A study headed by researchers at the University of Pittsburgh has found that everyone in a diverse, nearly 100,000-person sample from the National Institutes of Health’s All of Us Research Program (All of Us) carried at least one genetic variant that affects how their body processes medications. The results also showed that a quarter of those people had been prescribed a drug that is known to be impacted by the variant they carried.

The researchers say the discovery highlights the value of genetic testing for some medications and that electronic health record alerts could be helpful when a clinician prescribes one of these drugs. Such an alert would allow the clinician to consider prescribing an alternate medication or adjusting the dosage, if appropriate.

“Many people have experience with taking a medication that is not working well for them or that has a side effect,” said Philip E. Empey, PharmD, PhD, associate professor in Pitt’s School of Pharmacy and associate director for pharmacogenomics at the Institute for Precision Medicine at Pitt and UPMC. “While many things impact how a patient responds to medication, our research tells us that genetics could be [a] factor for a large proportion of patients and it points to the value of precision medicine in prescribing.”

Empey is senior author of the researchers’ published paper in Science Translational Medicine, titled “Frequency of pharmacogenomic variation and medication exposures among All of Us Participants.”

Pharmacogenomics (PGx) promises improved outcomes through individualized prescribing, the authors wrote in their paper. “PGx can impact drug effectiveness and toxicity. Many commonly prescribed medications have genotype-guided dosing or drug selection recommendations in their Food and Drug Administration (FDA) approved labeling or in guidelines developed by the Clinical Pharmacogenetics Implementation Consortium (CPIC).”

More than 300 medications have information on their labels about genetic variant interactions, where genetic testing may be of value to guide prescribing, Empey said. One example is a chemotherapy drug used for colon cancer that could have serious toxicity in up to 8% of patients who carry these genetic variants, so those patients are proactively tested before treatment. However, the authors noted, “Despite the strong evidence supporting the use of PGx data in clinical practice, broader implementation is limited in part by the relative paucity of data on the frequency of variants, alleles, and predicted phenotypes across diverse biogeographical groups.”

For their reported study the research team used data from the National Institutes of Health (NIH) All of Us Research Program, an initiative that aims to gather data from one million people across the U.S. to help better understand how lifestyle, environment, and genes influence health and disease. Pitt is a key partner in the program, launching All of Us Pennsylvania in 2018. “This study represents one of the largest and the most diverse PGx datasets with linked medication exposures events to date,” the team noted. “All of Us has particular value in identifying and understanding the frequency of both previously unknown and rare variants because of the size of the cohort, comprehensiveness in genotyping approach, and the genetic diversity.”

The team evaluated the frequency of 16 genetic variants known to impact the effectiveness or toxicity of various medications among nearly 100,000 All of Us participants. The results showed that everyone in the study was found to carry at least one such variant with a median of nine variants. “We found 100% of participants carried at least one known PGx variant and nearly all (99.49%) had a predicted phenotype for a gene which has a CPIC or FDA recommendation for a change in prescribing,” they stated. “Among nearly 100k participants in All of Us Research Program, pharmacogenomic variants and actionable results are common and the diversity of the cohort provided for identification of novel variants and population frequencies.”

By then matching the genetic data to the participants’ medical records, the research team also found that more than 24% of participants had been prescribed at least one medication known to interact with a variant they carried. “Clinical impact was high with 24.38% of participants having both an actionable phenotype for these pharmacogenes and a prior exposure to an impacted medication with pharmacogenomic prescribing guidance,” they wrote. The most common medications identified in the review were ondansetron (anti-nausea), ibuprofen (anti-inflammatory), omeprazole and pantoprazole (both treat acid reflux and heartburn), and atorvastatin (lowers cholesterol).

The team also identified over 17,000 novel variants and reported the frequency of known medication-linked genetic variants across multiple ancestry groups, including in populations where these frequencies were not previously estimated. “Importantly, we report thousands of novel variants as well as hundreds of alleles and predicted phenotypes that deviate from known frequencies and/or were previously unreported, especially within Americas and African ancestry groups.” they wrote in summary.

“The limited diversity of racial and ethnic groups in early studies is a challenge in genetic research and skews risk estimates,” Empey said. “That’s part of the beauty of the All of Us Research Program—it was intentionally designed to help close these gaps by including people from a wide range of age groups, backgrounds, and life experiences. It also underscores the value of having a large precision medicine dataset where whole genome testing data can be studied along with clinical data.”

Empey said it will be up to policy makers and health insurers to weigh the benefits of widespread genetic screening for variants that interact with medications against the cost, and that this is a very active area of research. He said it makes sense to screen patients with a panel test that can look for common variants that are known to affect many medications and have these results in their medical record, much like a test for kidney function. This approach is also being applied in situations where patients are on many medications at the same time or in patients starting certain medications known to be impacted by genetics, such as clopidogrel, a medication used after cardiac stenting.

People who have already undergone pharmacogenomic testing should be sure to share their results with their pharmacists and prescribers so that it is integrated with their electronic health record, said Empey, who is leading efforts at UPMC to make it easy for clinicians to see if a patient carries variants that may affect a medication that they’re prescribing and recommend changes when needed.

“Just like with any new technology, it comes down to responsible implementation,” Empey said. “Costs are coming down and the data is increasing, so it is important for patients and clinicians to be aware that the use of precision medicine in prescribing is becoming commonplace.”