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: Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such, they are involved in physiology, development of disease, drug pharmacokinetics, and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable inter-individual variation in physiology and pharmacotherapy. The purpose of this review is to provide a broad overview of how inherited variants in transporters are associated with disease etiology, disease state, and the pharmacological treatment of diseases. Given that there are thousands of published papers related to the interplay between transporter genetics and medicine, this review will provide examples that exemplify the broader focus of the literature. ... Read more

Abstract: Inter-individual variation in drug response and adverse drug reactions (ADRs) are well known in medicine. This individual variation in drug response could be at least, in part, due to genetic diversity among individuals. Although substantial studies that connect genetic variants to inter-individual variation in drug response have been documented in several diseases such as cancer and heart diseases, such studies are slowly progressing in ophthalmology. In recent years, advancement in technologies has led to the identification of genes associated with several eye disorders. At the same time, some small-scale studies have demonstrated the association of various genotypes or haplotypes with response to drug therapies. However, its integration into clinical practice in ophthalmology is not possible at present. This is because there are many challenging questions that remain to be addressed. For instance, in the case of complex disorders a single gene study is not enough. Multiple genes, environmental factors, multiple single nucleotide polymorphisms (SNPs), and rare or low frequency variants may contribute to the disease and they must be considered. The functional aspects of many genetic variants are not known. This raises questions of their biological importance and their clinical usefulness. In addition, there are legal, ethical, and social issues that need to be regulated. Moreover, physicians and patients must be educated about the limitation and sensitivity of genetic testing. At present pharmacogenetic studies in ophthalmology are still in their infancy and do not suggest that a pharmacogenetic basis of drug development in ophthalmology is a concept that can yield immediate results, but can become a reality in the future. In this article an attempt has been made to summarize some of the recent small-scale pharmacogenetic studies on two major eye disorders, age-related macular degeneration (AMD) and glaucoma. ... Read more

Abstract: The new mantra for delivering optimal cancer treatment is "personalized care." This extends beyond the holistic to using germline and somatic tumoral mutations to link a specific therapy to some prognostic or predictive factor which defines a particularly responsive patient subgroup who might benefit most from treatment. Furthermore, inherited polymorphisms have the potential to greatly modulate the side effects of treatment, especially for chemotherapy which has a notoriously narrow therapeutic window (Walther et al., 2009). ... Read more

Abstract: Pharmacogenetics, or pharmacogenomics, studies how a person's genetic makeup affects the person's response to drugs, holding out promise for medicine that caters to an individual's genomic makeup. Individualized medicine would be a paradigm shift from the current, centuries-old industry practice. Science, growing awareness of patients' needs, the hesitant but increasingly interested pharmaceutical industry, and government agencies are forging a movement towards personalization of drug treatments. ... 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: 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

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: 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

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