SEMINAR 4: Genetic information in treatment of disease

Context:

Knowledge of the human genome and its variation is growing rapidly. As the techniques to assess the large amount of genetic information gathered in population and patient studies evolves, important insights are being obtained into the association of genetics with disease risk and disease prognosis. These studies are also identifying potential therapeutic targets and approaches for investigation as demonstrated by recent advances in cancer therapeutics. Genetic factors can also contribute to variation in drug pharmacokinetics and pharmaco-dynamics and associations of both drug efficacy and safety with individual and population differences in genetics are being increasingly reported. However, as many factors can influence diseases and drug response the contribution of a single gene and its variation is frequently modest and the number of pharmaco-genetic tests that have been incorporated into clinical practice is still limited. This seminar will provide an overview of the contribution of genetic factors to variation in diseases and their treatment and in the second part will focus on hypertension and the pharmaco-genetics of antihypertensive therapies. Hypertension is an important risk factor for cardiovascular, cerebrovascular and renal disease. The benefits of reducing blood pressure (BP) on the risks of major cardiovascular disease have been well established. Despite major efforts, hypertension remains a leading cause of mortality worldwide and in Europe the proportion of patients with acceptable blood pressure is too low (about 30%). One reason for this is the variable and unpredictable response individuals have to pharmacologic treatment. Essential hypertension is a complex quantitative trait that is affected by combinations of genetic and environmental factors leading to numerous intermediate phenotypes. Attempts have been made to assess factors such as plasma rennin activity, salt-sensitivity, insulin resistance to predict the individual response; these predictors of response are of limited value. Pharmaco-genetics has the potential to further individualise antihypertensive therapy as the analysis of drug-gene interactions may provide new predictors for antihypertensive drug responses. To date, around 60 studies have investigated associations between genetic polymorphisms and response to antihypertensive drugs. The findings of these studies are inconclusive due to conflicting results. Moreover, the single gene effects on antihypertensive drug responses are small. Factors possibly leading to these inconsistent findings could be small sample sizes, population admixture, differences in phenotype definition, lack of statistical power, unknown environmental factors within a population and variation of the effects of polymorphisms in candidate genes due to interactions with such environmental factors. Before hypertension pharmaco-genetics can be translated into clinical practice an evidence base must be established, nevertheless optimism remains that pharmaco-genetics will play a useful role in the treatment of hypertension.

Teaching goals:

• to provide an overview of the current understanding of the contribution of genetic variation to diseases and their treatment.
• to summarise current knowledge on the influence of genetic factors on drug pharmacokinetics and pharmacodynamics.
• to convey the contribution of genetic and environmental factors to variation in drug response within and between individuals and populations.
• to illustrate that improving of antihypertensive drug therapy is necessary
• to evaluate the current knowledge on the pharmaco-genetics of blood pressure response to antihypertensives focusing on commonly used drug classes
• to discuss what needs to be done to translate hypertension pharmaco-genetics into personalised medicine

Learning objectives :

At the end of the seminar, the participants:

• will understand the complexity of defining the contribution of genetic factors to disease.
• will have insight into how genetic factors can influence drug absorption, distribution and metabolism as well as drug pharmaco-dynamics in relation to efficacy and safety
• will appreciate the contribution of genetic factors to inter-individual and population differences in drug response
• will be able to understand the importance of hypertension treatment.
• have a basic knowledge of genetic information relating to treatment of hypertension.
• understand the limitations in translating genetic information in personalised hypertension treatment