SNP genotyping is routinely used in the investigation of human disease. The transition from research application to clinical utility, however, has been a stumbling block for many technologies. The future role for SNP genotyping in the development of diagnostics is reviewed in this article.
The instructions that allow our bodies to develop and be maintained are shared by our species, but they are also unique to us as individuals. Typically our health is determined by this individuality in combination with our environment, and although our molecular cards are shuffled and dealt before we are born, only time reveals this hand as we progress through life.
So-called complex diseases typically result from the interaction of the body and environment, and this has made their understanding at the molecular level extremely challenging. Further still, the molecular basis of such disorders may involve variations at many places within our molecular instructions, and this has added another level of difficulty for those tasked with understanding diseases in order to develop therapeutics.
It was with considerable excitement that the profile of single nucleotide polymorphisms was raised as the genome sequencing projects progressed. SNPs, it seems, offer a promising means for investigation.
It was proposed that a set of SNPs evenly spread across the human genome could be used to screen two populations (typically populations with and without a disorder) and that some SNPs would associate more with the disease group, thus implicating the SNP, or a DNA sequence close by, in the disease state. A massive technological effort followed and whole genome scans, using tens of thousands of SNPs, were made a reality with the advent of array-based technologies.
Complementary technologies were developed to allow smaller numbers of SNPs to be screened against populations to build confidence that SNPs identified by array-based screens were indeed influential. For those on smaller budgets, this approach allowed educated guessing games where small numbers of SNPs, suspected to be involved in a disease, were screened economically in large populations. Initial efforts were frustrating, but progress has been made.
The successes are perhaps not on the scale that many had hoped for as the contribution to a disease state from any individual variant site has typically been demonstrated to be small. SNPs also offer a lot of potential for use in the field of personalized medicine, where therapeutics are tailored to an individual’s metabolism. In this field, correlation between variation in the genes of drug-metabolizing enzymes and drug metabolism is sought so that the patient can be prescribed a therapeutic agent based on his/her genetic profile. The reality of so-called theranostics is upon us.
In order for any genetic variation to be useful in a clinical setting, there must be a meaningful link to disease development or therapeutic effectiveness. SNPs can themselves be responsible for changing a particular amino acid encoded within a gene and thus may disrupt the protein altering its effectiveness within the body.
An extreme form of this disruption is mediated by a change that truncates or extends the protein, which may result in its influence being removed from the body. Equally, changes in control sequences can up- or down-regulate gene expression. More typically, SNPs involved in screening activities simply sit near by an as-yet unknown sequence that plays a role in the disease state.
Where this distance is small, the SNP will be representative of the causative sequence in most individuals. Where the distance is greater the meaningful correlation is likely to be reduced, as will the potential for clinical utility. Where SNPs are causative or highly associative and the effect of the disruption is strongly felt, such variations are prime candidates for use as diagnostic markers.
Genetic Risk Factors
It is clear that SNPs have a central role in identifying genetic risk factors and in helping us move toward more effective medicines, but they have limitations. There is a growing awareness of hereditary mechanisms that are not mediated solely by the sequence of the DNA bases within our body. The regulation of expression by DNA methylation is the most well-studied phenomenon in the field of epigenetics, and SNP-based screens may not identify these features that can change within the lifetimes of cells and bodies.
That said, SNPs remain an excellent research tool with diagnostic potential that has yet to be truly recognized, but such realization will also present challenges.
As patients, we like our physicians to be definitive in their decision making and we do not expect to make clinical decisions ourselves, particularly when drastic consequences such as surgery or radiation therapy may be involved. The successful identification of genetic risk factors through SNP genotyping poses problems for the medical community even if the diagnostic potential of these markers is realized.
With the development of an informative genetic test, medical practitioners can only advise on the risks presented to a patient and their subsequent therapeutic options. Even with complete understanding by both parties, a result expressed in terms of probability presents a difficult situation for doctor and patient alike. Even where the apparent certainty of theranostic testing is available to direct drug prescription, general practitioners must be trained adequately to use such tests effectively.
It follows that SNP-based technologies must deliver results in a dependable, clear, and interpretable fashion and that medical practitioners must have the knowledge and skill to convey the implications to the patient. If not, our impressive, SNP-based technologies will remain as research tools only.