in adolescence with severe hypokalemia.12 In this case potassium-sparing diuretics such as amiloride or triamterene are the drugs of choice to overcome the sodium channel aberrations. Spironolactone hasn't been found to be effective in these patients.13 About 5% of Blacks display an SNP of T594M. These patients responded more positively to amiloride therapy for BP control than to thiazide-based drugs.10 Therefore, serum sodium and potassium levels should be checked before prescribing a diuretic so that patients with these mutations can be treated appropriately with potassium-sparing diuretics.

Renin-angiotensin system antagonists include ACE inhibitors and ARBs. Clinical studies indicate that about 50% of the population failed to achieve adequate BP control when treated with an ACE inhibitor alone. In patients with heart failure, Blacks had higher morbidity and mortality from this therapy than Whites.10 If ACE inhibitor monotherapy doesn't yield an adequate response, an additional drug may be indicated.

Beta-blockers are commonly included in antihypertensive therapy, often in combination with ACE inhibitors to control BP and, more importantly, manage heart failure. Evidence has shown that beta-blocker monotherapy isn't effective for a significant number of patients, and some patients may have SNPs that put them at risk for heart failure with even low-dose beta-blocker therapy. Two SNPs that affect the beta-1 receptor have been identified and, in the future, may be used as a predictor of response to beta-blocker therapy. Other SNPs are also under investigation.9 In addition, many of the beta-blockers (propranolol, metoprolol, timolol, and carvedilol) are substrates of the CYP450 enzyme systems, namely CYP2D6 enzyme. Based on the SNPs present, variants in this enzyme can produce fast, slow, or extremely fast acetylation of the drugs, resulting in wide variation in blood levels and durations of action. In practice, the patient with heart failure would be the most affected.

Back to Top | Article Outline

Digoxin

Digoxin is a substrate of P-glycoprotein, an efflux transporter that's responsible for moving hydrophilic substances out of the brain and into the GI system, urine, and bile. P-glycoprotein affects the level of digoxin available for absorption and excretion. As with the CYP450 enzyme system, certain drugs are substrates of this protein (including carvedilol, diltiazem, and digoxin) or inhibitors of it. Inhibitors include verapamil, quinidine, cyclosporine, and ketoconazole. If P-glycoprotein is inhibited, blood levels of digoxin rise, as happens with coadministration of quinidine and digoxin.10 SNPs in the PGY1 gene can alter the blood levels and excretion of digoxin and other drugs that are substrates of P-glycoprotein.14 Practitioners need to consider the role of P-glycoprotein when prescribing cardiac therapeutic agents.

Back to Top | Article Outline

Anticoagulants and antiplatelet agents

Table. Examples of i...
Table. Examples of i...
Image Tools

The effect of the gene variant of CYP2C9 on warfarin blood levels has been discussed. The most disturbing result of this variant is the risk of bleeding. Alterations in pharmacodynamics or pharmacokinetics as a result of genetic SNPs in either CYP2C9 or VKORC1 can also alter the dosage requirements of the drug. Wilke and colleagues developed a mathematical model to be used for altering dosages based on the INR response during the first 30 days of warfarin use.15 A commercial test is available to determine whether either genetic variant is present.16 Research is now being conducted to determine the role of genetic mutations in the efficacy of glycoprotein IIb/IIIa inhibitors and aspirin. Mutations in receptor sites that affect platelet aggregation can alter the dose needed to reduce platelet activity, placing these individuals at risk for bleeding.

Back to Top | Article Outline

Lipid-lowering agents

SNPs are possible in at least six variations that would affect the efficacy of various statin agents. In the future, genetic testing may be used to prescribe statin drugs by determining who would benefit most from this expensive therapy versus those who would be more effectively treated with dietary modification. Rhabdomyolysis, an adverse reaction to statin therapy, can occur in higher numbers in individuals with a known variant. One SNP can place some individuals at higher risk for developing exercise-induced rhabdomyolysis, as was found in a study of military recruits; 40% showed development of exercise-induced rhabdomyolysis.17 Wappler et al. identified a mutation in C1840T and other gene sites, which placed patients at an increased risk for developing rhabdomyolysis.18 The capability to identify which patients would need lower dosages or very close observation during statin therapy will help practitioners personalize treatment for patients with lipid disorders.

Back to Top | Article Outline

Antiarrhythmic agents

Table. Examples of g...
Table. Examples of g...
Image Tools

SNPs may be the cause of drug-induced dysrhythmias in individuals who are prescribed antiarrhythmic agents, but have no other predisposing factors. Antiarrhythmic agents use various enzymes and ion channels. Procainamide is a sodium channel blocker that, once metabolized by the NAT-2 enzyme, becomes a potassium channel blocker. Multiple SNPs associated with the NAT-2 enzyme have been reported; these can produce slow, fast, or ultrafast acetylators of this drug. Slow acetylators appear in various populations (Whites, 50%; Blacks, 40%; and Asians, 10%) in differing frequencies. Slow acetylators are at risk for higher blood levels of the active drug and a higher incidence of drug-induced lupus syndromes. Rapid acetylation occurs in 6% of Whites, 12% of Blacks, and 45% of Asians, increasing the levels of the active metabolite resulting in increased potassium channel blockade. This process can lead to a widened QT interval and torsades de pointes. Propafenone, a sodium ion blocker, carries warnings associated with dysrhythmia initiation. This drug is metabolized by CYP2D6 and has the possibility of at least 50 SNPs contributing to varying speeds of acetylation. Slow acetylators may have higher blood levels of the drug and could experience beta blockade with prolongation of the PR interval and bradycardia. Other genetic variants can produce prolonged QT intervals with drugs such as sotalol, amiodarone, and macrolide antibacterial agents.10,19

Back to Top | Article Outline

Ethnic differences

In the 1920s, Paskind's research demonstrated a genetic difference in response to atropine sulfate. The greatest change in heart rate was observed in Whites compared with Blacks. These differences are the result of an SNP in the NAT-2 gene. Twenty such alleles of the NAT-2 gene are now known and vary from ethnicity to ethnicity. One group may have one allele and another a second allele, so testing for just one allele may miss one of the groups. Ethnic differences also occur in the two genes that affect warfarin dosages. A great variation in effective daily dosages can occur between White, Asian, and Black ethnic groups. When coupled with SNPs in CYP2D6, differences in weekly dosages among ethnic groups can vary from 24 mg/week for Asians to 36 mg/week for Whites and 43 mg/week for Blacks. This diversity highlights how some patients may be greatly undertreated.20

Back to Top | Article Outline

Genetic admixtures

Traditionally, ethnic groups were assigned by continent of origin, but research has shown that individuals may possess genetic markers that come from at least two continental populations. Although certain genetic SNPs are known to occur with higher frequency in one ethnic group versus another, like the ABCB1 gene in Blacks or the CYP2C9 in Asians, it's not safe to assume or predict an individual's possible genetic makeup based on phenotype of ethnicity or even ancestry.20

In 2003, Paabo's genomics study indicated that every human is just so many generations away from African ancestry. He classified humans as mosaics of haplotype blocks, with mitochondrial DNA passed down from our mothers and Y-chromosome DNA from our fathers. The shuffling of these haplotype blocks and additions and deletions from the original African genome resulted in variations among groups of humans and individuals.21 When comparing groups of individuals with Hispanic ancestry from Mexico, Colorado, and New York, the percentage of African ancestral history varied from 1.3% to 29.1%; the percentage of European ancestry varied from 4.2% to 62.7%. Mexicans were largely Amerindian (94.5%), Colorado Hispanics were predominately European (62.7%), and Puerto Ricans residing in New York were largely European (53.3%). Yet all three groups contained ancestral backgrounds from European, Amerindian, and African populations.22 The influence of admixture makes it impossible for the practitioner to simply say a drug will or won't work based on ethnicity alone. Pharmacogenetics, or individualized prescription, is advancing slowly.

Back to Top | Article Outline

Implications for practice

Practitioners must stay informed about research concerning new approaches in drug selection and dose prescription. Genetic tests that are available should be used to determine the proper drug and the dosage alteration needed for an individual patient as much as possible. Ethical concerns may arise about these tests, but unlike disease-based genetic tests, these assays look at specific markers associated with drug metabolism. Currently, tests are available for CYP2D6, CYP2C9, CYP2C19, CYP1A2, NAT2, and the Warfarin Safety Test identifying CYP2C9 and VKORC1 SNPs (see Examples of genetic tests associated with cardiac medications). These tests require only a cheek swab. Additional point-of-service testing for many mutations of CYP2D6 and CYP2C19 is available with AmpliChip by Roche.9 Practitioners should use ethical guidelines when educating patients about these tests. The benefits of testing include improved patient safety, improved cost containment (avoidance of ineffective drugs), improved patient outcomes, and reduced liability.

Clinically, practitioners should consider the variation of reactions to drugs when prescribing all medications. Careful history-taking and due diligence can go far to prevent clinical dilemmas due to drug reactions or failure of treatment. A working knowledge of the information listed in the enzyme and drug tables can make a difference by guiding decisions and clinical practice. Although the merging of pharmacology and genetics is an ever-evolving and highly complex process, it is here to stay. Nurses must stay current in order to provide state-of-the-art care to patients.

Back to Top | Article Outline

Pharmacogenomics terms2,11

Genetics is the study of genes and inheritance.

Genomics is the determination and study of an organism's entire DNA sequence and the identification and study of genes (disease-associated or otherwise) contained therein. Genomics focuses on the function of genes.

Pharmacogenetics is the study of genetic factors that influence an organism's reaction to a drug.

Pharmacogenomics is the study of how a patient's genetic inheritance affects the body's response to drugs.

Pharmacodynamics is the study of the concentration of a drug in the serum and the magnitude of biological or physiologic effects.

Pharmacokinetics is the study of drug absorption, distribution, metabolism, and excretion.

Genotype is internally coded, inheritable information carried by the organism. Variations in genotype represent differences in sequence within a species, such as SNPs, the location or the number of repeats, deletions, or critical splice sites.

Phenotype is the observable properties of an organism produced by the interaction of the genotype and the environment.

Genetic polymorphism, found in at least 1% of the population, is defined as multiple differences in a DNA sequence that often yields variation in a trait, such as the A, B, and O blood groups.

SNP is a variation in DNA sequence that occurs when a single nucleotide (A, T, C, or G) DNA sequence differs among members of a population. The incorporation of multiple SNPs into each DNA blueprint creates the uniqueness of individuals.

Back to Top | Article Outline

References

1. Kalow W. Pharmacogenetics: a historical perspective. In: Allen WL, Johnson JA, Knoell DL, et al, eds. Pharmacogenomics: Applications to Patient Care. Kansas City, MO: American College of Clinical Pharmacy; 2004:251–269.

2. Roden DM, Altman RB, Benowitz NL, et al. Pharmacogenomics: challenges and opportunities. Ann Intern Med. 2006;145(10):749–757.

3. Novak B. Significant pharmacogenetics and molecular factors in prescribing. Nurs Prescrib. 2007;5(8):358–362.

4. Kalow W. Historical aspects of pharmacogenetics. In: Kalow W, Meyer UA, Tyndale RF, eds. Pharmacogenomics. New York, NY: Marcel Dekker, Inc; 2001:1–9.

5. Carroll SB. The Making of the Fittest: DNA and the Ultimate Forensic Record of Evolution. New York, NY: WW Norton & Co.; 2006.

6. Smith RL. The Paton Prize Award. The discovery of the debrisoquine hydroxylation polymorphism: scientific and clinical impact and consequences. Toxicology. 2001;168(1):11–9.

7. Lehne R. Pharmacology for Nursing Care. St. Louis, MO: Saunders-Elsevier; 2007.

8. Youngkin E, Sawin K, Kissinger K, Israel D. Pharmacotherapeutics: A Primary Care Clinical Guide. 2nd ed. Stamford, CT: Appleton and Lange; 2005.

9. Lanfear DE, McLeod HL. Pharmacogenetics: using DNA to optimize drug therapy. Am Fam Physician. 2007;76(8):1179–1182.

10. Cavallari LH. Cardiovascular diseases. In: Allen WL, Johnson JA, Knoell DL, et al, eds. Pharmacogenomics: Applications to Patient Care. Kansas City, MO: American College of Clinical Pharmacy; 2004:495–528.

11. Arnett DK, Baird AE, Barkley RA, et al. Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: a scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation. 2007;115(22):2878–2901.

12. British Hypertensive Society, 2006. Liddle syndrome. http://bhsoc.org/bhf_factfiles/Liddle%20Syndrome%20Final%20Draft.doc.


14. Linardi RL, Natalini CC. Multi-drug resistance (MDR1) gene and P-glycoprotein influence on pharmacokinetic and pharmacodynamic of therapeutic drugs. Cienci Rural. 2006;36(1):336–341.

15. Lee CR. Warfarin initiation and the potential role of genomic-guided dosing. Clin Med Res. 2005;3(4):205–206.

16. Lakhman K. Days before warfarin label change: Genetex debuts DTC dosing dx. Pharmacogenomics Reporter. 2006. GenomeWeb. http://www.genomeweb.com/dxpgx/days-warfarin-label-change-genelex-debuts-dtc-dosing-dx-ashgs-validity-notice-co.

17. Sinert R, Kohl L, Rainone T, Scalea T. Exercise-induced rhabdomyolysis. Ann Emerg Med. 1994;23(6):1301–1306.

18. Wappler F, Feige M, Steinfath M, et al. Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology. 2001;94(1):95–100.

19. Howe LA, Eggert J. Influence of pharmacogenomics on disease and symptom management. Intern J Nurs Intell Dev Dis. 2007;3(2):2. http://ddna.org.

20. Engen RM, Marsh S, Van Booven DJ, McLeod HL. Ethnic differences in pharmacogenetically relevant genes. Curr Drug Targets. 2006;7(12);1641–1648.

21. Pääbo S. The mosaic that is our genome. Nature. 2003;421(6921):409–412.

22. Suarez-Kurtz G, Pena SD. Pharmacogenomics in the Americas: the impact of genetic admixture. Curr Drug Targets. 2006;7(12):1649–1658.


24. Evans WE, McLeod HL. Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med. 2003;348(6):538–549.

25. Hersh EV, Moore PA. Drug interactions in dentistry: the importance of knowing your CYPs. J Am Dent Assoc. 2004;135(3):298–311.

© 2011 Lippincott Williams & Wilkins, Inc.

Login