University of Utah Department of Human Genetics Pharmacogenomics Louisa A. Stark, Ph.D. Director

Adverse drug reactions Every year, over 106,000 people in the United States die from adverse reactions to correctly prescribed doses of drugs. Another 2.2 million suffer serious, but not deadly, side effects. A major health issue

4 th leading cause of death in the U.S. 15% of U.S. hospital admissions $136 billion in medical costs (2001) 80-85% of drug response is due to genetics Adverse drug reactions A major health issue

First emerged around the 1950’s Scientists began to notice that different responses to drugs ran in families and ethnic groups. Field of pharmacogenetics

Tour of the Basics DNA: The basis of genetics DNA Cell Chromosomes

We are all 99.9% similar in our DNA. Individuals vary by only 0.1% Individual variations may correlate with different responses to medicines and magnitude of disease risk. Human Genome Project data

Pharmacogenetics

Goal of pharmacogenetics

SNPs: The key to pharmacogenetics SNiPping Away at the Problem

Break down more than 30 classes of drugs –Beta-blockers, tricyclic antidepressants, morphine derivates, antiarrhythmics, etc. Poor metabolizers – need lower dose –6% of Caucasians –2% of African Americans –1% of Asians Ultra-rapid metabolizers – need higher dose –20% of Ethiopians –7% of Spanish –1.5% of Scandinavians Liver enzymes

Pharmacogenetics today: leukemia Chemotherapy for leukemia

5-flurouracil (5-FU)  Chemotherapy agent  Stops tumor formation  Used to treat colorectal, breast, lung, cervical, neck and head cancer  Effective for 20-30% of patients with colorectal cancer  Genotype predicts treatment effectiveness  Patients with 1 genotype are 5 times more likely to respond successfully to treatment with 5-FU than patients with another genotype Pharmacogenetics today: cancer

4 major statin drugs for lowering cholesterol Clinical trial looking for genetic associations in patient response to each drug Of 10,000 people in Iceland taking statins, 2,000 do not respond and are related to each other Pharmacogenetics today: cholesterol

Future applications: depression Three high school students, Marti, Toni, and Brianna, sought treatment for depression. Their doctor prescribed nortriptyline, a common antidepressant medication. After taking the medication for a month, Marti felt much better. She had few episodes of depression and no adverse reactions to the drug. Toni's depression also had subsided. However, she could not sleep and often felt nauseated and anxious. The medication didn't do much for Brianna: she felt neither better nor worse and had no adverse reactions to the drug.

Gene expression

Gene expression: application to obesity

Create diagnostic tests to predict whether a patient has a genetic predisposition to obesity. –Examine the DNA sequence of a person's obesity-related genes to detect genetic signatures that predict a predisposition to obesity. –Examine a tissue sample for abnormal gene expression patterns that indicate a predisposition to obesity. Design drugs intended to treat or prevent obesity. –Develop drugs that inhibit the function of proteins related to obesity. Design drugs to control expression of obesity genes. –Drugs would interact directly with DNA in key cells and tissues to prevent genes from being turned on or off. Gene expression: application to obesity

People vary in their risk of getting certain diseases. Example: –Two 15-year-old boys are the same height and weight, with similar diet and exercise habits. –Determine risk for developing diabetes. Determining disease risk

New, more accurate diagnostic tests – Predict a patient's response to specific drugs based on his or her genetic profile. Benefits of pharmacogenetics Personalized drug therapies –Match a patient with effective and safe medications based on information from diagnostic tests. Personalized disease prevention strategies –Developed using genetic tests that estimate a patient's risk of getting a particular disease, combined with personalized drug therapies.

Pharmacogenetics: public health issues Population-based screening tests  How will we weigh the medical and economic benefits of genotyping all individuals in order to direct an intervention to only a few?  Example: Women with the factor V Leiden allele who use oral contraceptives are at greatly increased risk of venous thrombosis. Should all women be tested for this allele before beginning to take oral contraceptives?

Issues related to pharmacogenetics Drug development for less-common SNP profiles  Who will pay for development of less profitable drugs? Insurance and Medicaid coverage  Will potentially expensive diagnostic tests be covered? Education of health care providers  How will providers be trained to understand new diagnostic tests and use them when treating and advising patients? Ethical and privacy issues  Who will have access to genetic information and databases?  How do families handle conflicts when one person wants to be tested and others do not?  Should parents decide whether their children should be tested?

Genetic Science Learning Center Website To learn more about pharmacogenomics ScientificAmerican.com