Can Genetic Information Change the Clinical Care of Rheumatology Patients?

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WASHINGTON, D.C.—Calling it an extremely challenging topic, Peter K. Gregersen, MD, professor and head, Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute, Manhasset, N.Y., said the current role of genetics in clinical practice is less about how to use genetic information to care for patients and more about how providers and patients can participate in improving our understanding of genetics and its relationship to both health and disease.

“The role of genetics right now in diagnosing and managing common rheumatic disorders is pretty nonexistent,” he said. “We have hundreds of genetic variants that we know are associated with a variety of rheumatic diseases, but, with the exception of autoinflammatory syndromes such as familial Mediterranean fever and a few others, knowledge of that genetic variation has no impact on the diagnosis or management of patients.”

Speaking to participants during a session titled Genetics in the Rheumatology Clinic: Can It Change the Clinical Care of Patients? at the 2016 ACR/ARHP Annual Meeting, Dr. Gregersen invoked the memory of John F. Kennedy by urging rheumatologists to focus less on what genetics can do for them in the clinic and more on what they can do for genetics.

“Even though we’ve done a lot of population studies of genetics and have found a bunch of genes with modest effect, we need to figure out how those genes work,” he said. “Rheumatologists need to get involved in studies that address this.”

Rheumatologists Encouraged to Support Studies

One major message Dr. Gregersen conveyed to rheumatologists was the need for them to get involved in studies aimed at understanding the function of disease-associated genetic variants to identify new pathways and targets for drugs.

To do this, he emphasized the importance of studying gene function in normal populations given the problems of confounding influences of ongoing inflammation and drug therapy in patients with disease.

He cited research done on the genetic variant tyrosine-protein kinase (Tyk2) as an example of the type of research needed to better understand how a specific gene functions and how this knowledge can be used to identify reasonable drug targets. Although the Tyk2 variants are uncommon (found in only 3% of the population), he emphasized that they are strongly protective for rheumatoid arthritis (RA); only 1.5% of people with RA carry these variants. Research shows that normal people who carry two copies of Tyk2 protective variants have partially compromised function in cytokine signaling, he said, which suggests a potential drug target. However, Dr. Gregersen cautioned that complete absence of Tyk2 causes immunodeficiency and therefore raises the question of safety of drugs developed to inhibit this target.

He suggested that a better way of thinking about targeting these pathways with drugs is not to completely stop the function of the pathway, but to change the threshold, or rheostat, of signaling in that pathway. He said Tyk2 is an example of using genetic information to identify an immune rheostat that may modify autoimmune activity.

How do rheumatologists get involved in this type of research? “There needs to be widespread devotion to finding a study for every patient seen in the clinic to address these kinds of issues,” said Dr. Gregersen. “Rheumatologists should encourage their patients and family members to participate in studies. That is the only way we’ll find answers.”

Given the importance of studying genetic variants in normal people, Dr. Gregersen said that he and his colleagues have created a genotype and phenotype (GaP) registry that currently holds data on more than 6,500 people. To date, more than 50 investigators across the U.S. are using the registry for clinical studies, he said. The registry can be found at www.gapregistry.org.

An important population to include in the registry, said Dr. Gregersen, are family members of patients who have rheumatologic diseases. He encouraged rheumatologists to speak to their patients to elicit support of family members to join the registry.

“My vision is to have the normal control registry available nationwide with multiple places and hundreds of thousands of people in it,” he said. “That will be an invaluable research infrastructure that will allow us to much more quickly get at what the functional meaning is of hundreds of variants, or combinations of variants, that we see in patients with autoimmunity.”

“That requires contribution from the rheumatology community to help build that research,” he said.

Potential Application: Pharmacogenetics

Dr. Gregersen also touched on the use of genetics for drug selection. The field of pharmacogenetics fell out of favor after initial negative reports on the management of coumadin were published in the New England Journal of Medicine;¹ but Dr. Gregersen emphasized that the field is enjoying a renaissance and expressed excitement on its potential currently being seen in such fields as cardiology and psychiatry.

In rheumatology, however, he highlighted that pharmacogenetics is limited and that particularly disappointing has been the lack of a role for the use of genetics in helping identify which patients are best suited for treatment with the biologics.

One area where he thinks pharmacogenetics may play a role in rheumatology, however, is in testing patients for the HLA-B58 genetic variant before prescribing allopurinol. People with this variant have a 50-fold increase in developing severe cutaneous adverse reactions. Although Dr. Gregersen said this syndrome is rare, he thinks all people should be tested for the HLA-B risk variant before allopurinol is prescribed.

Given the important potential of pharmacogenetics, Dr. Gregersen said he’d like to see it become a routine part of medical care and that every patient should have this information routinely in their charts, covering a wide variety of medications.

Mary Beth Nierengarten is a freelance medical journalist based in Minneapolis.

Reference

1. Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for Warfarin dosing. N Eng J Med. 2013 Dec 12;369(24):2283–2293.