Pharmacogenomics study finds rare gene variants critical for personalized drug treatment

The use of genetic tests to predict a patient's response to drugs is increasingly important in the development of personalized medicine. But genetic tests often only look for the most common gene variants. In a pharmacogenomics study published online today in Genome Research (www.genome.org), researchers have characterized rare genetic variants in a specific gene that can have a significant influence in disposition of a drug used to treat cancer and autoimmune disease, a finding that will help improve the effectiveness of personalized care.

The drug methotrexate is used to treat cancers such as , and including . Common genetic variants in the SLCO1B1 gene, which encodes a transporter in the liver important for clearance of medication from the body, are present in 10-15% of the population and affect the efficiency of methotrexate clearance from the body.

Low clearance of methotrexate results in high levels in the blood and increased side effects. Rare variants could also significantly affect drug clearance, but the influence of rare versus common SLCO1B1 variants in methotrexate clearance had not yet been explored.

In this report, an international team of researchers sequenced the exons of SLCO1B1, the that code for protein, in a cohort of pediatric patients receiving methotrexate, finding rare genetic variants that have an effect on the efficiency of clearance of the drug from the body. "We showed that rare inherited genomic variants, present in as few as 1 in 699 people, account for a significant percentage of variability in blood levels of methotrexate," said Dr. Mary Relling of St. Jude Children's Research Hospital, senior author of the study. "This means that the high blood levels present in 2% of people are due to very rare genetic variants."

The research group then utilized computational algorithms to predict the potential negative impact of genomic variants identified in this study on function of the SLCO1B1 protein in the transport of methotrexate. They then tested these predictions in laboratory cell lines, confirming that these genetic variants conferred lower transport of the drug.

"Our discovery of important but rare coding variants in SLCO1B1 not only has implications for , but also possibly for other drugs," explained Dr. Laura Ramsey of St. Jude Children's Research Hospital, primary author of the study. Ramsey noted that SLCO1B1 variants are tested to inform choice of the appropriate dosage of statins, commonly used to treat or prevent high cholesterol.

Ramsey added that clinical genetic tests are currently limited, generally only testing for the most common SLCO1B1 variants. "Our findings that there are additional rare functional coding variants in this gene suggest that genotyping tests would need to expand to include rare variants in order to avoid false negative test results."

Scientists from St. Jude Children's Research Hospital (Memphis, TN), Aarhus University (Aarhus, Denmark), MD Anderson Cancer Center (Houston, TX), the University of Tennessee Health Science Center (Memphis, TN), the Sidney Kimmel Comprehensive Cancer Center (Baltimore, MD), and the University of California, San Francisco (San Francisco, CA) contributed to this study.

More information: The manuscript will be published online ahead of print on December 6, 2011. Its full citation is as follows: Ramsey LB, Bruun GH, Yang W, Trevino LR, Vattathil S, Scheet P, Cheng C, Rosner GL, Giacomini KM, Fan Y, Sparreboom A, Mikkelsen TS, Corydon TJ, Pui C, Evans WE, Relling MV. Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition. Genome Res doi: 10.1101/gr.129668.111

Related Stories

Rare gene variants linked to inflammatory bowel disease

Oct 10, 2011

(Medical Xpress) -- An international team of scientists, including researchers from Karolinska Institutet, have identified several rare gene variants that predispose to IBD (Inflammatory Bowel Disease). The study provides ...

Is short stature associated with a 'shortage' of genes?

Nov 23, 2011

New research sifts through the entire genome of thousands of human subjects to look for genetic variation associated with height. The results of the study, published by Cell Press in the December issue of the American Jo ...

Recommended for you

Science of romantic relationships includes gene factor

12 hours ago

(Medical Xpress)—Adolescents worry about passing tests, winning games, lost phones, fractured bones—and whether or not they will ever really fall in love. Three Chinese researchers have focused on that ...

Stress reaction may be in your dad's DNA, study finds

Nov 21, 2014

Stress in this generation could mean resilience in the next, a new study suggests. Male mice subjected to unpredictable stressors produced offspring that showed more flexible coping strategies when under ...

More genetic clues found in a severe food allergy

Nov 21, 2014

Scientists have identified four new genes associated with the severe food allergy eosinophilic esophagitis (EoE). Because the genes appear to have roles in other allergic diseases and in inflammation, the ...

Brain-dwelling worm in UK man's head sequenced

Nov 20, 2014

For the first time, the genome of a rarely seen tapeworm has been sequenced. The genetic information of this invasive parasite, which lived for four years in a UK resident's brain, offers new opportunities ...

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.