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 acute lymphoblastic leukemia, and autoimmune diseases including rheumatoid arthritis. 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 gene regions 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 methotrexate, 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
Provided by Cold Spring Harbor Laboratory
- Study reveals basis of anticancer drug resistance in childhood leukemia Apr 15, 2008 | not rated yet | 0
- Rare gene variants linked to inflammatory bowel disease Oct 10, 2011 | not rated yet | 0
- Rare variants in gene coding may up risk of autoimmune disorders Jul 01, 2010 | not rated yet | 0
- Rare and common genetic variations responsible for high triglyceride levels in blood Jul 25, 2010 | not rated yet | 0
- Is short stature associated with a 'shortage' of genes? Nov 23, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Classical and Quantum Mechanics via Lie algebras
Apr 15, 2011 I'd like to open a discussion thread for version 2 of the draft of my book ''Classical and Quantum Mechanics via Lie algebras'', available online at http://lanl.arxiv.org/abs/0810.1019 , and for the...
- More from Physics Forums - Independent Research
More news stories
Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.
Genetics May 16, 2013 | 3 / 5 (1) | 0 |
Informed consent is the backbone of patient care. Genetic testing has long required patient consent and patients have had a "right not to know" the results. However, as 21st century medicine now begins to use the tools of ...
Genetics May 16, 2013 | 5 / 5 (1) | 3 |
Ethicists provide framework supporting new recommendations on reporting incidental findings in gene sequencing
In a paper published in Science Express, a group of experts led by bioethicists in the Center for Medical Ethics and Health Policy at Baylor College of Medicine provide a framework for the new American College of Medical Geneti ...
Genetics May 16, 2013 | not rated yet | 0
The use of genome-wide analysis (GWA), where the entirety of an individual's DNA is examined to look for the genomic mutations or variants which can cause health problems is a massively useful technology for diagnosing disease. ...
Genetics May 16, 2013 | not rated yet | 0
DNA databases might help identify victims of crime and human trafficking, but how do we safeguard the personal privacy of innocent victims and family members? A new report online May 15 in the Cell Press journal Trends in ...
Genetics May 15, 2013 | not rated yet | 0
Researchers at the University of Wisconsin have identified a potential new risk factor for obstructive sleep apnea: asthma. Using data from the National Institutes of Health (Heart, Lung, and Blood Institute)-funded Wisconsin ...
6 minutes ago | not rated yet | 0 |
A new study looking at sleep-disordered breathing (SDB) and markers for Alzheimer's disease (AD) risk in cerebrospinal fluid (CSF) and neuroimaging adds to the growing body of research linking the two.
16 minutes ago | not rated yet | 0 |
Gourmands and foodies everywhere have long recognized ginger as a great way to add a little peppery zing to both sweet and savory dishes; now, a study from researchers at Columbia University shows purified components of the ...
6 minutes ago | not rated yet | 0
In their quest to learn more about the variability of cells between and within tissues, biomedical scientists have devised tools capable of simultaneously measuring dozens of characteristics of individual ...
1 hour ago | not rated yet | 0 |
Scientists at Johns Hopkins have turned their view of osteoarthritis (OA) inside out. Literally. Instead of seeing the painful degenerative disease as a problem primarily of the cartilage that cushions joints, ...
1 hour ago | not rated yet | 0 |
The hunt for an HIV vaccine has gobbled up $8 billion in the past decade, and the failure of the most recent efficacy trial has delivered yet another setback to 26 years of efforts.
4 hours ago | not rated yet | 0