CASE 3 YOU, FROM A TO T: YOUR PERSONAL GENOME

The multiple genetic and environmental factors affecting complex traits imply that different people can have the same disease for different reasons. For instance, one person might develop breast cancer because of a mutation in the BRCA1 or BRCA2 genes, while another might develop breast cancer because of other genetic risk factors or even environmental ones. Similarly, one person might develop emphysema because of a mutation in the gene that encodes the enzyme alpha-1 antitrypsin (α1AT) (Chapter 15), and another might have emphysema as a result of cigarette smoking. Other examples where the same disease can be the result of different underlying genetic or environmental factors include elevated cholesterol levels, high blood pressure, and depression. Because the underlying genetic basis for the same disease may be different in different patients, some patients respond well to certain drugs and others do not.

The traditional strategy for treating diseases is to use the same medicine for the same disease. However, because we now know that the same disease may have different causes, another possibility has emerged: identifying each patient’s genotype for each of the relevant genes, and then matching the treatment to the genetic risk factors in each patient. The approach is known as personalized medicine. Personalized medicine matches the treatment to the patient, not the disease.

Personalized medicine not only aims to identify ahead of time medicine that will work effectively, but also to avoid medicines that may lead to harmful side effects, even death. Advertisements and enclosures with prescription drugs enumerate long lists of side effects that you may get if you take a particular medicine. At present, it is difficult to know in advance who will get one or more of these side effects and who won’t—that is, the side effects of taking medicine are themselves complex traits and the result of many underlying genetic and environmental factors. If we could identify ahead of time those patients who will respond negatively to a particular medicine and those who won’t, we could minimize potentially harmful effects of medicines on certain individuals.

Someday, it may be possible to determine each patient’s genome sequence quickly, reliably, and cheaply. At present, personalized medicine is restricted to studies of a few key genes known to have important effects on treatment outcomes. In the treatment of asthma, for example, some of the differences in response to albuterol inhalation have been traced to genetic variation in the gene ADRB2, encoding the β-(beta-)2-adrenergic receptor. Similarly, certain drugs used in the treatment of Alzheimer’s disease are less effective in women with a particular apolipoprotein E (APOE) genotype than in other classes of patients. Also, more than half of the cases of muscle weakness occurring as an adverse effect of drug treatment used to control high cholesterol can be traced to genetic variation in the gene SLCO1B1, which encodes a liver transport protein. Certain variants of this protein have decreased ability to transport the drug, resulting in higher concentrations remaining in the blood and a risk of muscle weakness.

Other factors in addition to genes are involved in these disorders, but genes play an important role. Knowledge of a patient’s genotype can help guide treatment. These are only a few of many examples, but they demonstrate the substantial potential benefits of personalized medicine.