Overview
All diseases, to a greater or lesser extent, are influenced by environmental and genetic actions. It is now recognised that small changes in genes can trigger, promote, prevent or alleviate diseases. With the completion of the Human Genome Project, scientists are beginning to determine the precise genes implicated in the development of many common diseases, including cardiovascular disease, hypertension, malignancy, osteoporosis, thrombosis, as well as how our bodies respond to and metabolise different medications. It is the dawn of a new age in personalised medicine and one which will allow individuals to make appropriate modifications to their lifestyle to minimise their risk of developing these diseases.
Genetics Conference 2007 has brought together some of the leading scientists and doctors in this field to summarise the latest advances in the genetics of common diseases. Talks will include an introduction to SNPs (single nucleotide polymorphisms), the genetics of heart disease, obesity and diabetes, pharmacogenetics, and an overview of how these will be of interest to the general clinician.
The symposium is recommended to all scientists and clinicians interested in the genetic basis of disease, and especially how this new knowledge can be translated into clinical practice. It will be of particular interest to general practitioners involved in preventive medicine, cardiologists, clinical pharmacologists, and diabetologists.
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SNPs – how they are measured and what do they do
Prof. Stephen Bustin
There are a number of techniques that make it possible to detect single nucleotide changes in the human genome. These use different methods to analyse and compare selected regions of a DNA sequence obtained from multiple individuals who share a common trait for SNP patterns. These are compared to patterns obtained by analysing the DNA from a group of individuals unaffected by the disease. This type of association study can detect differences between the SNP patterns of the two groups, thereby indicating which pattern is most likely associated with the disease-causing gene. This permits the establishment of SNP profiles that are characteristic of a variety of risks/diseases and can be used for screening individuals for risk or disease susceptibility by analysing their DNA samples for specific SNP patterns.
SNP analysis aims to answer some of the following questions:
- What is my individual risk of developing a particular disease?
- How likely am I to be allergic to any drugs I am being prescribed?
- How successful is the treatment regimen I am undergoing likely to be?
Although all chromosomes contain the same genes in the same order, the DNA sequences making up the genes are not identical. On average, one in every 300-500 base pairs of the genome differs from the sequence found in the majority of people. These randomly occurring changes, which are passed from generation to generation, are referred to as a single nucleotide polymorphisms, or SNPs. Consequently each person's genetic material contains a unique SNP pattern that is made up of many different genetic variations. SNPs that are physically close are inherited together as blocks and can be used to distinguish individuals and populations to determine what specific diseases or other traits are associated with different groups of SNPs.
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The Genetics of Coronary Heart Disease
Dr David Brull
Coronary heart disease (CHD) is the most common cause of death worldwide. Over the last 50 years the list of major cardiovascular risk factors has continued to grow as our understanding of vascular biology improves. There are a number of well accepted risk factors for the development of CHD include increasing age, smoking, diabetes, elevated blood pressure, high levels of total and LDL cholesterol and low levels of HDL. Although patients with CHD commonly have at least one identifiable risk factor many ischaemic events occur in the absence of any of these classical associations. In addition, cardiovascular risk tends to cluster in affected families, where there are a number of identifiable risk factors. This supports the importance of both a shared environment and shared genetic factors. Many of the known risk factors for development of CHD are themselves genetically determined quantitative traits.
A number of different approaches have been used study the impact of genetic variation and cardiovascular risk, including numerous linkage analysis and gene association studies. The recent development of high density genotyping arrays, so-called “chip technology,” now affords researchers the opportunity for genome-wide assessment of variants associated with common diseases such as CHD.
Earlier this year there were three ground breaking publications, including analysis of data from the Wellcome Trust Case Control Study, linking a locus on chromosome 9 (9p21.3), and more recently two other loci (6q25.1 and 2q36.3) with an increased risk of CHD. These observations will help identity potential targets for therapy and raise the prospect of population-wide genetic screening in order to more accurately stratify cardiovascular risk thus allowing more appropriate usage of drug therapy.
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Pharmacogenetics
Dr Mel Lobo
In everyday life, a doctor initiating a new prescription for a patient should have both a consummate understanding of the disease entity being treated and also be able to make an informed decision about the appropriate therapy. In an ideal world, such treatment decisions would automatically factor in data to enable the physician to prescribe a drug which will be both entirely safe and maximally efficacious for their patient. Historically however, medicines prescribing has largely been on a ‘one size fits all’ basis with little consideration given to inter-individual differences in responses to drugs and propensity for adverse reactions to drugs.
It is now understood that, due to both environmental factors and - much more importantly - genetic polymorphisms, there are very considerable differences in the way individuals may either handle drugs and/or respond to drugs. Recently the science of pharmacogenetics has given us exciting insights into exactly why some patients respond well to certain medications and others experience therapeutic failure. At the same time we have gained a much greater understanding of why some individuals are more likely to experience adverse reactions to drugs. In one or two instances, where drug toxicity may be potentially life-threatening, prospective genotyping/phenotyping is now routinely recommended. It is important to remember that whilst environmental factors affecting drug efficacy/toxicity vary throughout life, genetic variation or trait remains constant and needs to be tested for only once in a lifetime.
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Genetics of obesity and diabetes
Prof. Mark McCarthy
The strong genetic contribution to individual risk of type 2 diabetes and obesity means that important insights into disease mechanisms can be obtained by identification of the specific genes involved. Recent technological and biological advances have made it possible to undertake systematic “genome-wide” screens that are proving highly effective in defining these susceptibility genes. Through these studies, which include our own work within the Wellcome Trust Case Control Consortium, the number of genes clearly implicated in type 2 diabetes susceptibility is now in double figures, and the first common variants influencing weight and risk of obesity have been identified.
One can foresee two main ways by which findings such as these will lead to improvements in the management of these conditions. The first involves the opportunity to consider the disease pathways that have been implicated by these studies as a source of novel drug targets, a process that should lead to new approaches to treatment and prevention. The second route for translation involves use of the susceptibility variants identified as tools for individual prediction of disease risk and therapeutic response. The value of this latter approach is, for the time being, limited by the fact that the variants so far identified explain only a small proportion of overall risk; however, the prospects for improving risk prediction through further successes in susceptibility variant identification are good. A second limitation is the paucity of the evidence base demonstrating that knowledge of individual genetic predisposition results in the capacity to effect lifestyle changes, or implement therapeutic interventions, that have a specific benefit on health. Recent data indicating that variation at the TCF7L2 gene influences early response to sulphonylureas illustrate the kind of large-scale studies (employing observational, interventional and experimental strategies) that will be required to generate the evidence base which enables responsible clinical implementation. Recent discoveries provide support therefore for the belief that genetic information of this kind will ultimately have a role in the personalized management of multifactorial diabetes and obesity.
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Genotyping and its clinical utility in lifestyle management for disease prevention
Dr. Paul Jenkins
All diseases, to a greater or lesser extent, are influenced by environmental and genetic actions. Small changes in genes (single nucleotide polymorphisms, SNPs) can trigger, promote, prevent or alleviate diseases. With the completion of the Human Genome Project, scientists are increasingly discovering the precise SNPs implicated in the development of many common diseases, including cardiovascular disease, hypertension, malignancy, osteoporosis, thrombosis, as well as how our bodies respond to and metabolise different medications. For the first time, doctors are able to fill in the missing gaps in an individual’s overall risk profile of developing many of those diseases which cause significant morbidity and mortality. Given that many of the genetic effects are influenced by environmental and lifestyle influences, knowledge of their unique genetic ‘barcode’ allows individuals to make appropriate lifestyle modifications, to minimise their risk of developing these diseases. This includes specific dietary changes, as nutritional influences are also increasingly recognised to impact on gene phenotype. It is the dawn of a new age in personalised medicine and one which physicians will increasingly utilise in disease prevention.
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