As genetic medicine races ahead, docs are left behind

Genetic tests that can help predict and refine a patient's response to drug therapy may be the first big thing in personalized medicine. But the vast majority of physicians don't know how to use them, a new survey finds.

Breakthrough: Should you customize your drugs to your DNA?

Here's a shocker: Due to differences in DNA, up to 60% of the most common drugs are associated with adverse reactions. This includes medication used to treat common conditions like hypertension, heart failure, depression, high cholesterol, and asthma.

Hence the hope being pinned on "pharmacogenetics," a field of medicine that promises to improve health care by allowing doctors to customize medical treatment to suit a person's unique genetic signature. Though experts predict that it could be decades before personalized medicine becomes the norm, research is moving ahead: Last fall, for instance, researchers at Duke University reported that people with a specific genetic variant saw less reduction in LDL, or "bad" cholesterol, when taking statins.

But for some drugs, the future is now. A genetic test recently approved by the FDA should help doctors determine the optimal dose of warfarin (sold as Coumadin), a blood thinner used by 1 million Americans. Determining the right dose is crucial: Too much may result in an increased risk of excessive bleeding, while too little may cause a potentially fatal blood clot. By one estimate, using DNA analysis to prescribe warfarin would prevent about 17,000 strokes and 85,000 serious bleeding incidents.

A small but growing number of doctors and hospitals are also using genetic testing to tailor treatment for these medicines:

• Tamoxifen DNA testing identifies the 8% of women with genetic variants that keep them from metabolizing the breast cancer drug, rendering it ineffective.
  
• Painkillers like codeine Up to 8% of whites and 2% of Asians and African Americans are poor metabolizers of these drugs and won't get relief from them; for the 1% of "ultrarapid metabolizers," risks include respiratory problems.
  
• Antidepressants and antipsychotics Some of these drugs are metabolized by the CYP2D6 and CYP2C19 genes. In 2005, the FDA approved a test that looks for these gene variations, and now companies sell consumer versions. But experts advise against using the at-home tests without having your doctor interpret the results, notes Julie Johnson, PharmD, professor of pharmacy and medicine at the University of Florida. The reason: These genes are involved in the metabolization of 25% of all prescription drugs, including several where they're very important. If you misinterpret the results of an at-home test (and mistakenly think you don't have the gene), you might avoid taking one or more drugs you really need.

Simple genetic test determines transplant drug tolerance

A simple genetic test can determine a kidney transplant patient's tolerance for a potent anti-rejection medication, according to an upcoming study in the Journal of the American Society Nephrology (JASN). The test could allow doctors to individualize each patient's dose, optimizing the drug's benefits and minimizing its side effects.

Cyclosporine A is an important immunosuppressant therapy for individuals who receive kidney transplants - without it, many patients would experience organ rejection and would not survive. Unfortunately, cyclosporine A can cause serious side effects such as elevated blood pressure, increased risk of infections and cancers, and kidney function deterioration. The frequency and severity of cyclosporine A-related side effects vary among patients, even at comparable cyclosporin A levels in the blood. Determining which patients are more sensitive than others is a challenge for physicians who prescribe the medication.

Giuseppe Remuzzi, MD, FRCP, and Piero Ruggenenti, MD (Mario Negri Institute for Pharmacological Research, Italy), and their colleagues, hypothesized that genetics may influence patients' susceptibilities to cyclosporine A's side effects. In particular, they suspected that variations in a gene called ABCB1, which creates a protein that transports drugs out of cells, may play a role. In individuals who have certain genetic changes in the ABCB1 gene, the transporting protein is sluggish so that when a drug is present, it lingers within cells and tissues. This can amplify the drug's effects.

After studying the genetics of 147 kidney transplant recipients, the researchers found that patients with these genetic changes in the ABCB1 gene were more likely to experience side effects after receiving cyclosporine A than patients without the variants. These effects included delayed functioning of the transplanted kidney, increased need for anti-hypertensive medications, and the development of diabetes, infections, and cancers.

"The identification of particular genetic variants performed before transplantation, while patients are on the waiting list, could provide useful information to tailor cyclosporine A dose as early as possible after transplantation, with the ultimate goal to decrease toxicity, improve efficacy, and increase long-term graft survival," said Dr. Remuzzi.The authors report no financial disclosures.

The article, entitled "ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome," will appear online at http://jasn.asnjournals.org/ on May 21, 2009, doi 10.1681/ASN.2008080819.

http://www.asn-online.org/