Although the ultimate goal of developing specific intervention strategies for genetic primary care conditions (‘personalised medicine’) is still a distant prospect,26–30
there are outcomes of genetic epidemiology that are of more immediate interest, including the scientific gain of improved understanding of the biology of our species and the diseases we experience. Other outcomes have clinical relevance to primary care, and are summarised in Box 1
Box 1. Clinical outcomes of genetic epidemiology.26
- Improved understanding of the aetiological gene–environment interactions for many of the major conditions (for example, heart disease, diabetes and cancers).
- Increased genetic testing, from pre-conception onwards.
- Describing new taxonomies of pathophysiology and disease, based on molecular, classifications rather than signs and symptoms, with distinct information about prognosis and treatment.17
- Leading to targeted prevention and prognosis (‘dia-prognosis’)12 based on genetic or molecular factors.
- Linking with pharmacogenetics, towards targeted therapeutic drug strategies.29
- Determining the heritability and famililial aggregation of diseases or intermediate phenotypes, and thus directing further gene discovery studies.66–68
For example, recent research has found that variants of the dopamine D2
receptor determine responses to nicotine replacement therapy.31
Women with the variant T allele, which had a prevalence of 41%, were significantly more likely to be successful in giving up smoking up to 8 years post-intervention with the support of nicotine patches; however, in men this allele did not seem to affect the response.32
Similarly, polymorphisms in the cytochrome P450 CYP2C9 gene have been found to be associated with a fourfold increased risk of major haemorrhage when taking warfarin.33
Such findings will enhance our ability to target pharmacological interventions, optimising effectiveness and cost-effectiveness, while minimising the risk of serious adverse reactions. This will require increased communication between GPs and their patients, who will need to discuss probabilities of response or adverse reactions based on the results of genetic tests, and agree decisions about prescribing.28
Genetic aetiological factors are not generally amenable to direct intervention, other than by pre-natal selection. This is largely because there is an inevitable lag between identifying the genetic basis of diseases and the development of new treatments or prevention strategies. For the present this will produce a dilemma in being able to identify increased risk when no action to reduce risk is yet possible. However, an immediate and important outcome for primary care will be the distinction of environmental from genetic risk factors for important diseases. We are more able to manipulate our environment, through drugs, lifestyle and behaviour, than our genes.
Furthermore, we can potentially identify genetic factors that distinguish true positive from false positive high risks of disease,30
allowing a greater quantification and characterisation of risk, and more targeted disease prevention. For example, the great majority of individuals with hypertension do not go on to develop premature cardiovascular events: if we could identify a genetic factor that interacts cumulatively with this known risk factor, we could focus our antihypertensive efforts on those who have both, with consequent saving in time, drug costs and adverse drug reactions. The risk of breast cancer already offers an example of such targeting. A woman's family history of breast cancer is an imperfect predictor of her own future development of the disease. This is because of small family sizes, under-reporting of a family history of breast cancer (especially in second degree relatives), and incomplete penetrance of cancer-causing gene mutations.34
Genetic screening, for example for mismatch repair gene mutations, may represent a better approach to targeting interventions to prevent cancer.14,35
Discovering the BRCA136
gene mutations and their importance in predicting breast cancer has led to the offer of prophylactic oophorectomy for women with a relevant family history and one of these mutations, a procedure that appears to lead to a gain of approximately 4 years of life.38