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Convergent Mechanisms of Somatic Mutations in Polycythemia Vera


The Genetics of Asthma and Allergic Disorders

Abstract: Asthma and allergic diseases are complex conditions caused by a combination of genetic and environmental factors. More than 100 genes have been associated with asthma and related conditions through candidate gene approaches, but issues of insufficient replication have made conclusions difficult to draw. Despite this, several overarching themes in the biology and pathogenesis of asthma have been revealed as a result of this work. In mid-2007, the first genome wide association study (GWAS) targeting asthma was published, and in the intervening years more than a dozen such studies have been reported examining asthma, allergic diseases, and related intermediate phenotypes and quantitative traits. A few previously suspected genetic variants have been confirmed in these studies as asthma susceptibility loci, or as loci contributing to disease severity or response to treatment. Additionally, unexpected and largely uncharacterized genes have been identified as new susceptibility loci for asthma, altering lung function or perturbing immune function. In this review, we summarize these GWAS, as well as the functional themes and characteristics underlying asthma that have been revealed through decades of genetic and genomic research. ... Read more

The Genetics of Psoriatic Arthritis: Lessons from Genome-wide Association Studies

Abstract: Psoriatic arthritis (PsA) occurs in approximately 30% of psoriasis patients. Understanding the similarities and differences in the etiology of these related diseases may highlight pathways for intervention and allow risk prediction in the future. Both are complex diseases in which environmental susceptibility factors trigger disease in genetically susceptible individuals. In recent years, genome-wide association studies have been highly successful in identifying genetic susceptibility factors for psoriasis. Most of the psoriasis loci tested so far are also associated with PsA. For example, associations of HLA-Cw*06 and the IL12B and IL23R genes are well-established with both conditions. More recently, analysis of psoriasis genome-wide association studies in a PsA subgroup has also implicated IL23A, TNFAIP3, and TNIP1 genetic variants as conferring risk to PsA. One study has suggested that late cornified envelope (LCE) gene polymorphisms are associated with psoriasis but not PsA. However, this finding was not confirmed by a second study. Similarly, association of the 5q31 gene region encompassing the IL13 gene has been reported with PsA but not psoriasis by one group, but this awaits confirmation in other series. Dedicated genome-wide association studies of PsA are underway and are likely to reveal further insights into why some patients with psoriasis develop arthritis whilst the majority do not. ... Read more

BRCA and Beyond: A Genome-first Approach to Familial Breast Cancer Risk Assessment

Abstract: Breast cancer affects around 12% of women in the Western world, but individual lifetime risks vary significantly within any population. Currently, familial cancer services assess and manage familial breast cancer risk based on the presence of a family history of the condition or the identification of high-risk breast cancer susceptibility alleles. This model of clinical care provides an accurate genetic risk assessment for only the minority of families referred to these services. With increasing access to technologies that interrogate human variation at the genome-wide level, it is envisaged that familial breast cancer risk assessments will in the future assume a genome-first approach. This review discusses and highlights the different components of familial breast cancer risk, which will need to be integrated to make this new model of clinical risk assessment possible. ... Read more

Pharmacogenomics in Childhood Rheumatic Disorders: A Foundation for Future Individualized Therapy

Abstract: Investigating the effect of genotype on drug response in children is an evolving field, with many challenges, but there is great potential to optimize safe and effective use of drugs in children. An exponential increase in available medications for use in children with rheumatic disease has opened seemingly endless genotype/phenotype relationships to explore, but challenges inherent in studying rare diseases and the often overlooked role of ontogeny contribute to limitations in pharmacogenomic studies in this population. With careful recognition of the importance of development, improved phenotyping with the incorporation of biomarkers, and expanding collaborative efforts on a national and even international scale, the field of pediatric rheumatology has the opportunity to strategically study the new therapeutic armamentarium available and provide individualized safe and effective therapies to our population of patients. ... Read more

Pharmacogenomics, Personalized Medicine, and Heart Failure

Abstract: Heart failure, a major clinical problem affecting millions of people, may be modified by the genetic diversity of the affected individuals. A novel medical approach, personalized medicine, seeks to use genetic information to "personalize" and improve diagnosis, prevention, and therapy. The personalized management of heart failure involves a large spectrum of potential applications, from diagnostics of monogenic disorders, to prevention and management strategies based on modifier genes, to pharmacogenomics. In rare monogenic disorders causing heart failure, recent guidelines now assist the clinician in molecular diagnostics, genetic counseling, and therapeutic choices. Several lines of evidence suggest that common polymorphic variants of modifier genes can influence the susceptibility to heart failure, and it is expected that more advanced high throughput technologies will allow the discovery of a number of novel modifier genes that could be used for prognostic profiling and development of novel therapeutics. Finally, using pharmacogenomic approaches to affect heart failure management appears very promising. Common genetic variants of beta-adrenergic receptors, alpha-adrenergic receptors, and endothelin receptors among others significantly alter the response to heart failure therapy. This knowledge could be used to personalize and optimize heart failure therapy based on the patient's genetic profile. While the advances in technologies will continue to transition personalized medicine from the research to the clinical setting, physicians and in particular cardiologists need to reshape clinical diagnostics paradigms, learn how to use new genomic information to change management decisions, and provide the patients with appropriate education and management recommendations. ... Read more

Pharmacogenetic Mechanisms Underlying Unanticipated Drug Responses

Abstract: Because most medicines have not been encountered by individuals of our species prior to treatment, it follows that treatment could uncover a previously silent genetic predisposition or could interact with a known genetic variation(s) to produce an unintended outcome. Pharmacogenetics encompasses the discovery, testing, and application of genetic variation as applied to therapeutic treatment and outcome. Two broad divisions of pharmacogenetics are recognized: pharmacokinetics, which describes genetic variations that affect drug metabolism, and pharmacodynamics which describes similar processes that have effects on drug targets, including downstream signaling pathways. The genetic mechanisms that underlie an altered drug response recapitulates most known sources of genomic variation. The most commonly encountered is sequence variation. This includes changes in the primary nucleotide sequence of coding, regulatory, and splice regions of a gene, the product of which affects, or is affected by, a drug. Less common forms of variability in the structure and function of the genome have also been found to underlie an individualized response to medicines. Among these are sequence variation in microRNA (miRNA) binding sites, which affects the ability of miRNA to regulate translation; pharmacoepigenetics, which examines heritable chromatin modifications; and copy number variation. Among the 158 currently registered pharmacogenetic clinical trials, the most frequent conditions or disease processes being studied are cancer, psychiatric disorders, and coagulation/thrombosis. From this observation, it is postulated that pharmacogenetics has its greatest potential for optimizing the use of drugs with a high rate of failure or adverse outcomes. ... Read more

Integration of Genomics into Medical Practice

Abstract: Although some have wondered whether the sequencing of the human genome has led to major advances in medicine, in fact there are multiple examples where genomics has been integrated into medical practice. In the area of prevention, genomic approaches are now used for non-invasive prenatal testing of fetal DNA in the maternal circulation, for expanded preconceptional screening for carrier status, for autosomal recessive disorders, and for assessment of risk of common disease. In the area of diagnosis, major advances have been made in cytogenomics and in use of whole exome or whole genome sequencing. In therapeutics, pharmacogenetic testing is now feasible, tumor genome sequencing is being used to guide cancer therapy, and genomic discoveries are enabling development of new targeted therapies. Ultimately it is possible that genome sequencing may be done for all individuals on a routine basis, though there remain significant technical, ethical, and medical systems challenges to be overcome. It is likely that integration of genomics into medical practice will occur gradually over a long period of time, but the process is now well underway. ... Read more

The Relationship Between HMGCR Genetic Variation, Alternative Splicing, and Statin Efficacy

Abstract: Statins are a class of cholesterol lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the enzyme which catalyzes the rate limiting step of cholesterol biosynthesis. Although numerous trials have demonstrated statin efficacy in the reduction of cardiovascular disease risk, there is substantial variation between individuals in the magnitude of plasma LDL-cholesterol reduction. Pharmacogenetic studies have identified HMGCR genetic variation associated with this inter-individual variation. Here we describe how these studies lead to the discovery that HMGCR alternative splicing of exon 13 is not only a marker, but also a determinant of statin efficacy; not only for the treatment of hypercholesterolemia, but also as a chemopreventive agent for colorectal cancer. ... Read more

Prolactin in Breast and Prostate Cancer: Molecular and Genetic Perspectives

Abstract: Prostate and breast cancers affect millions of men and women, respectively. Advanced forms of the disease, which can no longer be controlled by hormonal disruption or chemotherapy, have very limited treatment options. Consequently, there is a major benefit to identify new targets for therapy in both types of cancer. The prolactin (PRL) signaling cascade, by virtue of its importance to the pathology of both diseases, has emerged as a potential treatment target. To date, several methods for antagonizing the PRL receptor (PRLR) and its signaling pathways have been developed which include protein-based and small molecule antagonists. However, a better understanding of the genetic and molecular characteristics of the PRL cascade is needed for the successful therapeutic application of antagonists. At the level of genetics, it is necessary to determine the functional significance of non-synonymous single nucleotide polymorphisms of the PRLR and their association with disease prevalence and severity. At the molecular level, a comprehensive knowledge of interactions of the PRL signaling pathway with other oncogenic molecules is warranted so as to identify beneficial combinatorial strategies. This review discusses multiple features of the PRL signaling cascade and how they can be exploited in the search for effective therapies for patients with breast and prostate cancers. ... Read more

Network Medicine Approaches to the Genetics of Complex Diseases

Abstract: Complex diseases are caused by perturbations of biological networks. Genetic analysis approaches focused on individual genetic determinants are unlikely to characterize the network architecture of complex diseases comprehensively. Network medicine, which applies systems biology and network science to complex molecular networks underlying human disease, focuses on identifying the interacting genes and proteins which lead to disease pathogenesis. The long biological path between a genetic risk variant and development of a complex disease involves a range of biochemical intermediates, including coding and non-coding RNA, proteins, and metabolites. Transcriptomics, proteomics, metabolomics, and other -omics technologies have the potential to provide insights into complex disease pathogenesis, especially if they are applied within a network biology framework. Most previous efforts to relate genetics to -omics data have focused on a single -omics platform; the next generation of complex disease genetics studies will require integration of multiple types of -omics data sets in a network context. Network medicine may also provide insight into complex disease heterogeneity, serve as the basis for new disease classifications that reflect underlying disease pathogenesis, and guide rational therapeutic and preventive strategies. ... Read more

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