Abstract: Glaucoma is a group of heterogeneous optic neuropathy and is the second leading cause of irreversible blindness worldwide. The two most common clinical types of glaucoma include primary open-angle (POAG) and primary angle-closure glaucoma (PACG). PACG is characterized by the closure of angles between iris and trabecular meshwork (iridocorneal angles) mainly because of anatomic abnormalities. The condition is more prevalent in Chinese, Asian Indians, and Eskimos. Because of an unusually high incidence of PACG among siblings of affected patients, it was suggested that genetic factors were involved in its pathology and the action of a large number of grouped or independently inherited genes along with environmental factors result in anatomical abnormalities of PACG. In PACG, the genetic basis is not well understood. Genome-wide association studies have identified several candidate genes in relation to PACG in several different populations. However, they are not reproduced from population to population or the results are controversial. This may indicate that the involvement of genetic abnormality in the pathogenesis of PACG is complex. The availability of spontaneously occurring large animal models such as dogs may provide an opportunity to identify genes responsible for the pathophysiology of PACG in the future. This article summarizes the current status of genetic investigations on PACG which is the most common cause of blindness worldwide. ... Read more

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

Abstract: Despite advances in surgery, chemotherapy, and radiotherapy over the last decades, the death rate from lung cancer has remained largely unchanged, which is mainly due to metastatic disease. Because of the overall poor prognosis, new treatment strategies for lung cancer patients are urgently needed. In this review, we summarize recent advances in non-small cell lung cancer (NSCLC) screening and diagnostic workup. We discuss current clinical management, highlighting stage-specific therapy approaches, chemotherapy options for advanced-stage patients, along with new agents such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) monoclonal antibodies, and the EGFR-targeting tyrosine kinase inhibitors erlotinib and gefitinib, and the anaplastic lymphoma kinase (ALK) inhibitor crizotinib. Finally, we give an outlook into NSCLC disease biology, focusing on the importance of EGFR activating mutations and the role of the tumor-microenvironment. CXCR4 chemokine receptors expressed on NSCLC cells are a central pathway of NSCLC cross talk with the tumor microenvironment, as they induce activation, migration, and tumor cell adhesion to stromal cells, which in turn provides growth- and drug resistance-signals. Because of the growing evidence that the microenvironment in NSCLC promotes disease progression, we expect that selected molecular pathways of cross talk between NSCLC cells and their microenvironment will become alternative therapeutic targets in the near future. ... Read more

Abstract: The study of microRNA (miRNA) regulation in the pathogenesis of autoimmune diseases and hematopoietic malignancies provides new understanding of the mechanisms of disease and is currently the focus of many researchers in the field. Autoimmune disorders and cancers of immune system comprise a wide range of genetically complex diseases that share certain aspects of dysregulated genetic networks, most notably deactivation of apoptosis. miRNA mechanisms control gene expression at the post-transcriptional level, linking mRNA processing and gene function. Considerable amount of data have been accumulated that indicate that the alteration of miRNA expression closely mirrors the development of immune system diseases and is likely to play a role in their pathogenesis. However, a knowledge gap remains in our understanding of how miRNA dysregulation and the specific effects of miRNAs on target gene expression underlay the disease phenotype. Here we review a number of studies describing miRNA alterations in autoimmune diseases and hematopoietic cancers and discuss potential miRNA-regulated mechanisms that differentially influence the development of autoimmunity as compared to cancer progression. ... Read more

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

Abstract: Polycythemia vera (PV) is an acquired blood disorder, with variable increase of clonal myeloid cells (erythrocytes, granulocytes and platelets) and mostly normal polyclonal T lymphocytes. Most patients have a somatic V617F gain-of-function mutation in JAK2 associated with acquired uniparental disomy (UPD) on chromosome 9p. Yet, the JAK2 V617F mutation is not a PV-initiating event and the family clustering of PV suggests a contribution of inherited genetic events. Using whole-genome SNP arrays, we assayed 34 T-cells and 66 granulocytes (including 32 pairs from the same patients), and identified multiple SNPs around JAK2 that are associated with PV susceptibility (rs11999802, P=1.8x10^-8, OR=4.4). We also developed a quantitative measure of the fraction of somatic single nucleotide variants (SNVs) based on allele-specific PCR, and a quantitative measure of somatic UPD based on "fractional copy-neutral loss-of-heterozygosity (LOH)" on SNP arrays. Somatic genomic changes in granulocytes revealed strong genetic heterogeneity, including 9p UPD and chromosomal gain. The magnitude of somatic 9p UPD was strongly associated with V617F dosage (r²=0.74, P=4.8x10^-12), suggesting that UPD preferentially increases the V617F subclone. In granulocytes with heterozygous rs11999802 genotypes, UPD increased the relative fraction of germline risk alleles (P=0.03). Thus, germline risk variants at JAK2 predispose to somatic point mutations within JAK2, whose allelic dosage can be further increased by a serial subclonal expansion of allele-specific UPD or copy number alteration, contributing to PV pathogenesis. We argue that PV represents a unique disease model to study the interplay between germline risk variants and convergent mechanisms of somatic mutations. ... Read more

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

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

Abstract: Background: We explored use of a canine model of heart failure (HF) for pharmacogenomic discovery, specifically analyzing response to beta blockers (BB). Methods: Dogs with HF that received BB (n=39) underwent genome-wide genotyping to test the association with changes in left ventricular (LV) volume and ejection fraction after treatment. Resulting candidate genes underwent RNA quantification in cardiac tissue from normal (n=5), placebo-HF (n=5), and BB-HF (n=7) dogs. Results: Three markers met whole-genome significance for association with improved LV end-systolic volume after BB therapy (each p<5x10^-7). RNA quantification of three candidate genes near these markers -- GUCA1B, RRAGD, and MRPS10 -- revealed that gene expression levels in BB-HF dogs were between that of placebo-HF dogs and normal dogs. Conclusion: Genome-wide pharmacogenomic screening in a canine model of HF suggests 3 novel BB response candidate loci. This approach is adaptable to discovering mechanisms of action for other drug therapies, and may be a useful strategy for identifying candidate genes for drug response in the pre-clinical setting. ... Read more

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