Geoffrey S. Ginsburg

The SLCO1B1*5 Genetic Variant Is Associated With Statin-Induced Side Effects

OBJECTIVES We sought to identify single nucleotide polymorphisms associated with mild statin-induced side effects. BACKGROUND Statin-induced side effects can interfere with therapy. Single nucleotide polymorphisms in cytochrome P450 enzymes impair statin metabolism; the reduced function SLCO1B1*5 allele impairs statin clearance and is associated with simvastatin-induced myopathy with creatine kinase (CK) elevation. METHODS The STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study was a pharmacogenetics study of statin efficacy and safety. Subjects (n = 509) were randomized to atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg followed by 80 mg, 80 mg, and 40 mg, respectively. We defined a composite adverse event (CAE) as discontinuation for any side effect, myalgia, or CK >3x upper limit of normal during follow-up. We sequenced CYP2D6, CYP2C8, CYP2C9, CYP3A4, and SLCO1B1 and tested 7 reduced function alleles for association with the CAE. RESULTS The CAE occurred in 99 subjects (54 discontinuations, 49 myalgias, and 9 CK elevations). Sex was associated with CAE (percent female in CAE vs. no CAE groups, 66% vs. 50%, p < 0.01). SLCO1B1*5 was associated with CAE (percent with > or = 1 allele in CAE vs. no CAE groups, 37% vs. 25%, p = 0.03) and those with CAE with no significant CK elevation (p < or = 0.03). Furthermore, there was evidence for a gene-dose effect (percent with CAE in those with 0, 1, or 2 alleles: 19%, 27%, and 50%, trend p = 0.01). Finally, the CAE risk appeared to be greatest in those carriers assigned to simvastatin. CONCLUSIONS SLCO1B1*5 genotype and female sex were associated mild statin-induced side effects. These findings expand the results of a recent genome-wide association study of statin myopathy with CK >3x normal to milder, statin-induced, muscle side effects.

Implementing genomic medicine in the clinic: the future is here

Although the potential for genomics to contribute to clinical care has long been anticipated, the pace of defining the risks and benefits of incorporating genomic findings into medical practice has been relatively slow. Several institutions have recently begun genomic medicine programs, encountering many of the same obstacles and developing the same solutions, often independently. Recognizing that successful early experiences can inform subsequent efforts, the National Human Genome Research Institute brought together a number of these groups to describe their ongoing projects and challenges, identify common infrastructure and research needs, and outline an implementation framework for investigating and introducing similar programs elsewhere. Chief among the challenges were limited evidence and consensus on which genomic variants were medically relevant; lack of reimbursement for genomically driven interventions; and burden to patients and clinicians of assaying, reporting, intervening, and following up genomic findings. Key infrastructure needs included an openly accessible knowledge base capturing sequence variants and their phenotypic associations and a framework for defining and cataloging clinically actionable variants. Multiple institutions are actively engaged in using genomic information in clinical care. Much of this work is being done in isolation and would benefit from more structured collaboration and sharing of best practices.Genet Med 2013:15(4):258–267

Personalized medicine: revolutionizing drug discovery and patient care

Advances in human genome research are opening the door to a new paradigm for practising medicine that promises to transform healthcare. Personalized medicine, the use of marker-assisted diagnosis and targeted therapies derived from an individuals molecular profile, will impact the way drugs are developed and medicine is practiced. Knowledge of the molecular basis of disease will lead to novel target identification, toxicogenomic markers to screen compounds and improved selection of clinical trial patients, which will fundamentally change the pharmaceutical industry. The traditional linear process of drug discovery and development will be replaced by an integrated and heuristic approach. In addition, patient care will be revolutionized through the use of novel molecular predisposition, screening, diagnostic, prognostic, pharmacogenomic and monitoring markers. Although numerous challenges will need to be met to make personalized medicine a reality, with time, this approach will replace the traditional trial-and-error practice of medicine.

An Integrated Genomic-Based Approach to Individualized Treatment of Patients With Advanced-Stage Ovarian Cancer

PURPOSE The purpose of this study was to develop an integrated genomic-based approach to personalized treatment of patients with advanced-stage ovarian cancer. We have used gene expression profiles to identify patients likely to be resistant to primary platinum-based chemotherapy and also to identify alternate targeted therapeutic options for patients with de novo platinum-resistant disease. PATIENTS AND METHODS A gene expression model that predicts response to platinum-based therapy was developed using a training set of 83 advanced-stage serous ovarian cancers and tested on a 36-sample external validation set. In parallel, expression signatures that define the status of oncogenic signaling pathways were evaluated in 119 primary ovarian cancers and 12 ovarian cancer cell lines. In an effort to increase chemotherapy sensitivity, pathways shown to be activated in platinum-resistant cancers were subject to targeted therapy in ovarian cancer cell lines. RESULTS Gene expression profiles identified patients with ovarian cancer likely to be resistant to primary platinum-based chemotherapy with greater than 80% accuracy. In patients with platinum-resistant disease, we identified expression signatures consistent with activation of Src and Rb/E2F pathways, components of which were successfully targeted to increase response in ovarian cancer cell lines. CONCLUSION We have defined a strategy for treatment of patients with advanced-stage ovarian cancer that uses therapeutic stratification based on predictions of response to chemotherapy, coupled with prediction of oncogenic pathway deregulation, as a method to direct the use of targeted agents.

Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells.

Apolipoprotein CIII (apoCIII), a lipid-binding protein involved in the transport of triglycerides and cholesterol in the plasma, is synthesized primarily in the liver and the intestine. A cis-acting regulatory element, C3P, located at -90 to -66 upstream from the apoCIII gene transcriptional start site (+1), is necessary for maximal expression of the apoCIII gene in human hepatoma (HepG2) and intestinal carcinoma (Caco2) cells. This report shows that three members of the steroid receptor superfamily of transcription factors, hepatocyte nuclear factor 4 (HNF-4), apolipoprotein AI regulatory protein 1 (ARP-1), and Ear3/COUP-TF, act at the C3P site. HNF-4 activates apoCIII gene expression in HepG2 and Caco2 cells, while ARP-1 and Ear3/COUP-TF repress its expression in the same cells. HNF-4 activation is abolished by increasing amounts of ARP-1 or Ear3/COUP-TF, and repression by ARP-1 or Ear3/COUP-TF is alleviated by increasing amounts of HNF-4. HNF-4 and ARP-1 bind with similar affinities to the C3P site, suggesting that their opposing transcriptional effects may be mediated by direct competition for DNA binding. HNF-4 and ARP-1 mRNAs are present within the same cells in the liver and intestine, and protein extracts from hepatic tissue, HepG2, and Caco2 cells contain significantly more HNF-4 than ARP-1 or Ear3/COUP-TF binding activities. These findings suggest that the transcription of the apoCIII gene in vivo is dependent, at least in part, upon the intracellular balance of these positive and negative regulatory factors.

Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events

Background—Molecular tools may provide insight into cardiovascular risk. We assessed whether metabolites discriminate coronary artery disease (CAD) and predict risk of cardiovascular events. Methods and Results—We performed mass–spectrometry–based profiling of 69 metabolites in subjects from the CATHGEN biorepository. To evaluate discriminative capabilities of metabolites for CAD, 2 groups were profiled: 174 CAD cases and 174 sex/race-matched controls (“initial”), and 140 CAD cases and 140 controls (“replication”). To evaluate the capability of metabolites to predict cardiovascular events, cases were combined (“event” group); of these, 74 experienced death/myocardial infarction during follow-up. A third independent group was profiled (“event-replication” group; n=63 cases with cardiovascular events, 66 controls). Analysis included principal-components analysis, linear regression, and Cox proportional hazards. Two principal components analysis–derived factors were associated with CAD: 1 comprising branched-chain amino acid metabolites (factor 4, initial P=0.002, replication P=0.01), and 1 comprising urea cycle metabolites (factor 9, initial P=0.0004, replication P=0.01). In multivariable regression, these factors were independently associated with CAD in initial (factor 4, odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74; P=0.02; factor 9, OR, 0.67; 95% CI, 0.52 to 0.87; P=0.003) and replication (factor 4, OR, 1.43; 95% CI, 1.07 to 1.91; P=0.02; factor 9, OR, 0.66; 95% CI, 0.48 to 0.91; P=0.01) groups. A factor composed of dicarboxylacylcarnitines predicted death/myocardial infarction (event group hazard ratio 2.17; 95% CI, 1.23 to 3.84; P=0.007) and was associated with cardiovascular events in the event-replication group (OR, 1.52; 95% CI, 1.08 to 2.14; P=0.01). Conclusions—Metabolite profiles are associated with CAD and subsequent cardiovascular events.

Targeted Therapies for Cancer 2004

The regulatory agency approvals in the United States and Europe of imatinib mesylate (Gleevec) for patients with bcr/abl-positive chronic myelogenous leukemia, cetuximab (Erbitux) for patients with epidermal growth factor receptor overexpressing metastatic colorectal cancer, the antiangiogenesis agent bevacizumab (Avastin), and the proteasome inhibitor bortezomib (Velcade)--and the considerable public interest in new anticancer drugs that take advantage of specific genetic defects that render the malignant cells more likely to respond to specific treatment--are driving a new era of integrated diagnostics and therapeutics. The recent discovery of a drug response predicting activating mutation in the epidermal growth factor receptor gene for patients with non-small cell lung cancer treated with gefitinib (Iressa) has intensified this interest. In this review, the history of targeted anticancer therapies is highlighted, with focus on the development of molecular diagnostics for hematologic malignancies and the emergence of trastuzumab (Herceptin), an antibody-based targeted therapy for HER-2/neu overexpressing metastatic breast cancer: The potential of pharmacogenomic strategies and the use of high-density genomic microarrays to classify and select therapy for cancer are briefly considered. This review also considers the widely held view that, in the next 5 to 10 years, the clinical application of molecular diagnostics will further revolutionize the drug discovery and development process; customize the selection, dosing, route of administration of existing and new therapeutic agents; and truly personalize medical care for cancer patients.

The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health–Centers for Disease Control and Prevention Multidisciplinary Workshop

The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.

The oral microbiome in health and disease and the potential impact on personalized dental medicine

Every human body contains a personalized microbiome that is essential to maintaining health but capable of eliciting disease. The oral microbiome is particularly imperative to health because it can cause both oral and systemic disease. The oral microbiome rests within biofilms throughout the oral cavity, forming an ecosystem that maintains health when in equilibrium. However, certain ecological shifts in the microbiome allow pathogens to manifest and cause disease. Severe forms of oral disease may result in systemic disease at different body sites. Microbiomics and metagenomics are two fields of research that have emerged to identify the presence of specific microbes in the body and understand the nature of the microbiome activity during both health and disease. The analysis of the microbiome and its genomes will pave the way for more effective therapeutic and diagnostic techniques and, ultimately, contribute to the development of personalized medicine and personalized dental medicine.

Atherosclerosis and Cancer

Abstract: Recently, a series of shared molecular pathways have emerged that have in common a significant role in the pathogenesis and progression of both atherosclerosis and cancer. Oxidative stress and the cellular damage that results from it have been implicated in a wide variety of disease processes including atherogenesis and neoplasia. Toxic metabolites produced by cigarette smoking and increased dietary fat intake are implicated in the pathogenesis of both diseases. It has been hypothesized that atherosclerosis may begin when an injury or infection mutates or transforms a single arterial smooth muscle cell in the progenitor of a proliferative clone similar to the most widely held theory of carcinogenesis. Cell proliferation regulatory pathways including genes involved in the G1S checkpoint (p53, pRb, p15, p16, and cyclins A, D, E, and cdk 2,4) have been associated with plaque progression, stenosis and restenosis after angioplasty as well as in cancer progression. Alterations in cell adhesion molecules (integrins, cadherin‐catenins) have been linked to plaque formation and thrombosis as well as to tumor invasion and metastasis. Altered expression of proteases associated with thrombolysis has been implicated in atherosclerotic plaque expansion and hemorrhage and in the invasion and metastasis of malignancy. Ligand‐growth factor receptor interactions (tyrosine kinases) have been associated with early atherosclerotic lesions as well as cancer development and spread. Nuclear transcription factors such as NFκB have been associated with progression of both diseases. Angiogenesis modulators have recently been linked to plaque expansion and restenosis of atherosclerotic lesions as well as local and metastatic tumor expansion. Common disease treatments, such as the use of growth factor inhibitors and radiation treatment, established anticancer treatments, were recently introduced into atherosclerosis therapeutic strategies to prevent restenosis after angioplasty and endarterectomy. In conclusion, a series of molecular pathways of disease development and progression common to atherosclerosis and cancer support that the worlds two most common diseases are far more closely aligned than previously believed and that emerging anti‐inflammatory and antiproliferative therapeutic strategies may ultimately be efficacious in both conditions.