Diagnostic molecular biology is arguably the fastest growing area of laboratory medicine and has the potential for a major impact on clinical medicine within the next decade. As this area develops, so will our understanding of how structural variations in DNA and RNA are associated with the development of chronic diseases. New technologies have contributed to the dramatic acceleration in our capacity to investigate the genetic components of disease. Future developments in this area will be fuelled by improvements in technology and the availability of large, carefully documented study populations.
Many genes responsible for monogenic diseases have been successfully isolated and are used for the clinical diagnosis of disease, identification of gene carriers or predictive testing of subjects who may develop certain diseases. Genes that cause complex diseases, such as cardiovascular disease, asthma and osteoporosis are being studied but it will take time before the use of these genetic risk factors are used in clinical practice due to the complexity of the interactions between genetic and environmental risk factors.
Diagnostic molecular biology is widely used in a number of areas including haematology, immunology and microbiology with possibly the least developed area being clinical biochemistry. Apart from diseases such as cystic fibrosis and genetic haemochromatosis, most genetic diseases tested for in clinical biochemistry laboratories are rare in the general population. However, molecular methods will be increasingly incorporated into all areas of pathology, not to replace current tests but as an aid in evaluating the future risk of disease.
In this issue of the Clinical Biochemist Reviews a series of manuscripts have been selected that highlight a snapshot of the ‘state-of-art’ of diagnostic molecular biology testing in clinical laboratory medicine.
The opening article by Siah et al. provides a comprehensive review of iron metabolism and pathophysiology of iron overload. The identification of the HFE gene by Feder et al. in 1996 was a major step forward in understanding iron metabolism and has provided considerable impetus to the study of iron metabolism. Genotyping for the common variants of the HFE gene is the most requested genetic test performed in clinical medicine. Possibly because it was the first genetic test to be listed for reimbursement on the Medicare Benefit Schedule for patients with an elevated transferrin saturation or serum ferritin; or for a patient who has a first degree relative with haemochromatosis or a relative with homozygosity for the C282Y genetic mutation, or compound heterozygosity (www.medicareaustralia.gov.au). In 2004/05 there were 39,404 HFE tests claimed through Medicare at a cost of $1,257,832.
Pharmacogenomics is the study of the effect of genetic variations on drug response, efficacy, and metabolism. This area has the potential to be one of the first large-scale clinical applications of diagnostic molecular biology. It is certain to have an enormous impact on the practice of clinical medicine by deciding on the most effective choice of drugs and avoiding their potentially dangerous side effects. However, to-date there are very few examples of polymorphisms that have a clinically relevant effect on drug response. It is likely that drug response will be complex, influenced by the environment and multiple genetic factors. In the second article in this issue, Dr Jan van der Weide and Dr John Hinrichs from the Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands discuss the role of pharmacogenomics on the metabolism of antipsychotic and antidepressant drugs. They note that in their psychiatric clinic, TDM and genotyping for CYPD6 and CYP2C19 polymorphisms are routinely performed for all hospitalised patients, whereas in Australasian laboratories these tests are almost never performed in routine clinical practice.
The third and fourth articles in this collection cover areas that are not associated with clinical biochemistry but are commonly studied in clinical medicine. The article on the diagnosis of haemoglobinopathies by Professor Ron Trent covers an important and growing area for the application of molecular biology techniques in Australasia. Haemoglobinopathies are the commonest genetic defect worldwide with an estimated 269 million people who are carriers. The author reviews the area and provides a three-tier approach for the diagnosis of haemoglobinopathies. In the next article Dr David Speers discusses how molecular biological methods for the detection and characterisation of microorganisms have revolutionised diagnostic microbiology with the rapid diagnosis of microorganisms of public health importance. Treatment of certain microorganisms has been improved by viral resistance detection and viral load testing for the monitoring of responses to antiviral therapies.
The fifth manuscript by Dr Kristine Barlow-Stewart and Professor Leslie Burnett covers the ethical issues associated with the use of DNA testing. This paper discusses the ethical implication of many of the recent advances in genetics and highlights some of the still unresolved issues. As clinical biochemists, we have always dealt with ethical issues relating to biochemistry results. However, as the authors point out, we need to better understand the shared nature of genetic information within families, and the greater sensitivity and privacy issues associated with genetic information.
The final manuscript by Dr Cyril Mamotte provides a comprehensive overview of the modern techniques used for the detection of polymorphisms in DNA. The revolution we are experiencing within the area of genetics is technology driven. As newer and more cost efficient techniques are developed to study the structure of DNA, the area will develop at an even faster rate.
As clinical biochemists, we are working in a unique period of time where DNA technology is developing quickly and the potential importance of the area is widely recognised. We have the opportunity to help develop evidence for the usefulness of DNA testing to assist with the diagnosis of chronic diseases, and hopefully improve the health of the community.
The manuscripts compiled in this issue are a fair representation of the current uses of diagnostic molecular biology in clinical laboratory medicine. Diagnostic molecular pathology will become a greater part of routine clinical biochemistry in the future, but only when it can be applied as a risk factor (predictor) for the common complex diseases. At the present it is not possible to say how long this will take, but I am certain it will happen.