Genetic Factors That Increase Susceptibility to Drug Side Effects

Some people take a common medication and feel fine. Others get sick-sometimes dangerously so-from the same dose. It’s not always about dosage, allergies, or lifestyle. Often, it’s written in their DNA.

Why Your Genes Make You React Differently to Medications

Your body doesn’t process drugs the same way everyone else’s does. That’s because of tiny differences in your genes that control how drugs are absorbed, broken down, and used. These differences can turn a safe medicine into a dangerous one-or make it completely ineffective.

For example, the CYP2D6 gene controls how your liver breaks down over 25% of commonly prescribed drugs, including antidepressants, painkillers like codeine, and even tamoxifen for breast cancer. Some people have a version of this gene that makes them ultra-rapid metabolizers. They turn codeine into morphine so fast that it can cause life-threatening breathing problems, especially in babies nursing from mothers who take it. Others are poor metabolizers-they barely break down the drug at all. That means the medicine builds up in their system, causing side effects like dizziness, nausea, or even organ damage.

Then there’s CYP2C19, which affects drugs like proton pump inhibitors (PPIs) used for acid reflux. People with certain variants of this gene can have five to ten times higher drug levels in their blood. For kids, that means they need much lower doses to avoid side effects like bone loss or nutrient deficiencies. The FDA lists these gene-drug pairs in its official Table of Pharmacogenetic Associations, updated in October 2023, with clear recommendations for doctors.

When a Gene Can Trigger a Life-Threatening Reaction

Not all side effects are mild. Some are sudden, severe, and deadly. The HLA-B*15:02 gene variant is one of the clearest examples. People with this variant who take carbamazepine or phenytoin-common anti-seizure drugs-have a 100 to 150 times higher risk of developing Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN). These are rare but devastating skin conditions where the top layers of skin blister and peel off, like a severe burn. The reaction can be fatal.

Because of this, doctors now test Asian patients for HLA-B*15:02 before prescribing these drugs. If the variant is present, they avoid the medication entirely. The negative predictive value here is nearly 95%. That means if you don’t have the gene, you’re extremely unlikely to get SJS/TEN from these drugs. That’s one of the strongest genetic safeguards we have in medicine today.

Another example is HLA-B*57:01, which predicts a severe reaction to the HIV drug abacavir. About 5% of people who carry this gene will develop a dangerous hypersensitivity reaction. But here’s the twist: 95% of people who carry it won’t react at all. So while the test is perfect for ruling out risk (negative predictive value is 100%), it’s not great at predicting who will react. That’s why doctors still monitor all patients closely-but they won’t give abacavir to anyone who tests positive.

Why Heart Drugs Can Be Risky for Some

Cardiac drugs are especially tricky. A drug meant to treat irregular heartbeat can accidentally trigger a dangerous rhythm called torsades de pointes. About 5% of patients who develop this side effect have hidden mutations in genes like KCNQ1, KCNH2, or SCN5A. These are the same genes linked to congenital Long QT Syndrome-a condition people are born with that makes their heart’s electrical system unstable.

In other words, some people don’t have a diagnosed heart condition until a drug reveals it. The drug doesn’t cause the problem-it uncovers it. That’s why genetic screening is becoming more common before prescribing certain antiarrhythmics or even some antibiotics and antipsychotics that can affect heart rhythm.

Even something as common as statins for cholesterol can cause muscle damage in people with a variant in the SLCO1B1 gene. That variant makes it harder for the liver to clear the drug, so it builds up and breaks down muscle tissue. A 2024 study showed that a combination of 15 genetic markers-not just one-could predict this side effect with 82% accuracy. That’s a big step beyond testing just one gene.

Why Some Side Effects Are Easier to Predict Than Others

Not all side effects are created equal when it comes to genetics. A 2024 study in PLOS Genetics found that cardiovascular side effects-like high blood pressure, fast heartbeat, or irregular rhythm-are the most predictable. The positive predictive value (how often a genetic marker actually leads to the side effect) was nearly 30%. That’s high for genetics.

Gastrointestinal side effects-like nausea, diarrhea, or stomach pain-are much harder to predict. Their genetic links are weak. That’s because these symptoms often come from how the drug irritates the gut, not from how your genes process it. So if you get nauseous on a pill, it’s more likely the drug is just rough on your stomach, not because of your DNA.

This matters because it tells doctors where to focus. Testing for HLA-B*15:02 before giving carbamazepine? Absolutely. Testing for a gene that causes nausea on antidepressants? Not worth it yet.

What’s Being Done About It

The science is solid. The tools exist. But using them in real clinics? That’s still a challenge.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has created 24 clear guidelines for doctors on how to adjust doses or avoid drugs based on genetics. But only 10-15% of doctors actually use them in daily practice. Why? Many feel untrained. A 2023 survey found 68% of physicians didn’t feel confident interpreting genetic test results.

Hospitals like Mayo Clinic and Vanderbilt have built systems that test patients ahead of time-before they even get a prescription. At Vanderbilt’s PREDICT program, genetic results changed prescribing decisions for over 12% of patients. Most of those changes meant avoiding a drug or lowering the dose to prevent harm.

But it’s expensive. A full pharmacogenetic test costs between $250 and $500. Insurance doesn’t always cover it. Medicare Advantage plans covered preemptive testing for only 28% of patients in 2023. And integrating the results into electronic health records? That can cost a hospital over a million dollars and take over a year.

What You Can Do

If you’ve had a bad reaction to a medication, or if your family has, it’s worth asking your doctor about pharmacogenetic testing. It’s not a magic bullet-but it can prevent serious harm.

Some people get tested through direct-to-consumer services like 23andMe or Color Genomics. But be careful: not all results are clinically validated. The FDA has issued warnings to companies that overstate what their tests can do. Always talk to a doctor or pharmacist before making changes based on a test.

If you’re starting a new medication-especially for mental health, heart conditions, or chronic pain-ask: “Is there a genetic test I should have before taking this?”

And if you’ve had a side effect that no one could explain, your story could help. Patient data is helping researchers find new gene-drug links every year.

What’s Next

The future is moving fast. The FDA now requires genetic testing for 18 drugs and is pushing for 35+ by 2027. The All of Us Research Program has already returned pharmacogenetic results to over 200,000 people-and found that 42% carry at least one actionable variant.

Eventually, your entire genome might be stored in your medical record, checked automatically when a new drug is prescribed. That’s not science fiction-it’s already happening in top hospitals.

The goal isn’t to eliminate side effects. It’s to make them rare. To make the right drug, at the right dose, the first time-for everyone.