Category Archives: Genetic Medicine

ScienceDaily (Feb. 24, 2012) — The RIKEN Center for Genomic Medicine is examining how drugs can be matched to a patient's genetic information through the study of single nucleotide polymorphisms. Taisei Mushiroda from the Laboratory for Pharmacogenetics explains...

Drugs are not equally effective on all patients. A treatment that is dramatically effective on some patients can be ineffective on others. Drugs can also have serious side effects; in the worst case, a drug used to treat a disease can produce a fatal outcome. By examining genetic differences among individuals and administering drugs on the basis of such findings, the impact of side effects can be reduced. Taisei Mushiroda, the Laboratory Head of the Research Group for Pharmacogenomics at the RIKEN Center for Genomic Medicine, is making advances in personalized medicine with research into how drugs can be tailored to a patient's genetic information through the analysis of single nucleotide polymorphisms (SNPs).

Identifying the single nucleotide polymorphism (SNP) that plays a key role in drug rash

Japan's Ministry of Health, Labor and Welfare announced that the gout treatment allopurinol, the antiepileptic drug carbamazepine and the analgesic, anti-inflammatory, antipyretic drug loxoprofen hold the highest incidence of serious drug rash.

"The data we collected showed that the great majority of drug rash cases were caused by carbamazepine. We therefore proceeded to clarify the relationship between carbamazepine and drug rash, using Genome- Wide Association Study (GWAS). We divided our study population into two groups: those who experienced side effects and those who did not. We performed a comprehensive analysis of single nucleotide polymorphisms (SNPs) on the genome to statistically extract SNPs that are significantly associated with drug rash. The gene involved in drug rash was then identified from among those positioned near the SNPs"

Strands of DNA carry genetic information in the sequenced arrangement of the four bases A (adenine), T (thymine), G (guanine) and C (cytosine). Consisting of some three billion base pairs, the human genome carries the complete genetic information of a human being. Although there is more than 99% base sequence homology in all people, the remaining 1% of base sequences differ individually. "These differences are SNPs. It is estimated that more than 10 million SNPs are present in the human genome. They are associated with the appearance and constitution of the individual, and even with how drugs work and what side effects develop."

Relationship between drug rash caused by the antiepileptic drug carbamazepine and the HLA-A*3101 gene

Mushiroda and his colleagues conducted a study on Japanese epileptic patients undergoing treatment with carbamazepine. Of the sixty-one patients who experienced drug rash, 37 (about 61%) were found to have the HLA- A*3101 gene. In contrast, of the 376 patients who did not experience drug rash, 329 (about 88%) were found to lack HLA-A*3101.

"Reportedly, about 3% of Japanese patients experience drug rash when taking carbamazepine. About 60% of those have HLA-A*3101. It is therefore recommended that 60% of 3% (about 2%) of Japanese epileptic patients take antiepileptic drugs other than carbamazepine. In this way, the incidence of drug rash can be reduced by 2%," says Mushiroda. However, as this association was only discovered in 2010, further evidence must be presented before it can be useful in a clinical setting.

Personalized medicine expected to find clinical applications in 1 or 2 years

The next step after identifying the associated SNP is to determine its applicability in the clinical setting. It is also necessary to verify that SNP diagnosis is effective in both therapeutic and cost-benefit aspects. In ongoing prospective clinical research of nevirapine, it has been estimated that SNP diagnosis would cut annual medical expenditures by about US$60,000 (about ¥5 million) per hospital. This next phase will be necessary for successful application of the new system to the antiepileptic drug carbamazepine.

Before SNP genotyping can be firmly established in medical practice, however, a quick and accurate method to examine SNPs at the lowest cost is needed. In collaboration with Toppan Printing Co. Ltd. and RIKEN Genesis Co. Ltd., Mushiroda's team have developed the TPSA-003 genotype analysis system which can help to deliver more economical SNP genotyping (Fig. 3). The system provides results automatically in just one hour, simply by placing a single drop of untreated blood in the dedicated container and inserting the sample in the machine. "This is a groundbreaking machine. The conventional method involves the complex process of separating leukocytes from the blood sample, extracting the DNA from the leukocytes and applying the DNA to the machine to analyze SNPs. Conventionally, DNA extraction alone requires at least half a day even when undertaken by a highly skilled person. With the new system, the same task, including SNP genotyping, is completed in 60 minutes. This means that an accurate diagnosis can be obtained while the patient stays in the waiting room. Quick diagnosis is a big advantage for the patient as well."

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Advancing personalized medicine: Tailoring drugs to fit a patient's genetic predisposition

Washington, Feb 24 (ANI): Scientists have identified genes whose expression levels can identify people with age-related macular degeneration (AMD) as well as tell apart its subtypes.

AMD is one of the leading causes of blindness worldwide, especially in developed countries, and there is currently no known treatment or cure or for the vast majority of AMD patients.

It is estimated that 6.5 percent of people over age 40 in the US currently have AMD. There is an inheritable genetic risk factor but risk is also increased for smokers and with exposure to UV light. Genome-wide studies have indicated that genes involved in the innate immune system and fat metabolism are involved in this disease.

However, none of these prior studies examined gene expression differences between AMD and normal eyes.

In order to address this question, researchers at the University of California Santa Barbara, the University of Utah John Moran Eye Center, and the University of Iowa combined forces and used a human donor eye repository to identify genes up-regulated in AMD. The ability of these genes to recognize AMD was tested on a separate set of samples.

The team discovered over 50 genes that have higher than normal levels in AMD, the top 20 of which were able to "predict" a clinical AMD diagnosis. Genes over-expressed in the RPE-choroid - a tissue complex located beneath the retina - included components of inflammatory responses, while in the retina, the researchers found genes involved in wound healing and the complement cascade, a part of the innate immune system.

They found retinal genes with expression levels that matched the disease severity for advanced stages of AMD.

"Not only are these genes able to identify people with clinically recognized AMD and distinguish between different advanced types - some of these genes appear to be associated with pre-clinical stages of AMD. This suggests that they may be involved in key processes that drive the disease. Now that we know the identity and function of many of the genes involved in the disease, we can start to look among them to develop new diagnostic methods, and for new targets for the development of treatments for all forms of AMD," Monte Radeke, one of the project leaders, said.

The study has been published in BioMed Central's open access journal Genome Medicine. (ANI)

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Genetic basis of age-related macular degeneration identified

08-02-2012 18:24 (October 25, 2011) Associate Professor at the Stanford School of Medicine, Joseph Wu explores how stem cells may be used in the future to repair hearts that have failed. This course is a single-quarter, focused follow-up to the the yearlong Mini Med School that occurred in 2009-10. The course focuses on diseases of the heart and cardiovascular system. The course is sponsored by Stanford Continuing Studies and the Stanford Medical School. Stanford University http://www.stanford.edu Stanford Continuing Studies http:///continuingstudies.stanford.edu/ Stanford University School of Medicine med.stanford.edu Stanford University Channel on YouTube: http://www.youtube.com

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5. Stem Cells for Cardiac Repair | Mini Med School - Video

Public release date: 23-Feb-2012
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Contact: Dr. Habibul Ahsan
habib@uchicago.edu
773-834-9956
Public Library of Science

A large-scale genomic study conducted in Bangladesh has discovered genetic variants that control arsenic metabolism and elevate the risk of skin lesions in people chronically exposed to arsenic. In PLoS Genetics, researchers from the University of Chicago, Columbia University, the International Center for Diarrheal Disease Research in Bangladesh, and the University of North Carolina report that genetic variants found near the enzyme for metabolizing the chemical into a less toxic form are associated with an individual's risk of developing arsenic-related disease.

Since the installation of hand-pumped wells to tap groundwater sources in the 1970s, as many as 77 million people ? about half the population of Bangladesh ? have been accidentally exposed to dangerous levels of arsenic. The World Health Organization calls the exposure "the largest mass poisoning of a population in history" (WHO, 2000).

For over a decade, Habibul Ahsan and colleagues have studied the epidemiology of arsenic-related diseases such as skin lesions, diabetes, and cardiovascular and respiratory illnesses in this population, as well as the effectiveness of interventions to prevent toxicity. In this new study, nearly 3,000 Bangladeshis were genotyped for variants throughout the genome, in a search for answers as to why some individuals appear to be at higher risk for developing disease after arsenic exposure.

The research team found genetic variants associated with arsenic metabolite levels and skin lesion risk in the region of a likely candidate gene: arsenite methyltransferase, an enzyme critical for arsenic metabolism. A study of gene expression levels found that those same variants were associated with reduced expression of the enzyme. Boosting arsenic metabolism may be an effective intervention in individuals exposed to the toxin and at high genetic risk from arsenic-related disease.

"These results add clarity to the genetic architecture that is playing a role in the arsenic toxicity and its underlying biological basis," said Ahsan. "It's an important study for a major problem affecting millions of people around the world, and it opens up opportunities for genetic studies of other major public health problems in developing countries."

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FINANCIAL DISCLOSURE: This work was supported by NIH Grants P42ES010349, R01CA102484, R01CA107431, and P30CA014599 and by Department of Defense grant W81XWH-10-1-0499. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

COMPETING INTERESTS: The authors have declared that no competing interests exist.

CITATION: Pierce BL, Kibriya MG, Tong L, Jasmine F, Argos M, et al. (2012) Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh. PLoS Genet 8(2): e1002522. doi:10.1371/journal.pgen.1002522

CONTACT:

Habibul Ahsan
University of Chicago
Health Studies, Medicine and Human Genetics and Cancer Research
AMB N102A (MC 2007)
5841 South Maryland Avenue,
Chicago, Illinois 60637

UNITED STATES
PHONE: 773-834-9956
FAX: 773-834-0139
EMAIL: habib@uchicago.edu

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Genetic variants affect arsenic metabolism and toxicity in Bangladesh

Public release date: 23-Feb-2012
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Contact: Robert Mitchum
robert.mitchum@uchospitals.edu
773-795-5227
University of Chicago Medical Center

One of the first large-scale genomic studies conducted in a developing country has discovered genetic variants that elevate the risk for skin lesions in people chronically exposed to arsenic. Genetic changes found near the enzyme for metabolizing the chemical into a less toxic form can significantly increase an individual's risk for developing arsenic-related disease.

The discovery could point the way to new screening and intervention options for people who are exposed to groundwater with high levels of arsenic, said scientists at the University of Chicago Medicine, Columbia University, and in Bangladesh in a study published in PLoS Genetics.

"These results add clarity to the genetic architecture that is playing a role in arsenic toxicity and its underlying biology," said senior author Habibul Ahsan, MD, MMedSc, Louis Block Professor of health studies, medicine and human genetics at the University of Chicago Medicine. "It's a rare type of study for a major problem affecting millions of people around the world, and it opens up opportunities for genetic studies of other major public health problems in developing countries."

The group's genome-wide association study, or GWAS, was conducted in nearly 3,000 individuals exposed to arsenic for decades in Bangladesh. Since the widespread installation of hand-pumped wells to tap groundwater sources in the 1970s, as many as 77 million people ? about half the population of Bangladesh ? have been accidentally exposed to dangerous levels of arsenic. The World Health Organization calls the exposure "the largest mass poisoning of a population in history."

For more than a decade, Ahsan and colleagues have studied the epidemiology of arsenic-related disease, such as skin lesions, diabetes, and respiratory illnesses, in this population, as well as the effectiveness of interventions to prevent toxicity. In the new study, funded by the National Institute of Environmental Health Sciences and the National Cancer Institute, the researchers sought genetic answers for why some individuals appear to be at higher risk for developing disease after arsenic exposure.

"Whatever the source of exposure, different individuals vary with respect to their susceptibility to the toxicity of arsenic," Ahsan said. "Even if they consume or are exposed to arsenic at the same dose and duration, some individuals will manifest toxicity phenotypes and others won't."

Researchers genotyped thousands of arsenic-exposed individuals from the group's main studies for single nucleotide polymorphisms (SNPs) throughout the genome, and looked for associations with arsenic metabolite levels and risk of skin lesions.

After ingestion, the body metabolizes inorganic arsenic into first monomethylarsonic acid (MMA) and then dimethylarsinic acid (DMA). MMA is considered to be more toxic, while DMA is water-soluble and more easily excreted. Higher levels of DMA or lower levels of MMA measured from an individual's urine are associated with lower toxicity.

A research team led by Ahsan and Brandon Pierce, PhD, an assistant professor of epidemiology at the University of Chicago Medicine, then used GWAS to search for SNPs associated with DMA and MMA levels. They found several significant genetic variants in the region of a likely candidate gene: arsenite methyltransferase (As3MT), an enzyme critical for arsenic metabolism. A second GWAS looking for SNPs associated with the development of skin lesions after arsenic exposure, pointed to many of the same variants. In a further study of gene expression levels, those same SNPs were associated with reduced expression of the arsenic metabolizing enzyme.

"This makes perfect sense," Ahsan said. "It gives us a very coherent story that we can now investigate in relation to other arsenic pathologies and in relation to a wide range of arsenic doses in this population."

"Now that we understand the molecular basis of some of this disease risk, it is conceivable to now think of incorporating this information into testing, evaluating, or potentially coming up with successful biomedical interventions," Ahsan continued. "By exploiting these metabolic pathways for a subgroup of individuals who will really be at higher risk for getting those diseases, we may be able to reduce fatal outcomes in this population."

The genetic findings provide strong evidence that efficient metabolism of arsenic through methylation protects against the toxin. Compounds that boost methylation, such as folic acid, could reduce arsenic toxicity ? a strategy currently being tested by co-author Mary Gamble, PhD, associate professor of Environmental Health Sciences at Columbia University.

"If we could somehow find a way to do that in Bangladesh, it would make individuals much better methylators of arsenic, and as this current study shows if you're a better methylator you're at a lower risk for disease," said co-author Joseph Graziano, PhD, Professor of Environmental Health Sciences and Director of Superfund Research Program at the Mailman School of Public Health of Columbia University.

Risk variants may also help assess the potential toxicity of cancer chemotherapies which use arsenic or related compounds. SNPs associated with elevated sensitivity to arsenic toxicity could steer oncologists toward lower doses or alternative treatments in certain cancer patients, Ahsan said.

Beyond the clinical applications, the current study demonstrates that large-scale genomic studies are possible in a largely rural population of a developing country. The study offers a rare example of a GWAS result with clear, immediate potential for translational impact.

"Many genomic signals that we see are not robust enough or do not pertain to a large population," Ahsan said. "But in this study, that is not the case. The finding is robust, and the impact is massive."

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The study, "Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh," will be published online February 23rd by PLoS Genetics. For a full list of authors, see xxx.

Funding for the research was provided by the National Institute of Environmental Health Sciences and the National Cancer Institute.

For more news from the University of Chicago Medical Center, follow us on Twitter at @UChicagoMed, or visit our Facebook page at facebook.com/UChicagoMed, our research blog at sciencelife.uchospitals.edu, or our newsroom at uchospitals.edu/news.

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Genetic risk for elevated arsenic toxicity discovered

07-02-2012 10:33 Solve for X is a forum to encourage and amplify technology-based moonshot thinking and teamwork. http://www.wesolveforx.com G+ goo.gl Life is the software that makes its own hardware. Juan gives us a glimpse into the coming revolution of synthetic genetics and then reminds us that one of the moonshots we could collective take is to make sure that the path is clear for innovation to happen and that regulators factor in the cost of impeding progress as well as allowing it. Juan Enriquez is the Managing Director of Excel Venture Management. He sailed around the world with Dr. J. Craig Venter on a sampling expedition that increased the number of known genes by 10X and was the Founding Director of the Harvard Life Sciences Project.

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Solve for X: Juan Enriquez on harnessing synthetic genetics - Video