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Danger Abounds When Meds and Your Genes Don’t Mix

dna strand

Feb. 28, 2019 -- This month, Karen Daggett celebrated 10 years of life she didn’t think she’d have. On Valentine’s Day 2009, she didn’t feel well enough to go out to a couple’s dinner with her friends in Marco Island, FL. But her husband insisted she go with him, and for that, Daggett is thankful.

“If I had stayed home [alone] that night, I probably would have died,” she said.

Daggett hadn’t been herself since a heart procedure for atrial fibrillation (irregular heartbeat) at Mayo Clinic in Rochester, MN, a few months earlier. The procedure went as planned, but afterward, she just got sicker and sicker. Her blood pressure was out of control -- always too high or too low. She was nauseated. Her vision was sometimes blurred. And her usually soft, rosy complexion was ashen, scaly, and leathery.

“I looked like death,” she said. “Chalky gray and dull eyes -- that’s what I looked like.”

At the restaurant, Daggett’s vision went black at times. She grabbed her husband’s arm. “I need to go to a doctor now,” she said to him.

When Daggett arrived at the emergency room 30 minutes away in Naples, she couldn’t remember her birthdate, and muscle tremors rippled through her body. Doctors put her on IV fluids for severe dehydration and ordered her to suck down a lemonade loaded with potassium. She did, and her birthdate came back to her.

She remained stable on IV fluids, but without them, she’d dehydrate again. Her liver simply wasn’t working, and no one knew why. After 5 days of tests, the doctors threw up their hands and suggested she go back to Mayo, where doctors knew her.

After 8 more days of tests at Mayo, Daggett heard the words she’d been waiting to hear for months. “My doctor hugged me and said, ‘We know what’s wrong with you,’ ” she recalls.

A genetic test showed that she had a variation in one of her genes -- CYP2D6 -- that made her body unable to process the medications she received after her heart procedure. Metabolized by the liver, the drugs had built up there and nearly caused the organ to shut down. “The doctor said, ‘You cannot metabolize anything we’ve been giving you. You’re done. All your meds are gone,’” Daggett recalls. As she stopped her medications over the coming months, she slowly recovered.

Genes can have a big impact on how well your medications work for you. “When we pick a medication, we want it to have the best efficacy with the fewest side effects. There are lots of things that go into that decision, and one of them is genetics,” says Tracy Glauser, MD, who co-directs the Genetic Pharmacology Service at Cincinnati Children’s Hospital.

What Is Pharmacogenomics?

Your genes, passed down from your parents, play a big role in what you look like: things like the color of your hair, and whether you have a chin cleft or detached earlobes. But, perhaps more importantly, your genes carry the instructions for all the things your body does. That includes metabolizing medicine. Pharmacogenomics is the study of the relationships between genes and the drugs (or pharmaceuticals) that they help process.

Different genes tell the body how to break down different drugs. A variant in one of those genes could affect how you process one, some, or all of the medications that gene is responsible for. Some gene variants could make you so sensitive to a drug that you only need half as much as most people to get the same response. Another variant could mean that you need twice as much. Still another could cause you to have a potentially fatal reaction to certain drugs.

Almost everyone -- 99% of people -- has at least one gene variant that would cause them to respond to one or more medications differently than expected. Many people have several of these variants. Researchers have discovered some 200 (and counting) drug-gene pairs in which a specific variant changes how a person responds to a single drug or a whole class of drugs. These drugs treat depression, heart disease, cancer, HIV, and pain, among other common conditions.

“The older you get, as you take more medications, the more likely you are to be prescribed a high-risk drug,” says Mary Relling, PharmD, who co-leads the Clinical Pharmacogenetics Implementation Consortium (CPIC), a team of experts that writes guidelines for doctors on how to treat patients whose genetic makeup may interfere with a needed drug.

You might expect that the chance of a bad reaction -- or the chance of having no response to a drug at all -- is just a risk you have to take to reap the benefits of modern medicine. But your genes could help predict those risks. Genes could be behind some of the 1 million emergency room visits linked to medication problems every year. A simple cheek swab DNA test, before your doctor ever writes a prescription, could prevent those bad reactions and help you get just the right medication, at the right dose, at the right time.

For people who have a known gene variant that affects drug metabolism, “it shortens the list of drugs that you need to keep trying. Going from one drug to another that isn’t working or is having severe side effects can be a frustrating, time-consuming, and costly experience,” says Jennifer Hockings, PharmD, a pharmacogenomics clinical specialist in the Genomic Medicine Institute at Cleveland Clinic.

An Inherited Gene

Daggett’s CYP2D6 gene has little to no activity. She is what’s called a CYP2D6 poor metabolizer. Unfortunately, this gene is responsible for processing 1 in 4 drugs on the market today, including a slew of heart medications -- quite a few of which she has taken -- and most antidepressants.

Drug-metabolizing genes -- just like the genes that contribute to physical appearance -- vary by ethnic group. About 1 in 10 Caucasians are CYP2D6 poor metabolizers. Only about half that many African-Americans are.  These gene variants run in families, too.

After Daggett’s ordeal, she sent a letter to as many siblings, cousins, and other relatives as she could reach, explaining why they should be tested for the gene variant, too. Twenty-three family members shared the same hereditary variant, and many made big changes to their health care because of it. One of Daggett’s sisters got a breast cancer diagnosis 2 weeks after learning about the gene. The variant meant that she couldn’t take tamoxifen -- a drug used to keep breast cancer from coming back. Had she taken the drug, it could have had no impact on her risk of the disease returning. Doctors put her on another drug and, 10 years later, she continues to be cancer-free.

“For the 10% of women who have this genetic defect, we know that they will benefit more from a different drug besides tamoxifen,” says Relling. “This recommendation applies to a high number of patients with a serious disease.”

Another of Daggett’s sisters learned why her blood pressure medication had never worked for her, and doctors put her on a more effective dose. A brother learned why pain medication had never seemed to work for him. Daggett’s niece couldn’t have general anesthesia for a recent surgery because of her genetic inability to metabolize it. She had to have the surgery under epidural anesthesia instead.

Many Genes, Many Drugs

Other genes besides CYP2D6 can stop a drug from doing its job.

Any one of several specific variants in the gene HLA-B can trigger a potentially lethal reaction to allopurinol (a drug for kidney stones and gout), abacavir (a drug for HIV), and carbamazepine (an anti-seizure drug that can also treat nerve pain and bipolar disorder). People with one of these variants who take one of these medications are at high risk for Stevens-Johnson syndrome and toxic epidermal necrolysis. In these severe skin conditions,  the skin blisters and falls off as it would in a serious burn.  About 3 in 10 people who get toxic epidermal necrolysis will die from it.

Most prevalent in Asian populations, these HLA-B variants can be so dangerous that the National Health Security Office in Thailand offers gene testing and provides ID cards for people with risky variants to carry in case they land in a hospital where a doctor needs to give them one of the implicated drugs.

A variation in OPRM1 can make opioid-based painkillers useless. Opioids latch onto opioid receptors in the brain and block pain. A variant in OPRM1 can change those receptors so that the drugs can’t latch onto them and do their job. Someone with this variant who receives Dilaudid (hydromorphone), for example, in order to pass a kidney stone would feel every excruciating second of the process.

A change in the gene SLC6A4 can mean that some antidepressants take longer than the typical 4 to 6 weeks to get into your system and have an effect, but that they will eventually work. This could help people who switch from one antidepressant to the next for months without relief.

“I had a patient who, over the course of a couple of years, had tried several different antidepressants, each one for about 6 weeks, but kept coming back and saying ‘I’m not feeling any better,’ ” Hockings says. Genetic testing showed the patient needed more time to respond to antidepressants. A plan was made, and “this time, instead of switching, we stayed the course. Twelve weeks later, sure enough, the patient was doing better.”

Personalized Prescriptions

Some hospitals, such as St. Jude Children’s Research Hospital and Cincinnati Children’s, preemptively test or offer to test every patient for genetic variants related to drug metabolism when they are admitted.

“Within any 1-year period, 50% of patients are likely to be prescribed a high-risk pharmacogenetic drug,” says Relling, who also chairs the Pharmaceutical Sciences Department at St. Jude Children’s Research Hospital, where every child admitted is offered genetic testing to help predict drug response.

At Cincinnati Children’s, every child who comes in for psychiatric problems has a genetic test to help guide prescribing. Genes can interfere with some 36 psychiatric drugs, says Glauser. “Trial and error results in lots of serious side effects along with a delay in getting you where you want to go with your treatment.”  

When there is enough evidence for an interaction between a particular gene and drug, and when an alternative exists, the Clinical Pharmacogenetics Implementation Consortium writes guidelines for doctors on how to treat patients who have a variant that could interfere with a drug they need.

The FDA requires special labeling or package inserts about potential gene-drug reactions on more than 200 medications. In some cases, such as the HIV drug abacavir, the label advises doctors to test for a risky gene variant before prescribing the medication.

Otherwise, a curious person might seek testing simply to have the information or to see whether their medications could work better for them. For that, you could pay a few hundred dollars out-of-pocket. But, if not, doctors might only discover genetic reactions to drugs after they have already taken a toll.

Daggett doesn’t want anyone to go through that. “There’s no earthly reason that I should still be alive,” she says. She tells family, friends, and neighbors about how genes can interact with drugs every chance she gets. “I don’t mind talking to anybody about it. I preach it all the time.”

WebMD Health News Reviewed by Neha Pathak, MD on February 28, 2019

Sources

Karen Daggett, Frazee, MN.

Mary Relling, PharmD, chair, pharmaceutical sciences, St. Jude Children’s Research Hospital; team leader, Clinical Pharmacogenetics Implementation Consortium.

Jennifer Hockings, PhD, PharmD, pharmacogenomics clinical specialist, Genomic Medicine Institute, Cleveland Clinic.

Tracy Glauser, MD, co-director, Genetic Pharmacology Service, Cincinnati Children’s Hospital.

The Journal of Molecular Diagnostics: “Preemptive Pharmacogenomic Testing for Precision Medicine: A Comprehensive Analysis of Five Actionable Pharmacogenomic Genes Using Next-Generation DNA Sequencing and a Customized CYP2D6 Genotyping Cascade.”

FDA.gov: “Table of pharmacogenomics biomarkers in drug labeling.”

Office of Disease Prevention and Health Promotion: “Adverse drug events.”

Stanford University: “Understanding genetics.”

University of Utah: “Observable human characteristics.”

National Library of Medicine, Genetics Home Reference.

Medical Genetics Summaries: “Tamoxifen therapy and CYP2D6 genotype.”

PharmGKB: “Very important pharmacogene: HLA-B.”

Mayo Clinic: “Stevens-Johnson Syndrome.”

F1000 Research: “Toxic epidermal necrolysis.”

Frontiers in Genetics: “HLA-B allele and haplotype diversity among Thai patients identified by PCR-SSOP: evidence for high risk of drug-induced hypersensitivity.”

Clinical Pharmacogenetics Implementation Consortium.

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