Nature Medicine | Spoonful of Medicine

Study challenges genetic conventions in personalized medicine


A more refined genomic approach to personalized medicine could make drugs such as statins safer for patients, the authors of a new paper recommend.

Hospitals increasingly use genetic testing to determine whether people are at risk for developing toxic levels of certain drugs in their bloodstreams due to common genetic variants that cause slower clearance of medication by the liver. A study published today in Genome Research strengthens the case for health providers to incorporate tests for rare variants that also influence how the body clears medications from the blood.

The study focused on the medication methotrexate, used to treat acute lymphoblastic leukemia as well as autoimmune disorders such as rheumatoid arthritis. (The drug is sold as Trexall, Rheumatrex by Teva Pharmaceutical Industries and DAVA Pharmaceuticals, respectively.) The SLCO1B1 gene encodes a transporter in the liver that is important for clearing the drug from the body.

Scientists already know that about 10% of the population possesses a common variant of the SLCO1B1 gene that causes methotrexate to be cleared from the body more slowly. As a result, doctors personalize the dosage of methotrexate based on common gene variants to avoid increased side-effects in those patients with low drug clearance. The side–effects of methotrexate are far from trivial — a build-up of medication in the blood can lead to mouth and intestinal sores and kidney failure.

However, in the report published today researchers report that in an additional 2% of people with low clearance, rare gene variants in SLCO1B1 are to blame.

“They were very robust results,” says lead author Mary Relling, head of pharmaceutical sciences at St. Jude Children’s Research Hospital in Memphis, Tennessee. “In a clinical setting like this one, finding a genetic test that could help 2% of patients is a big step.”

The research group sequenced SLCO1B1 completely in children receiving methotrexate. In a small portion of people in the study — 14 in 699 — rare inherited variants of the gene showed up and affected methotrexate clearance.

The findings have potential implications beyond methotrexate treatment. The SLCO1B1 gene is also used to determine the appropriate dosage of cholesterol-lowering drug simvastatin (the brand-name version, Zocor, is sold by Merck).

“Since we have showed that rare variants are important, this might provide enough evidence that doctors will entirely sequence the gene rather than just looking for common variants,” says study co-author Laura Ramsey, a post-doctoral fellow at St. Jude’s. She points out that as sequencing costs fall, it will be easier for hospitals to afford rare variant analysis

In addition, the Clinical Pharmacogenetics Implementation Consortium (CPIC), an organization founded in 2009 to bring pharmacogenetic tests such as this one to clinical settings, is looking into adding both rare and common variants of SLCO1B1 to its list of drug/gene pairs. That addition would help bring rare variant genetic testing to patients being prescribed methotrexate and statins.

Relling is a member of CPIC and thinks SLCO1B1 is a good candidate for implementation because of its implications for statin prescription. She adds, “If you really want to be complete, you have to look at rare variants as well.”

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    david frenkel md said:

    How interesting, and useful for the slow metabolizers. I wonder what the cost for the testing is, versus the total cost savings of using lower doses . Thanks for the interesting blog!