photo by Clay Eals
About half of Caucasian and Asian individuals carry a genetic mutation that interferes with their ability to metabolize folate, a B vitamin found in fruits, grains, and dark green, leafy vegetables.
Also available in supplement form as folic acid, this important nutrient perhaps is best known for its role in preventing birth defects in the brain and nervous system.
People with sluggish folate metabolism generally are at no greater disease risk than the rest of the population. However, when exposed to a poor diet or certain drugs, these people can suffer significant clinical consequences, particularly if they are among the 10 percent of Americans born with the most limited ability to process this nutrient.
Dr. Neli Ulrich, investigator in the Public Health Sciences Division, and colleagues from the Hutch and the University of Washington reported these findings in the July 1 edition of Blood.
The study involved co-investigators from the Clinical Research Division (Drs. Rainer Storb, Mark Schubert and John Wagner) and PHS (Drs. John Potter, Yutaka Yasui and Jeanette Bigler). Others in both divisions also contributed substantially to the work. Funding for this pilot study came from an interdisciplinary support grant from the National Cancer Institute.
The analysis involved 220 bone-marrow transplant patients who received methotrexate, an antifolate drug used as standard therapy for preventing graft-vs.-host disease, a common complication of marrow transplantation. In analyzing the patients' stored DNA, Ulrich and colleagues found that those with the lowest activity of a key folate-metabolizing enzyme (called methylenetetrahydrofolate reductase, or MTHFR) suffered the highest degree of toxicity and treatment complications.
Side effects of methotrexate include oral mucositis and delayed blood-platelet recovery. Oral mucositis is characterized by a painful inflammation of the tissues lining the mouth, throat and gastrointestinal tract. Delayed platelet recovery can interfere with blood clotting and require expensive platelet transfusions.
Patients with two copies of the MTHFR variant had less than half the rate of folate-enzyme activity compared to those with no copy of the mutation, resulting in a 36 percent increase in oral mucositis symptoms and a 34 percent slower recovery of platelet counts. The study is the first of its kind to show the impact of this variant on drug response.
"Oral mucositis is one of the worst side effects of marrow transplantation from the patient's perspective because it interferes with their eating, drinking, talking and sometimes even breathing," said Ulrich, who is also a research assistant professor of epidemiology at the UW. "It also increases the risk of infection as well as the cost and duration of the hospital stay."
In addition to preventing graft-vs.-host disease in marrow-transplant patients, methotrexate is used to treat certain cancers and, in lower doses, immune diseases such as rheumatoid arthritis. The drug works by temporarily interfering with the body's use of folic acid, a nutrient needed for cell growth.
The reason patients with the MTHFR gene mutation suffer more severe side effects of antifolate chemotherapy, Ulrich hypothesized, is that their bodies lack the adequate folate necessary to produce nucleotides - a key component of the DNA-repair machinery. Patients with variations in the MTHFR gene, in the future, may be candidates for more customized therapy, from altered dosages to alternative drugs.
"We know that every patient reacts somewhat differently to the drugs they're given and, until recently, our ability to understand how a patient will react has been limited, based on characteristics like patient's age and body weight," Ulrich said.
"Now, with our increasing understanding of genetics, we can better predict how patients will process a drug and thus provide the appropriate dose for that patient. Ultimately, this will allow us to tailor our drug dosages to reduce toxicity, or side effects, and increase effectiveness."
Ulrich next plans to study the effects of this variant on graft-vs-host disease, as well as the effects of other genetic alterations in folate metabolism.
"If these results are confirmed by further research," she said, "testing people for this common genetic variant may become a cost-effective strategy for customizing treatment based on a patient's unique genetic makeup."
Rounds extend Ulrich's research reach
A chance to step into another scientist's shoes can take research in new directions.
That's what Dr. Neli Ulrich, an epidemiologist in the Public Health Sciences Division, found when she donned a white coat and joined Hutch bone-marrow transplant physicians on clinical rounds for three weeks in 1998.
As an effort to foster interdisciplinary research and to help non-clinical researchers understand cancer treatment, Hutch scientists may apply to spend two to four weeks as an observer on rounds on the inpatient bone-marrow transplant wards.
While on clinical rounds, Ulrich met Dr. Rainer Storb, director of Transplantation Biology in the Clinical Research Division, and the two began a collaboration that capitalized on each of their areas of expertise.
"When I met Rainer and learned more about graft-vs.-host disease, I saw a way to link my dissertation research on folate metabolic enzymes to cancer care," she said.
The ensuing collaboration was a success, resulting in a study published last month. Ulrich and the study's co-investigators plan to seek funding for a larger study of the topic.