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Based on genes, nearly everyone is likely to have an atypical response to at least one drug

Stanford Medicine researchers found that, based on genetic makeup, 99.5% of people are likely to have an atypical response to at least one drug.

Every drug, from morphine to ibuprofen, has a standard dose -- a sort of one-size-fits all recommendation. But a new study suggests that when it comes to drug doses, "one size fits all" rarely applies.

Stanford Medicine professor Russ Altman, MD, PhD, and a team of scientists found that almost everyone (99.5% of individuals) is likely to have an abnormal or "atypical" response to at least one therapeutic drug. This, at least, is the case for people in the United Kingdom, as the study's data came from the UK Biobank, a project that collects, studies and shares data.

The research found that nearly a quarter of the study's participants had been prescribed a drug for which they were predicted to have an atypical response, based on their genetic makeup. On average, participants were predicted to have an atypical response to 10 drugs.

"Ultimately, the hope is that we can show how pervasive drug response variability is and encourage more doctors to rethink the standard prescription protocols that are largely used today and use genetic testing to predict and adjust for this variability," said Altman, who is an expert in pharmacogenetics, a field that studies the intersection of drugs and genetics.

Genes encode how we react to drug molecules

An "atypical" drug response encompasses a lot of things; but generally speaking, it means a certain drug might not affect one person the way it does another.

For instance, someone who has an atypical metabolic response might process that drug more efficiently, strengthening its initial effects but decreasing its efficacy over time. On the flip side, it could mean that that person is unable to metabolize the drug at all, leaving them without therapeutic aid, or even with dangerous side effects.

These differences in response to a drug are partially due to our genetics. Specific proteins -- workhorse molecules in the body -- break down drugs in order for the body to benefit from the therapeutic. Those proteins are regulated by a specific group of genes. Natural variation in those genes leads to differences in how an individual's body reacts to a given drug molecule.

Altman and his team, including graduate students and first authors of the study Greg McInnes and Adam Lavertu, analyzed data from nearly 500,000 participants.

For 230,000 participants in the study, the team had primary care data going back about 30 years. That includes which drugs had been prescribed, the dose, and all of the patient's different diagnoses. The researchers also had access to detailed genetic information about each patient. They paid special attention to genetic variations in a group of genes that are known to influence the human drug response.

By comparing an individual's genetics against the variations known to exist in the group of drug-response-associated genes, the researchers could predict how any given patient might respond to a drug.

Expanding drug-gene variant interaction analyses

"Pharmacogenetics as a field has been around for a long time, but it hasn't really been adopted into clinical use," McInnes told me. "It's been growing in the last few years as more people realize the impact that it could have on personalized health. For a long time, it's been this overlooked aspect of genetics that I think is actually one of the most clinically actionable advances that has come out of human genetics."

What's more, he said, the wide variability in the human drug response applies to common therapeutics most everyone has encountered or is familiar with -- ibuprofen, codeine, statins and beta blockers among others.

Moving forward, Lavertu says that the goal is to expand drug-gene variant interaction analyses into more diverse populations. The data from the UK Biobank provided critical insight, but it was largely only representative of a British population, where the majority shares European ancestry. A next step for the researchers is to investigate the same genes in the Million Veteran Program, a government research program with a more diverse study population, that is examining how genes, lifestyle and military exposures affect health and illness.

"Our hope is that doing more of these studies will help us find new relationships between genetic variants and drug response, so that pharmacogenetics can benefit more people," Lavertu said.

Photo by Michał Parzuchowski 

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