Inherited risk factors increase odds of developing childhood acute lymphoblastic leukemia (ALL)

January 16, 2010

January 16, 2010 – This contribution has just been published in the ScienceBlog – Pharmacogenetics at this locoation. It is presented here in its original state and with all credentials and rights resting with the original author.

Scientists at St. Jude Children’s Research Hospital have identified inherited variations in two genes that account for 37 percent of childhood acute lymphoblastic leukemia (ALL), including a gene that may help predict drug response.

The findings stem from the first complete search of the human genetic blueprint or genome to look for inherited risk factors for ALL, the most common childhood cancer. Published in the August 16 advance online issue of Nature Genetics, the work offers the first proof based on a complete survey of the human genome that inheritance plays a role in childhood ALL.

Mary Relling, Pharm.D., St. Jude Pharmaceutical Sciences chair and the paper’s senior author, estimated that individuals who inherited variations in genes known as ARID5B or IKZF1 are almost twice as likely to develop ALL as those without the variations. Even then, she said, the risk remains low. ALL strikes roughly one in every 75,000 Americans. Sixty percent are children and teenagers.

“The genetic variations alone are not enough to cause the cancer. Like all cancers, pediatric ALL is a multi-factor disease,” Relling explained. “But these findings may give us a handle on the mechanism of the disease and drug responsiveness to it.”

Exactly the same genes, ARID5B and IKZF1, were confirmed to be altered in British children with ALL. That study was published by the Institute of Cancer Research in Surrey, England, in the same issue of Nature Genetics.

In the St. Jude study, researchers collaborated with colleagues from the Children’s Oncology Group (COG), who provided additional cases for genetic analysis. COG is an international group of medical institutions that cooperate in research studies and clinical trials of childhood cancer treatment.

Researchers scanned the genomes of 441 children with ALL and a control group of 17,958 cancer-free individuals for more than 300,000 common genetic variations known as single nucleotide polymorphisms or SNPs.

The search found 18 SNPs that differed significantly in frequency between individuals with and without ALL. Six of the 18 SNPs were associated with one of the four main subtypes of ALL.

The six included two SNPs linked to the ARID5B gene. About 11 percent of those in the control group inherit the leukemia-risk ARID5B variations from both mother and father, Relling said. In comparison, the same high-risk ARID5B SNPs were found in 38 percent of patients with a type of ALL known as hyperdiploid ALL. That subtype accounts for about 20 percent of ALL patients.

Three more SNPs were traced to the genes IKZF1 and DDC, which are next to each other on chromosome 7. IKZF1 is also known as IKAROS. Earlier research from St. Jude and COG linked acquired changes in IKZF1 to an increased risk of ALL relapse. The new evidence tying inherited variation in IKZF1 to an increased risk of developing ALL underscores the need for medications targeting variations in this gene, Relling said.

Both ARID5B and IKZF1 play important roles in normal development of lymphoid or white blood cells, she said. ARID5B belongs to a family of genes that make transcription factors, which help regulate gene activity. “If they have an inherited variation that affects the function of those genes, these are plausible pathways for how a normal lymphoid cell could be disrupted and transformed into a cancer cell,” Relling said.

Inherited variations in ARID5B might also influence patient response to chemotherapy, particularly to the drug methotrexate. “We found this same inherited variation also affected accumulation of the drug in leukemia cells. It accumulates better. That allows us to use a lower dose and still cure the leukemia,” Relling explained. “These findings may identify a new marker that could be used to help decide on doses of methotrexate in patients with varying ARID5B status.”

Scientists are not sure how the SNPs they identified influence cancer risk. But studies of variation in gene expression associated with the ARID5B gene indicate the inherited variations have a biological function. Researchers must still determine what it is.

Other authors of this paper include Lisa Trevino, Wenjian Yang, Deborah French, Geoffrey Neale, James Downing, Susana Raimondi, Ching-Hon Pui and William Evans, all of St. Jude; Stephen Hunger, University of Colorado, Denver; William Carroll, New York University Medical Center, New York; Meenakshi Devidas, University of Florida, Gainesville; and Cheryl Willman, University of New Mexico, Albuquerque.

This study was supported by the National Cancer Institute, the National Institutes of Health/National Institutes of General Medical Sciences Pharmacogenetics Research Network and ALSAC.

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Mutant genes linked to Parkinson’s disease in some patients of Japanese or European descent

November 20, 2009

November 20, 2009 – Two independent studies which tried to uncover genetic associations behind Parkinson’s disease have been published in the latest issue of Nature Genetics. They are the largest studies of this type to date and involved more than 25’000 participants.

The two research teams have found that people of Japanese and European descent who have mutant versions of five genes may be at higher risk of developing Parkinson’s disease.

The first study in Japan looked at ethnic Japanese  only while the second study, performed in the United States, focused on people of European heritage only.

Thus, in the first study, researchers at the Kobe University in Japan and sequenced the genes of 2’011 participating patients with Parkinson’s disease and 18’381 other study participants without the disease. They found that those with the disease were carriers of genetic variants of the PARK16, BST1, SNCA and LRRK2 genes. In the second study, researchers at the National Institutes of Health’s (NIH) Laboratory of Neurogenetics in the US analyzed the genes of more than 5’000 patients of European ancestry who suffer from the disease and detected strong links between Parkinson’s and genetic variants of the genes SNCA and MAPT. The two teams later compared their data and found that variants of PARK16, SNCA and LRRK2 carry risk of Parkinson’s disease in both Japanese and European populations, while genetic variants of BST1 and MAPT, repectively, seemed to specific for patients of Japanese or European descent.

The researchers hope that the better understanding of the underlying genetic variants involved in the progress of Parkinson’s disease will lead to better insights into the causes and underlying biology of this disease. Eventually, this knowledge will one day provide physicians with strategies to delay, or even prevent, the development of Parkinson’s disease.

Parkinson’s disease is a neurodegenerative disease that affects one to two percent of people over the age of 65. It is characterized by tremors, sluggish movement, muscle stiffness, and difficulty with balance. Although medical treatments today may improve symptoms, there are none that can slow down or halt the progression of the disease.


Sperm donor passed on sudden death heart defect

October 24, 2009

October 24, 2009 – Sperm donation is an increasingly common practice for achieving pregnancy in the absence of a male partner or when fertility is problematic. The unintended consequence in which genetic diseases are unwittingly transmitted to offspring is an underrecognized public health issue not previously prioritized by US Food and Drug Administration guidelines.

An asymptomatic 23-years old man who had no personal knowledge of underlying heart disease and who underwent standard testing that was negative for infectious diseases, repeatedly donated sperm over a 2-year period (1990-1991). The donor was later shown to be affected (in 2005) by a novel β-myosin heavy-chain mutation that caused hypertrophic cardiomyopathy (HCM), after an offspring was clinically diagnosed with this disease.

Of the 24 children known to be offsprings of the donor, including 22 children who were products of fertilization via sperm donation and 2 children conceived by the donor’s wife, a total of 9 genetically affected children, age 2 to 16 years (6 of them being male), have been identified with HCM.  Three of the 9 gene-positive children have currently expressed phenotypic manifestions of HCM, including one child who died at the age of 2 years due to progressive and unrelenting heart failure with marked hypertrophy, and also 2 survivors with extreme left ventricular hypertrophy at the age of 15 years. The latter two children and the donor are judged likely to be at increased risk for sudden death.

This case series underscore the potential risk for transmission of inherited cardiovascular diseases through voluntary sperm donation, a problem largely unappreciated by the medical community and agencies regulating tissue donation. Recommendations include improved screening guidelines for donors to exclude cardiovascular diseases (e.g., HCM) such as consideration for 12-lead electrocardiograms.

Hypertrophic cardiomyopathy (HCM) thickens the heart and makes it harder to pump blood. It affects about one in 500 people; many more likely have the genetic defect without symptoms, Symptoms can include an irregular heartbeat and shortness of breath but many cases go undetected until sudden death. The condition is often the culprit when young athletes collapse and die suddenly. Treatment includes medication and an implanted defibrillator to prevent sudden death.

Neither the sperm bank nor the donor were identified. The donor, now 42, had no symptoms of genetic heart disease and no obvious family history when he donated sperm in the early 1990s. His own condition wasn’t diagnosed until after a child born through sperm donation was diagnosed. Maron declined to provide more details on the donor’s health, citing privacy concerns.

Access the full study report at JAMA, the Journal of the American Medical Association.


Gene May Predict Response to Hepatitis C Therapy

August 19, 2009

August 18, 2008 – A slight difference in a person’s genetic code could determine whether they respond to a grueling round of treatment for hepatitis C infection or not.

Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of Peginterferon-2b (PegIFN-2b) or Peginterferon-2a (PegIFN-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment was and continues to be a high priority. A recent study, led by D.B. Goldstein and published in the Journal Nature reported that a genetic polymorphism near the IL28B gene, encoding interferon-3 (IFN-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10-25) and African-Americans (P = 2.06 x 10-3). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.

Genetic tests looking for that particular genetic variant could be used to help treating physicians decide which patients are most likely to benefit from the current PegIFN-2b or PegIFN-2a based therapies. Of course, the findings of this study do not mean poor responders should not be offered therapy but it may alter their decision-making.


Gene Responsible For Acetaminophen-induced Liver Injury Identified

May 15, 2009

May 14, 2009 – Drugs containing the pharmacologically active ingredient acetaminophen are among the most commonly used over-the-counter (OTC) drugs in the United States (US).

Acetaminophen is considered safe over long-term use, but recent studies have indicated that even over a relatively short period, the maximum allowable dose can induce elevated levels of the liver enzyme ALT in blood serum in approximately one third of healthy individuals, suggesting possible liver injury. It is possible that if given high doses, many of these individuals would be susceptible to acute liver failure. There is likely to be a genetic predisposition, but finding the responsible variant genes by scanning human subjects alone may be very difficult, requiring large studies with many participants.

A team of researchers at the North Carolina State University used the help of mouse genetics in the search for candidate genes linked to acetaminophen-induced liver injury in humans.  The group used a genetically diverse population of mice to model human genetic variation, taking advantage of the known genetic differences in these strains to find genes linked to variable responses to acetaminophen treatment. Once the researchers narrowed their search to a few candidate genes in mouse, they sequenced the genetic code of the counterparts of the same genes in human patients exhibiting elevated levels of serum ALT in response to acetaminophen. They found that a single letter change (i.e. a so called single nucleotide polymorphism (SNP) to the DNA sequence in one of these candidate genes, called CD44, is significantly associated with elevated serum ALT in these patients. While the role of this gene in liver toxicity is not yet known, CD44 could serve as a potentially useful marker to identify people at risk for acetaminophen-induced liver damage.

There is still some research  to be done in order to determine the allele frequency of the CD44 T-Allele in the general population versus its abundance in patients with acetaminophen-induced liver damage (measured by elevated serum ALT-levels) as well as both the positive and the negative predictive values for the association of the CD44 T-Allele with acetaminophen-induced liver damage.

This article is adapted from materials at Cold Spring Harbor Laboratory. “Gene Responsible For Acetaminophen-induced Liver Injury Identified.” ScienceDaily 11 May 2009. 15 May 2009 <http://www.scienceddaily.com= /releases/2009/05/090504171943.htm>. See also the full journal article  reference: Harrill, A.H., Watkins, P.B., Su, S., Ross, P.K., Harbourt, D.E., Stylianou, I.M., Boorman, G.A., Russo, M.W., Sackler, R.S., Harris, S.C., Contractor, T., Wiltshire, T., Rusyn, I., and Threadgill, D.W. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res, DOI: 10.1101/gr.090241.108

See also the drug labels for  FDA-approved  drugs  and generics containing  the pharmacologically active ingredient acetaminophen at Drugs@FDA or at DailyMed.


Serious and fatal hypersensitivity reactions in patients with the HLA-B*5701 allele under abacavir therapy

March 30, 2009

In the light of the previous post, the FDA informed healthcare professionals some times ago (July 2008) that serious and sometimes fatal hypersensitivity reactions caused by abacavir therapy are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*5701. Abacavir is sold under the trade name Ziagen and is part of the combination products Epzicom and Trizivir.

FDA reviewed data from two studies that support a recommendation for pre-therapy screening for the presence of the HLA-B*5701 allele and the selection of alternative therapy in positive subjects. Patients who carry the HLA-B*5701 allele are at high risk for developing a hypersensitivity reaction. Avoiding abacavir-containing therapy in patients who carry the HLA-B*5701 allele has been found to reduce the risk of a potentially serious or fatal hypersensitivity reaction.

Genetic tests for HLA-B*5701 are available and all patients should be screened for the HLA-B*5701 allele before starting or restarting treatment with abacavir or abacavir-containing medications. Development of clinically suspected abacavir HSR requires immediate and permanent discontinuation of abacavir therapy in all patients, including patients negative for HLA-B*5701. More information is available here.


Limitations of Skin Patch Testing for Diagnosing Hypersensitivity Reactions with Abacavir

March 30, 2009

The American FDA is cautioning healthcare professionals against using skin patch testing to immunologically confirm suspected cases of hypersensitivity reaction in patients treated with the antiretroviral drug abacavir. Abacavir is sold under the trade name Ziagen and is part of the combination products Epzicom and Trizivir.

Abacavir is associated with serious and potentially fatal hypersensitivity reactions. Patients with a particular HLA allele, HLA-B*5701, have a higher risk of developing these reactions if they are treated with abacavir, and so abacavir is not recommended for these patients. Because of this, a boxed warning recommends that all patients be screened for the HLA-B*5701 allele before starting or restarting abacavir therapy. If a hypersensitivity reaction is suspected in any patient, even those without the allele, the drug should be stopped immediately and permanently, because rechallenging the patient with abacavir could be fatal.

Abacavir hypersensitivity reactions can be difficult to diagnose because they can be confused with adverse events from the patient’s other HIV medications, or they may mimic the infections that frequently occur in HIV patients.

Several research reports have described using skin patch testing to confirm suspected cases of abacavir hypersensitivity immunologically. However, data suggest that skin patch testing may miss cases of true hypersensitivity reaction or provide false positive results. FDA points out that the accuracy of skin patch testing is unknown, and that using skin patch testing to confirm cases of abacavir hypersensitivity has not been validated clinically. Given that rechallenging a patient with a suspected hypersensitivity reaction could be fatal, these reactions must continue to be diagnosed clinically.

More Information can be found at:

FDA Drug Safety Newsletter Volume 2, Number 1, 2009.
http://www.fda.gov/cder/dsn/2009_v2_no1/postmarketing.htm#abacavir

FDA MedWatch Safety Alert. Abacavir (marketed as Ziagen) and Abacavir-containing Medications. July 24, 2008.
http://www.fda.gov/medwatch/safety/2008/safety08.htm#Abacavir


Is There A Genetic Predisposition of Asian Patients For Serious Skin Reactions Under Phenytoin and Fosphenytoin Treatment?

March 19, 2009
FDA is investigating new preliminary data suggesting an increased risk of serious skin reactions from the anti-epileptic drugs phenytoin and fosphenytoin if they are taken by Asian patients who are positive for the human leukocyte antigen allele HLA-B*1502. These reactions include Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN). Phenytoin is marketed as Dilantin, Phenytek and generics. Fosphenytoin sodium is marketed as Cerebyx and generics.

It is estimated that in parts of China, Taiwan, Thailand, Malaysia, Indonesia and the Philippines, 15 percent or more of the population may carry the HLA-B*-1502 allele. The frequency in South Asia, including India, is somewhat lower, and in Japan and Korea it is under one percent.

It was previously established that another anti-epileptic drug, carbamazepine, increases the risk of these skin reactions in Asian patients with the HLA-B*1502 allele. FDA has recommended screening patients of Asian ancestry for this allele before prescribing carbamazepine and not starting the drug unless the expected benefit clearly outweighs the risk..

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