Building a better transplant
What can genetic testing tell us about higher rates of kidney rejection in African Americans?
Author: Katherine Hill
Edited by: Sienna Schaeffer, Reed Owens-Kurtz, Madeline Nicol
Kidney disease is one of the leading causes of sickness and death in the United States (1). For the 17,000 Americans each year who are lucky enough to receive a kidney transplant, the operation can be life-changing (1). Sadly, transplant success is not guaranteed. For a small but significant number of patients the new organ is rejected, leaving them with all the woes of a major operation but none of the benefits of a functional kidney.
The chance of a failed transplant is not equally distributed among patients. African Americans are significantly more likely to experience this heartbreaking outcome than Caucasians (2). Researchers at the University of Minnesota are attempting to decrease this disparity by examining how genetic differences affect the use of common post-transplantation drugs.
While most patients are ecstatic to receive a new kidney, their immune system usually does not share their enthusiasm for the new houseguest. Instead, the immune system mistakes the organ for a foreign invader and attempts to destroy it. When the immune system succeeds in its unwelcome mission, the new kidney is rejected.
Almost all organ transplants would be rejected if not for life-saving immunosuppressive drugs that calm the immune system and prevent it from attacking the new organ. Determining the correct dose of immunosuppressive drugs can be a delicate balancing game; too low and the organ will be rejected, too high and the patient can experience severe side effects. One of the most commonly used drugs, tacrolimus, can ironically cause kidney damage at high doses (3).
The amount of a drug a patient needs is determined by how quickly the patient’s body metabolizes, or inactivates, the drug. When a body metabolizes a drug quickly, the drug blood level drops too low to be effective before the patient takes another dose. At lower levels, the drug is less effective and the immune system is less inhibited. Research has shown that, on average, African Americans metabolize the anti-rejection drug tacrolimus at a faster rate than Caucasians, which could at least partially explain why African Americans also suffer from higher rates of kidney rejection (4).
The majority of tacrolimus metabolism is performed by the CYP3A5 enzyme, which is encoded by the conveniently named CYP3A5 gene (4). Most genes have different versions, or alleles, that vary between different people. Some alleles, more formally known as loss-of-function alleles, contain a mistake that renders the enzymes that they produce non-functional. The CYP3A5 gene is no exception. It has a well-known loss-of-function allele, known as CYP3A5*3, that is much more common in Caucasians than African Americans.
Putting two and two together, researchers speculated that African Americans might have higher rates of rejection because their (functional) CYP3A5 enzymes metabolize tacrolimus much faster. It sounded plausible, but was it true? A team at the University of Minnesota decided to find out.
The scientists genotyped 197 African American participants who had received a kidney transplant and were being treated with tacrolimus to prevent rejection. They then compared participants’ genotypes with how quickly they metabolized tacrolimus. The researchers used this data to determine whether certain alleles were correlated with faster or slower metabolism.
As expected, the CYP3A5*3 allele was correlated with slower tacrolimus metabolism. More surprisingly, the experiment found that two other alleles of the CYP3A5 gene led to reduced tacrolimus metabolism. Although scientists knew of the existence of both, no one had realized that they were loss-of-function alleles that decreased the rate of tacrolimus metabolism
Why had no one recognized the importance of these alleles? Possibly because the mutations are found almost entirely in African Americans, whereas previous research on tacrolimus metabolism has been performed predominantly with Caucasians.
According to Dr. Pamala Jacobson, a professor of experimental and clinical pharmacology at the University of Minnesota and one of the researchers involved in the study, “You may have 2 or 3 minorities in a large trial. Well, if they responded differently you wouldn’t be able to detect that statistically. It just goes to show we need to be better at getting other individuals in these trials.”
One or two missed alleles may seem insignificant, but in this case those alleles can have a large impact. Factoring in the two newly recognized loss of function alleles, 75% of the African American patients in the study had at least one nonfunctional copy of the CYP3A5, which is much higher than was previously believed.
As important as it is to make certain that all populations are adequately represented in clinical trials, the results of this experiments also demonstrate the folly of treating individuals as part of a homogeneous racial group. These two ideas may seem contradictory, but are actually interrelated. African Americans may have fewer loss of function alleles on average, but people are not averages and, as this experiment revealed, it is entirely possible that a particular African American patient could have only one or even no functional CYP3A5 alleles. If there was a standard race-based dose, this patient would be given too much medication and would be at risk for serious side effects.
“You can’t use race as a surrogate to predict how someone is going to metabolize tacrolimus,” said Dr. William Oetting, a professor of experimental and clinical pharmacology at the University of Minnesota who was also involved in the study. “Even though we can show this population difference, you need to go down to the genotype to really figure out what is going on and how to treat that person.”
The lack of African Americans in previous tacrolimus studies is not an anomaly. The relative dearth of minority groups in clinical trials is well documented (5). The reasons for this disparity are numerous and include, but are not limited to, the fact that minority groups often have decreased access to health care in general and a reluctance to enroll in experiments by groups that have historically been mistreated by the medical establishment.
The importance of enrolling a wide variety of people in clinical trials is becoming ever more apparent as scientists begin to understand the crucial role that genetics plays in drug metabolism. “Drug therapy is very expensive and especially drug therapy that fails,” said Dr. Jacobson, “So from a societal perspective we have to make sure that we give people the right drugs at the right dose at the right time and genetics can help us do those things.”
Genetic tests are already available for many commonly prescribed drugs, including Prozac and warfarin (6). Many more are likely to follow as researchers unravel the complicated interactions between genetics, environmental factors, and drug metabolism. If trials continue to include primarily Caucasians, they are likely to miss many genetic variants that are more common in other populations, which could dramatically impact the quality of care for patients who carry those variants.
At least for tacrolimus, research may soon make a real difference for African American patients. Researchers performed a second study with 354 African American kidney recipients (7). By examining all CYP3A5 variants, including the two newly discovered alleles, scientists were able to build a more accurate model for tacrolimus dosing based on genotype. Without the inclusion of the new alleles, researchers found that almost 50% of their patients would have been given too much medication.
The team has applied for funding for a clinical trial to test their model against current standards. If all goes well, new genotype-based dosing recommendations may soon help patients receive more accurate doses of tacrolimus, which will hopefully reduce both unnecessary side effects and transplant rejections.
References
1) U.S. Department of Health and Human Services. Kidney Disease Statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases (2015). Available at: https://www.niddk.nih.gov/health-information/health-statistics/Pages/kidney-disease-statistics-united-states.aspx. (Accessed: 19th January 2017)
2) Neylan, J. IMMUNOSUPPRESSIVE THERAPY IN HIGH-RISK TRANSPLANT PATIENTS: Dose-Dependent Efficacy Of Mycophenolate Mofetil In African-American Renal Allograft Recipients. Transplantation 64, 1277–1282 (1997).
3) van Sandwijk, M. S., Bemelman, F. J. & Ten Berge, I. J. M. Immunosuppressive drugs after solid organ transplantation. Neth J Med 71, 281–289 (2013).
4) Oetting, W. S. et al. Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles. American Journal of Transplantation 16, 574–582 (2016).
5) Hussain-Gambles, M., Atkin, K. & Leese, B. Why ethnic minority groups are under-represented in clinical trials: a review of the literature. Health & Social Care in the Community 12, 382–388 (2004).
6) Mayo Foundation for Medical Education and Research. Drug-Gene Testing (Pharmacogenomics). Mayo Clinic Center for Individualized Medicine (2017). Available at: http://mayoresearch.mayo.edu/center-for-individualized-medicine/drug-gene-testing.asp. (Accessed: 10th February 2017)
7) Sanghavi, K. et al. Genotype-guided tacrolimus dosing in African-American kidney transplant recipients. Pharmacogenomics J (2015). doi:10.1038/tpj.2015.87
