Pros and Cons of Candidate Gene Approach

Besides the examples listed above, there are numerous exploratory association studies that have identified many potential polymorphism biomarkers for treatment response in membrane transporter, drug-metabolizing enzyme, and drug target genes. The methodology and statistical analysis for the candidate gene approach are simple; the results are easy to interpret.

Fig. 1. An example of power calculation to detect the indicated odds ratio for a range of risk factor prevalence and event rate with a sample size of 300 patients.

Hazard Ratio

Fig. 2. An example of power calculation to detect the indicated hazard ratio for a range of variant allele frequency with a sample size of 300 patients.

Hazard Ratio

Fig. 2. An example of power calculation to detect the indicated hazard ratio for a range of variant allele frequency with a sample size of 300 patients.

The limited number of candidate polymorphisms reduces the probability of type I errors (false positives). The sample size requirement is smaller and the cost is lower. However, the results from the candidate gene approach have been inconsistent and contradictory, due to the fact that the candidate gene approach was originally intended to identify a large, independent main effect for a single locus (polymorphisms) based on the assumption of a monogenic trait. The best scenario for the success of the candidate gene approach would be if, for a certain drug, there exists a major drug metabolism or major target gene, there is a polymorphism in that gene that confers significant changes to its function, and the frequency of this polymorphism is relatively high. This would result in an acceptable cost-benefit ratio for pharmacogenetic testing.

Unfortunately, it is rare to find such a strong, monogenic candidate polymorphism for currently used chemotherapeutic drugs. Instead, most candidate gene studies have used the candidate gene approach to investigate polygenic traits. In these studies, the hypotheses were not particularly strong, the effects were not expected to be large, and there was no consideration of gene-gene interactions. For polygenic traits, the small associations between individual polymorphisms and outcomes are expected, because treatment response is usually a multigenic step, and because any single genetic polymorphism usually does not have a dramatic effect on outcome. Therefore, it is not surprising that the literature of pharmacogenetic studies using the candidate gene approach is littered with so many inconsistent results. This situation is unlikely to change, due to the small number of patients evaluated, patient and tumor heterogeneity, different treatment regimens and schedules, and failure to evaluate the effect of multiple pathophysiologically related genes. Large studies with homogeneous patient populations and uniform treatment regimens are needed to obtain consistent data of small effects. However, even if confirmed by large studies, these modest response-predicting polymorphisms are less likely to be clinically relevant single predictors. On the other hand, the real predictor polymorphism may be left out at first place due to the limited available information.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment