nita limdi labNita Limdi, Ph.D., Pharm.D., UAB professor of neurology

A new report from researchers at the University of Alabama at Birmingham demonstrates that clinical and genetic factors affecting dose requirements for warfarin vary by race. The study, published online today in Blood, the Journal of the American Society of Hematology, proposes race-specific equations to help clinicians better calculate warfarin dosage.  

Warfarin is the most widely used blood thinning medication, or anticoagulant, prescribed to prevent stroke and to treat blood clots. Determining the optimal warfarin dose to prevent clots while avoiding dangerous bleeding is difficult. To ensure that a safe balance is achieved, patients taking warfarin must regularly visit their doctor for blood tests.

Investigators have identified several factors that affect how the body breaks down warfarin and that consequently influence dose requirements. These include clinical factors such as height and weight and the presence of genes that help the body break down warfarin (CYP2C9) and help to activate clotting (VKORC1).

While researchers agree that these clinical and genetic factors affect individual patients’ dose requirements, whether this translates to achieving and maintaining a safe level of anticoagulation was explored in two recent clinical trials with conflicting results.

In 2013, the EU-PACT trial reported that calculating a patient’s warfarin dose based on the presence of genetic factors (known as genotype-guided dosing) improved anticoagulation control. Meanwhile, the Clarification of Optimal Anticoagulation through Genetics trial reported that a similar genotype-guided dosing strategy did not appear to make a difference among patients enrolled. Of note, the COAG trial included more African-Americans than did EU-PACT (27 percent of the study population vs. 0.9 percent), and the African-Americans enrolled actually fared worse after receiving genotype-guided therapy.

According to a research group led by Nita Limdi, Ph.D., Pharm.D., professor in the UAB Department of Neurology and interim director of the Hugh Kaul Personalized Medicine Institute, the studies’ disparate findings may be attributed to differences in racial diversity among participants.

Warfarin is the most widely used blood thinning medication, or anticoagulant, prescribed to prevent stroke and to treat blood clots. Determining the optimal warfarin dose to prevent clots while avoiding dangerous bleeding is difficult. To ensure that a safe balance is achieved, patients taking warfarin must regularly visit their doctor for blood tests.

“As the outcomes of disease can vary by race, so can response to medications,” Limdi said. “Therefore, warfarin dosing equations that combine race groups for analysis (race-adjusted analysis) assume that the effect of variables — such as age and genetics — are the same across race groups, which may compromise dose prediction among patients of both races.”

In order to better understand how genetics and clinical factors influence warfarin dose across race groups, investigators analyzed 1,357 patients (595 African-American; 762 European-American) treated with warfarin, calculating and comparing their recommended dose according to both race-adjusted dosing models (e.g., COAG) and race-specific dosing models. As 43 percent of the study population was African-American, the research team was able to conduct a robust assessement of the impact of clinical and genetic factors on warfarin dose by race.

After calculating and comparing recommended warfarin dose for study participants according to race-combined dosing models and race-specific dosing models, researchers made several significant observations. While genetic factors accounted for a larger proportion of the dose variability for European-American patients, clinical factors accounted for a larger dose variability in African-Americans. They noted that gene variants may have a different effect on dose across race groups. For example, European-Americans with a variant of CYP2C9 (CYP2C9*2) required less of the drug according to race-specific dosing models, yet African-Americans did not. While all participants, regardless of race, who carried VKORC1 required lower dose, according to race-specific dosing models, the proportional dose reduction was greater among European-Americans.

Researchers conclude that the influence of genetic and clinical factors on warfarin dose differs by race, and therefore recommend that race-specific equations, rather than race-adjusted equations, be used to guide warfarin dosing.

“Our findings highlight the need for adequate racial representation in warfarin dosing studies to improve our understanding of how the factors that influence warfarin dose differ according to race,” said Limdi. “This is the first step to developing race-specific algorithms to personalize therapy.”

By Bob Shepard
UAB Media Relations

  •                      glioma cells large Researchers at the University of Alabama at Birmingham have identified a chemical pathway that may be associated with seizures and shorter patient survival in some patients with malignant glioma, the most common and deadly form of brain tumor. In findings published May 27 in Science Translational Medicine, the researchers suggest that a transporter known as SXC is responsible for boosting levels of glutamate in the brains of some glioma patients.
    cell1System x­c-(SXC) expression in human glioma cells growing in vitro. The catalytic subunitof SXC, SLC7A11/xCT (green) is highly expressed in approximately half of gliomas. The cell structure (red) and nuclei (blue) show the morphology of these glioma cells. Confocal image by Stephanie Robert and Ian Kimbrough.Glutamate is a vital neurotransmitter in the brain; but increased expression of glutamate can kill healthy cells surrounding a malignant tumor, giving the tumor more room for growth. Glioma-produced glutamate may also be responsible for seizures that are present in about half of all glioma patients.
    “We hypothesized that the SXC glutamate transporter, and in particular a sub-unit called SLC7A11, was responsible for this increase in glutamate,” said Harald Sontheimer, Ph.D., professor in the Department of Neurobiology and senior author of the study. “In both animal models and in human glioma cells, we found that approximately 50 percent of patient tumors had elevated SLC7A11 expression, and those tumors grew faster, killed more healthy cells, induced seizures and shortened overall survival than did tumors lacking this transporter.”
    cell2Human astrocytes expressing glial fibrillary acidic protein (GFAP, blue) and their nuclei (orange) in the brain of a patient suffering from seizures. Confocal image by Stephanie Robert and Ian Kimbrough. Analysis of human glioma tissue showed that 54 percent of glioma patients had elevated tumor SLC7A11 expression, whereas the remaining 46 percent had lower expression, comparable to controls. Gliomas with elevated SLC7A11 corresponded well with the incidence of tumor-associated seizures reported in the glioma patient population. The findings also showed that lack of SLC7A11 expression conferred an improved clinical outcome for patients, who lived nine months longer on average.
    “These findings suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and seizures,” said Stephanie M. Robert, a graduate trainee in the M.D/Ph.D. program in Sontheimer’s laboratory and first author of the paper.
    The team had previously discovered that an FDA-approved drug for ulcerative colitis and inflammatory bowel disease called sulfasalazine can inhibit glutamate release via SLC7A11. The researchers then conducted a clinical pilot trial with nine glioma patients. Using magnetic resonance spectroscopy, glutamate levels were measured before and after patients took an oral dose of sulfasalazine.
    cell3Spectral image of human glioma cells expressing enhanced green fluorescent protein (EGFP, green) growing intracranially in a mouse. Confocal image by Ian Kimbrough.“In the nine glioma patients with biopsy-confirmed expression of SXC, we found that the presence of SXC positively correlates with glutamate release, which is acutely inhibited with oral sulfasalazine,” said Sontheimer, who is also the director of the UAB Center for Glial Biology in Medicine.
    While the study findings suggest that reducing glutamate levels in patients with elevated expression of SXC would be beneficial in controlling seizures and slowing tumor growth, sulfasalazine is an imperfect drug for that role.
    “Sulfasalazine is approved as an oral medication, and most of each dose is absorbed in the gut. Perhaps as little as 20 percent makes it to the brain,” Sontheimer said. “It also has a very short biological half-life and quickly loses its effectiveness. More specific SXC inhibitors with improved specificity and bioavailability are under development and may soon enter clinical trials.”
    Also of potential clinical relevance is the finding that magnetic resonance spectroscopy may serve as a tool to determine whether a patient has elevated tumor SLC7A11 expression.
    cell4Human glioma cells (green) expressing enhanced green fluorescent protein (EGFP) migrating away from the tumor mass (bottom left of image) along the vasculature of the brain.Image acquired in a live mouse using two-photon microscopy. In vivo two-photon image by Ian Kimbrough. “Future studies will be needed to examine whether SXC-mediated glutamate release measured by magnetic resonance spectroscopy may serve as a sensitive, noninvasive clinical marker to identify those patients who will experience more rapid disease progression and seizure complications,” Robert said. “This screening could also help identify patients who may benefit from therapies that target SXC inhibition.”
    The wide-ranging study benefited from diverse UAB expertise in several fields. UAB’s neuro-oncology program, led by co-author Louis B. Nabors, M.D., professor in the Department of Neurology, was instrumental in conducting the clinical studies. Co-author Adrienne C. Lahti, M.D., professor in the Department of Psychiatry and Behavioral Neurobiology, brought expertise in magnetic resonance imaging from studies she is doing examining the association of glutamate with anti-psychotic drugs.

Other co-authors are:

Susan C. Buckingham, Ph.D., Susan L. Campbell, Ph.D., Stefanie Robel, Ph.D., Kenneth T. Holt, Toyin Ogunrinu-Babarinde, UAB Center for Glial Biology in Medicine; Paula Province Warren, UAB Division of Neuro-oncology; David M. White, Meredith A. Reid, Ph.D., UAB Department of Psychiatry and Behavioral Neurobiology; and Jenny M. Eschbacher, M.D., and Michael E. Berens, Ph.D., Cancer and Cell Biology Division, the Translational Genomics Research Institute, Phoenix, Ariz.

By: Bob Shephard
UAB Media Relations

        SOM bannerThe University of Alabama at Birmingham has been chosen by the Michael J. Fox Foundation for Parkinson’s Research as one of five academic centers to host the inaugural class of the Edmond J. Safra Fellowship in Movement Disorders.

    By increasing resources for specialized training for clinician-researcher neurologists, the program — made possible by The Edmond J. Safra Foundation — aims to grow the global base of movement disorder specialists treating people with Parkinson’s and contributing to research toward breakthrough treatments for the disease.

    “There is a growing need for neurologists with additional training in movement disorders,” said David G. Standaert, M.D., Ph.D., professor and chair of the Department of Neurology. “We are honored to have been selected by The Michael J. Fox Foundation to grow the number of clinician-researchers equipped to provide optimal care to Parkinson’s patients and conduct the urgent work to learn more about this disease and to develop new therapies.”

    UAB is now recruiting a neurology resident for the 2016-2018 Edmond J. Safra Fellowship in Movement Disorders class.

    A committee of advisers selected by MJFF named the five centers. The others are Columbia University Medical Center in New York; Emory University in Atlanta; Northwestern University in Chicago; and Toronto Western Hospital in Ontario, Canada

    “People with Parkinson’s disease are the true beneficiaries of this program,” said Mrs. Lily Safra, chair of the Edmond J. Safra Foundation. “These prestigious institutions are equipped to offer fellows the training and experience that will help them better serve their Parkinson’s patients.”
    BY: Bob Shepard/UAB Media Relations