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.
