New Strategy Used to Identify Genetic Polymorphisms that may Underlie Susceptibility to Adverse Drug Reactions
The development of safer drugs is the ultimate goal of pharmacogenomics and a recent study carried out by scientists at the North Carolina State University (NC, USA) identified a gene in mice that could be linked to the risk of acetaminophen-induced liver injury that is found in humans. Therefore, this promising finding could use pharmacogenomics to help develop safer drugs. Their findings were published online by Genome Research in May 2009.
Acetaminophen (or paracetamol) is one of the most widely used over-the-counter analgesic and antipyretic drugs. Although acetaminophen is generally safe when taken at recommended doses, it has been known to cause severe liver injury and/toxicity if taken in high doses. Also, there have been recent studies that have demonstrated in approximately a third of healthy individuals, the allowable dosage could induce elevated serum levels of the liver enzyme, alanine transaminase (ALT), causing possible liver damage and if given at higher doses these individuals could be susceptible to liver failure. This, therefore, leads to the hypothesis that there may well be a genetic predisposition that contributes to developing acetaminophen-induced liver injury. “If genetic differences are included in early safety testing, more accurate predictions of clinical response will be obtained…the end result will be safer drugs”, enthused Dr David Threadgill (University of North Carolina, NC, USA), a lead author of the paper.
In the above mentioned study, the team of scientists incorporated mouse genetics into their quest to find candidate genes that may be linked to acetaminophen-induced liver injury in humans. “We approached the study from the perspective that drugs are used in very heterogeneous patient populations, and that drug-induced toxicities are likely the result of a person‘s genetic makeup”, explained Threadgill.
Whole-genome association analysis and targeted sequencing in a diverse population of mice revealed polymorphisms in the genes: Ly86, Cd44, Cd59a and Capn8. These were also found to correlate strongly with liver injury. The scientists were then able to demonstrate that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen sensitivities in two independent cohorts. Their results indicate a potential role for CD44 in the modulation of susceptibility to acetaminophen hepatotoxicity in humans.
They concluded that their studies demonstrated that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing. They also noted that their study has broader implications for drug testing since, up until now, genetic differences in humans has not been considered in preclinical tests using animal models.
Source: Harrill AH, Watkins PB, Su S et al.: 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 (2009) (Epub ahead of print).
Research into Lithium as a Treatment for Bipolar Disorder Highlights Potential Benefit for Carriers of Variant Gene IMPA2
A recent study has highlighted the potential for pharmacogenetic research to aid in the treatment of bipolar patients. A team from Cardiff University (Cardiff, UK) has shown that lithium may help to overcome the aberrant signaling caused by a genetic variant that has previously been associated as a cause of bipolar disorder.
Lithium is commonly used to treat patients with bipolar disorder, and while the exact mechanisms of its activity are unclear it is thought it may act through the inhibition of inositol monophophatase, which when over expressed, results in elevated levels of phosphatidyl inositol triphosphate (PIP3), which are associated with bipolar disorder. The team confirmed that lithium does in fact inhibit phosphoinositide synthesis in Dictyostelium and HL60, a human neutrophil cell line.
“Altered PIP3 signaling is linked to other disorders, including epilepsy and autism, so this well-established drug could be used to treat other conditions. Research into lithium could become very important over the next few years,” explained Professor Adrian J Harwood from Cardiff University, one of the authors of the study commented, “By better understanding lithium, we can learn about the genetics of bipolar disorder and develop more potent and selective drugs.”
Elevated PIP3 levels are also seen in carriers of IMPA2, a gene that encodes a variant form of inositol monophophatase. It is hoped that lithium may be a successful treatment for carriers of this gene suffering from bipolar disorder and other disorders associated with the variant.
Source: King JS, Teo R, Ryves J et al.: The mood stabiliser lithium suppresses PIP3 signalling in Dictyostelium and human cells. Dis. Model. Mech. 2(5–6), 306–312 (2009).
TOP2A Gene Variants Found to be Associated with a Better Response to Anthracycline Therapy
The topoisomerase II α (TOP2A) gene has recently been identified in a study carried out by investigators from the University of Toronto (Toronto, Canada) to more likely be associated with the responsiveness to anthracycline-containing chemotherapy in breast cancer patients – possibly even more of an association than the amplification of the HER2 gene with response to therapy.
The team of investigators, led by Dr Kathleen I Pritchard, studied a total of 438 tumors from 710 premenopausal women with node-positive breast cancer who received adjuvant chemotherapy (including either: cyclophosphamide, epirubicin and 5-fluorouracil [CEF] or cyclophosphamide, methotrexate and 5-fluorouracil [CMF]). Their patient cohort came from the randomized National Cancer Institute of Canada Clinical Trials Group Mammary 5 (MA.5) trial. They then analyzed TOP2A alterations as well as HER2 amplification from the samples using fluorescence in situ hybridization. They found that in women whose tumors harbored the TOP2A gene alterations (either amplifications or duplications), had a 65% better relative relapse-free survival and 67% better relative overall survival when treated with CEF compared with CMF and these differences were proved to be statistically significant as well. However, they found that in women whose tumors had the wild-type TOP2A, they seemed to exhibit a similar response to the two regimens. Their results for the women who had the TOP2A altered gene demonstrated an additional benefit when treated with anthracycline-based therapy and they speculate that this benefit is also similar to the benefit found in women who had HER2-positive tumors. “Our data suggest that measurements of TOP2A alteration and HER2 amplification appear to have similar value in guiding the selection of anthracycline-containing regimens”, explained the authors.
The investigators of the study concluded that “TOP2A gene alterations (amplifications or deletions) are associated with an increase in responsiveness to anthracycline-containing chemotherapy regimens relative to nonanthracycline regimens that is similar to that seen in patients with HER2 amplification”. However, they do note that their sample size was too small to determine whether the effect seen was independent of HER2.
Source: O‘Malley FP, Chia S, Tu D et al.: Topoisomerase II a and responsiveness of breast cancer to adjuvant chemotherapy. J. Natl Cancer Inst. 101, 644–650 (2009).
Aspirin use may Lower the Risk of Coronary Heart Disease for Carriers of a Particular Genetic Variant
New research has further added to the debate concerning the preventative effects of aspirin for those at risk of coronary heart disease (CHD). Among those carrying a variant of the gene encoding apolipoprotein(a) (LPA), aspirin use significantly decreased the risk of developing CHD. The findings were presented by a team from Celera (MD, USA) and scientists from the The University of Texas, Baylor College of Medicine (TX, USA), and Brigham and Women‘s Hospital (MA, USA) at the 2009 Arteriosclerosis, Thrombosis and Vascular Biology Annual Conference in Washington, DC, USA.
Variation in the LPA gene has previously been associated with an elevated risk of CHD in both men and women, and this study set out to assess the clinical impact of this variant and whether aspirin use affected the risk of CHD in carriers of the mutation.
The study assessed 6752 participants in the Atherosclerosis Risk in Communities (ARIC) Study which is being conducted in the USA. Their findings corroborated with previous research that a specific substitution of methionine for isoleucine in LPA leads to over a twofold increased risk for CHD in both males and females. Carriers of the gene assessed in the study had a hazard ratio of 1.57 when compared with noncarriers, but only among the nonaspirin users. However, this ratio was heavily reduced among the 1422 aspirin users studied to 0.86, suggesting that aspirin can negate the risk conferred by the mutant allele.
Professor Eric Boerwinkle from the University of Texas, a senior researcher from the study, explained the significance of the results, “This study indicates that carriers of the LPA gene variant are both at higher risk of cardiovascular disease and that this risk is not observed among users of aspirin. These data could provide a genetic method for defining subpopulations with differential benefit from aspirin therapy for prevention of coronary heart disease.”
“We believe this supporting evidence for our previous findings regarding the LPA gene variant in a population that includes aspirin treatment information in both men and women is an important step toward demonstrating the clinical utility among different segments of the population,” said Thomas White, PhD, Chief Scientific Officer at Celera. “We believe these findings make a compelling case for testing for LPA status, and further our commitment to be a leading provider of genetic tests used routinely in personalizing disease management.”
Source: Celera Press Release www.liquidia.com/press/NFID_Vaccine_Release__v_05_final.pdf