WHAT ARE OTHER WAYS YOUR DNA CAN GUIDE DRUG TREATMENTS?
Our DNA also affects drug metabolism, side effects, and drug–drug interactions. This information can be extremely valuable because a wrong drug dose or dangerous side effect can have life-threatening consequences. This area has been studied extensively, and to date there are several hundred identified genes that affect drug response. Many of these genes encode proteins such as the cytochrome P450s, which normally modify natural compounds to make hormones or help remove toxins in our bodies. We have 80 CYP genes encoding cytochrome P450s in our genome. These proteins affect the metabolism of drugs we take, either by directly modifying the drug, or by modifying prodrugs (precursors to drugs) that are administered to patients, and thus affect the amount of drug that is available to act in the body. Other genes that affect drug response encode transporters that either deliver drugs into our cells in order for them to work or evict them from the cell so they cannot reach their intended target.
One of the best studied cases of genes affecting drug dose is that of warfarin (also known as Coumadin). Warfarin is an anticlotting agent that is administered to patients with existing or heightened risk of forming clots in their vasculature or to prevent clot formation in their hearts due to cardiac arrhythmias or mechanical valve replacements. The metabolism of warfarin is affected by two genes, VKORC1 and CYP2C9. The -1639G>A SNV in the promoter of the former leads to less protein produced, and so less warfarin is required to thin patients’ blood adequately. For CYP2C9, the variant forms CYP2C9*3 (I359L) and CYP2C9*2 (R144C), metabolize the drug more slowly; patients with these variants are also typically administered lower doses. Thus, genetic screening should theoretically be useful for administering the proper drug amount and help reduce morbidity and mortality from excessive blood thinning and consequent uncontrollable bleeding.
Another example is tamoxifen, which is used for treatment of endocrine responsive breast cancer. Tamoxifen is given to patients postsurgery and dramatically reduces the rate of cancer recurrence. This drug is metabolized by cytochrome P450 2D6, the product of the CYP2D6 gene. Based on their DNA, there are patients with little CYP2D6 activity who are poor metabolizers and others with high activity who are extensive metabolizers. An FDA-approved genetic test exists for finding the variants of the CYP2D6 gene to help guide tamoxifen administration, but the lack of study data demonstrating its role in improving patient outcomes has, to date, led insurance companies to refuse to cover the test.
Beyond having ramifications for drug efficacy, genetics also may play a role in the side effects of drugs. Many patients with atherosclerosis take statin drugs. A known but relatively rare side effect of this class of agents is a sensation of muscle burning (myalgia) due to muscle breakdown (rhabdomyolysis). Multiple mutations have been found that modulate one’s susceptibility to this particular adverse effect. One mutation appears to be specific for a certain, widely used statin drug, so a patient’s genetic information could, in theory, be used to choose which drug he/she should take. Interestingly, the medical society’s approach to these findings has been to recommend against placing any new patients on the highest doses of this statin, an across-the-board solution that otherwise could be individualized with genetic information.
It is important to note that nearly all drugs have side effects. Thus, altering doses often goes hand in hand with altering side effects. For these reasons, it is useful to incrementally increase the drug dose to the optimal level for therapeutic response, but not so high as to cause unwanted side effects.
Finally, though it seems obvious that drug choice and dosing can and, therefore, should be tailored to a person’s genomic sequence, there are presently few trials that substantiate the benefits of genetic testing for drug treatments. Furthermore, even in the most obvious cases for which the benefits should be evident, such as with warfarin, the trials sometimes do not support the value of genetic testing. The reason for this present situation is not clear, but how the trials were performed may have played a role.