NewsletterIs genotyping the “next frontier” of periodontitis treatment?
Jennifer Byrne
The field of personalized medicine, which relies on both genetic and clinical patient characteristics to deliver individualized treatment, seems poised to revolutionize all areas of healthcare. With more sophisticated testing methods, advances in pharmacogenetics, and a savvier patient population, the opportunity exists to deliver unprecedented levels of personalized patient care.
Although general dentists may consider personalized medicine a concept for the future, or perhaps an idea that only has practical applications in fields such as oncology, the reality is that its direct application to everyday dentistry is closer than one might think. Indeed, the use of personalized medicine in dentistry—and in particular periodontology—is already progressing beyond theory to a new way for clinicians to approach and deliver oral care in their practices.
A recent study suggests that by incorporating a personalized medicine model into preventive care for periodontitis, general dentists can more efficiently apportion time and resources to the patients at highest risk for this condition. The study, conducted at the University of Michigan1 under the direction of William Giannobile, DDS, DMSc, endowed professor of dentistry and biomedical engineering and the director of the Michigan Center for Oral Health Research at the University of Michigan School of Dentistry, used a personalized medicine approach in the preventive care of patients at high and low risk for periodontitis.
The researchers found a correlation between certain patient risk factors—both genetic and acquired—and the degree of benefit the patient derived from twice-yearly cleanings. Dr. Giannobile says of the study’s objective, “The goal was to use a personalized medicine approach for the identification of different levels of what we hypothesized were risk factors for the development of periodontitis and then to look at one of the end results of advanced and progressive periodontitis—tooth loss.”
The study, which evaluated tooth loss in 5,117 patients over a 16-year period, had several components. First, it stratified the patients into high- and low-risk groups based on three risk factors: smoking, diabetes, and polymorphism of the interleukin-1 (IL-1) genotype. The IL-1 group of cytokines plays an important role in the body’s inflammatory and immune responses. Patients with none of these risk factors were deemed low risk, whereas those with one or more of the risk factors were classified as high risk.
Next, the investigators divided the low-risk group into patients seen annually for routine hygiene and patients who had two cleanings per year to compare the rate of tooth loss. “Our question was: Based on that risk stratification, did low-risk patients benefit by going twice a year, or did they maybe not need such frequent cleanings?” explains Dr. Giannobile.
The researchers found that in the low-risk patients, the rate of tooth loss was the same, regardless of whether they had undergone one or two cleanings annually, suggesting that one cleaning was sufficient in these patients. In the high-risk group, however, there were notable changes based on the frequency of preventive cleanings. In patients who had one of the three risk factors, one yearly visit was not adequate to prevent tooth loss, and in those with two risk factors, more than two visits were needed to minimize tooth loss.
The study’s results suggest that clinicians should individualize their approach to preventive care based on initial risk assessment. “The findings indicated that patients probably need to be treated differently based on their risk for disease, versus saying, across the board, that all patients should get two cleanings a year,” Dr. Giannobile concludes. “We found that high-risk patients really do benefit from more frequent preventative cleanings, whereas if a patient has no risk factors, it’s questionable whether they benefit from more frequent recall.”
Periodontist Donald S. Clem III, DDS, from Fullerton, California, who was not part of the Michigan study, observes that the information gleaned from this research presents a valuable opportunity for general dentists.
“As a periodontist, I would say to my dental colleagues, ‘You have the opportunity now to stratify your patient population and begin to deliver more personalized healthcare to them,” Dr. Clem says. “We know that approximately 47% of Americans—almost half of the United States population—has some form of periodontitis, either early, moderate, or severe. And now, for the first time, the general dentist can begin to think about risk assessment, rather than disease detection.”
Dr. Clem recommends that general dentists make individualized recommendations to patients based not only on risk stratification, but also on an annual comprehensive periodontal examination. “Dentistry needs to use the power of the evaluation as a separate entity, rather than trying to combine an examination with the preventive visit. The exam may certainly occur in the same office, during the same visit, but they need not be done together,” he says. “As in medicine, dentistry needs to reinstitute the value of the examination for this increasingly complex aging population. Treatment should only be rendered after a diagnosis and risk assessment is completed. There is great value in this for the patient.”
Consideration of the risk factors—diabetes, smoking, and genetics—are also key to personalizing periodontal care, an approach that Dr. Clem believes should be clearly explained to the patient. “If I’m the general dentist, I might sit down with Mrs. Jones and say, ‘Mrs. Jones, you look healthy, but because you smoke, and because you’re genetically positive, you’re at higher risk than a patient who doesn’t have these risk factors. Therefore, I’d like to see you three times a year instead of one.’” Conversely, a patient who falls into the “low-risk” category would be advised to follow a less aggressive preventive regimen. “So, to Mrs. Smith, I would say, ‘You’ve looked very healthy all these years, so I think I can cut you down to one cleaning per year, and then I’d like to see you back for an exam.”
In terms of workflow, Dr. Giannobile says customizing patient care generally means a more efficient use of time. “I think by personalizing preventive care, we can put our resources toward the individuals who are at higher risk of losing teeth. We can also ensure that patients who are known to be low-risk don’t get overtreated.”
The relationship between oral disease and systemic disease—ie, the perio-systemic link—is now well established. Recently, research on the nature of the relationship has shifted from focusing exclusively on bacterial mechanisms to examining the impact of inflammation.
“The life expectancy today is about 77 years, and the incidence of chronic diseases are increasing as we age,” says Philadelphia, Pennsylvania, periodontist Louis F. Rose, DDS, MD. “And in most of these chronic diseases, there is a strong association with inflammation. Most all chronic diseases have an inflammatory component.”
Dr. Clem points out that diabetes in particular seems to have reached alarming proportions. “We’re in the middle of a diabetes epidemic in this country,” he warns. “There are more and more adolescents being diagnosed with type 2 diabetes due to obesity. It really is approaching 35% of the US population, people who are diabetic or prediabetic.” As these patients age and develop chronic systemic disease, he says, the general dentist’s ability to evaluate the patient’s risk over a lifetime is essential.
The state of public health today is described by Dr. Clem as “a coming together of events” that includes an aging population that is living longer, developing chronic disease, and taking more medication than ever before. “We also have periodontal disease that can be predicted in terms of risk factor,” he notes. “We clearly have the potential for increases in periodontitis. And because of that, risk assessment is very important.”
One of the more futuristic risk factors assessed in the University of Michigan study was the presence of variations in the IL-1 genome. “What the IL-1 marker indicates is that those patients who are genetically positive have an increased potential for inflammatory responses to a challenge,” Dr. Clem says. “That challenge is periodontal bacteria. When those patients are challenged by these bacteria, they have a high production of an inflammatory mediator. That response results in a higher incidence of greater bone loss and periodontitis.”
Dr. Clem maintains that in addition to predicting the onset of periodontitis, the IL-1 marker has demonstrated the ability to predict the extent of the disease. 2,3 “There is significant evidence to show that those patients who are genetically positive for the IL-1 marker have a much higher risk of acquiring severe periodontitis at some point in their lifetime,” he says. In addition, the marker is interesting, he maintains, in that it’s not only a marker for incidence risk factor, it’s also a severity factor.
Based on the evidence of its value, Dr. Clem says dentists should consider administering the IL-1 genetic test, which involves a simple cheek swab, to all adult patients. “I think for adult patients, as part of a comprehensive periodontal evaluation, one can make a very strong argument that genetic testing would be valuable.” This, he says, is especially important for patients who have other risk factors associated with periodontitis. Depending on his clinical findings in an examination, he himself often performs the cheek swab during that same visit.
Due to increased public awareness of genetic testing, Dr. Clem finds that his patients are usually agreeable to the test, and take its results seriously. He calls test results indicating genetic susceptibility “a very powerful communication tool” with patients, and notes that the public acceptance of genetic testing has been spurred by its increased cultural relevance. This has been due in part to the media attention to the topic garnered by celebrities such as Angelina Jolie, who raised public awareness of genome-guided breast cancer treatment and prophylaxis, and consumer test kits offer customized genome-based health recommendations for everything from inherited disease to gluten sensitivity. “Look at what’s happening now, even in the marketplace— you can go online and get your whole genome mapped.” He says patients understand and appreciate receiving such objective information. “If I’m a patient making treatment decisions, I’m going to want to know what’s my risk, what are my chances of success, and what level of care do I need.”
In addition to a more rigorous preventive care regimen, Dr. Clem says some high-risk patients may benefit from a multidisciplinary approach to treatment even before severe disease is present. “Once early disease is detected, if it’s detected, I think the dentist ought to make a decision about possibly partnering with a periodontist early in that diagnosis.” He continues, “If I can see a patient with early-to-moderate periodontitis—even the high-risk patients—I can tailor my treatment to manage those patients much more predictably than if I see the patients late in the game.”
Dr. Clem says explaining this advantage to patients can help them understand the need for a specialist. “You can say things like, ‘Mrs. Jones, you have the signs of bone loss and periodontitis, and normally, we might take a wait-and-see approach and increase your visits to see if we can address this. But because you have this genetic marker, or have diabetes, or have cardiovascular disease and are taking medications that can affect your periodontal health, you are a high-risk patient, and I’d like to partner with a specialist in order to manage you early.”
Dr. Clem is quick to note that not all patients with periodontitis require referral to a specialist, such as patients who have periodontitis but lack any of the risk factors. “I’ve seen patients with early-to-moderate disease who are referred by the general dentist, and their risk factors are comparatively low, and my treatment for them was pretty simple,” he explains. “They probably could have been treated in the general dentist’s office.”
However, the ability of general dentists to identify the high-risk patients, and, if necessary, refer them to a periodontist, will enable the dentist to provide the patient with the most suitable care. “I think we are past the point now where we base the decision strictly on the severity of the disease,” he explains. He says patients stratified in terms of risk in the general dentist’s office can receive care that is better, more timely, and more cost efficient, and that it is “special patients” who should be sent to a specialist. “The general dentist is beginning to acquire the risk-assessment tools to identify those who will be the most difficult to manage early in the game. This minimizes the dentist’s liability and maximizes patient care,” he concludes.
As researchers continue to learn more about periodontitis and its risk factors, the treatment of these patients will likely become more customized. “The public needs to understand that periodontal disease is not just a dental problem, it’s a systemic problem,” Dr. Rose says. “We need to know what the health status of our patient is before we start treating them. So there would be a more comprehensive history that would be necessary.”
Dr. Giannobile suspects that in the future, additional genetic markers will be identified as playing a role in periodontitis. “We only looked at one gene, and I think it’s very important, but I think it’s likely not the only gene responsible for periodontal disease,” he says. “I would surmise that there are at least a dozen genes that are very important in the progression of periodontitis.”
Dr. Rose believes the advent of personalized periodontal care will present an exciting opportunity for dentists to be at the forefront of genetic medicine. “In dentistry, periodontics may be the first healthcare profession to incorporate a genetic approach to long-term disease management,” he says.
In addition to evaluating risk, Dr. Clem anticipates that genetic markers may also aid in customizing a patient’s treatment approach. “I think this is just the beginning. We’re going to identify more risk factors through genetic markers, and I think we’re going to see an explosion in terms of what we can do to regenerate bone and soft tissue,” he says. “I also think these advances are going to take advantage of understanding a patient’s genetic composition in terms of how well they respond to specific treatments. I expect this is going to be the next frontier.”
1. Giannobile WV, Braun TM, Caplis AK, et al. Patient stratification for preventive care in dentistry. J Dent Res. 2013;92(8):694-701.
2. McDermitt M, Wang H, Knobleman C, et al. Interleukin-1 genetic association with periodontitis in clinical practice. J Periodontol. 2000;71(2):156-163.
3. Karimbux NY, Saraiya VM, Elangovan S, et al. Gene polymorphisms and chronic periodontitis in adult whites: a systematic review and meta-analysis. J Periodontol. 2012;83(11):1407-1419.
Expanding the foundation for personalized medicine: implications and challenges for dentistry
The authors present an overview of the opportunities and challenges that influence the oral health community’s full participation in personalized medicine. Highlights include selected research advances that are solidifying the foundation of personalized oral healthcare, a discussion of their impact on dentistry, and an exploration of the obstacles toward their adoption into practice.
J Dent Res. 2013;92(7 suppl):3S-10S.
Genome technologies and personalized dental medicine
Application of genomic testing has already begun to find its way into the practice of clinical dentistry. It is vital that dental care providers, consumers, and policymakers be aware of genomic approaches to understanding, diagnosing, and treating oral diseases. Ethical, legal, clinical, and educational initiatives are also required to responsibly incorporate genomic information into dentistry.
Oral Dis. 2012;18(3):223-235.
Fine-mapping of 5q12.1-13.3 unveils new genetic contributors to caries
Previous work has identified the interval 5q12.1-5q13.3 as linked to low caries susceptibility in Filipino families. The authors fine-mapped this region in order to identify genetic contributors to caries susceptibility. Statistically significant and borderline associations were found between low caries experience and four genes spanning 13 million base pairs.
Caries Res. 2013;47(4):273-283.
Genome-wide association studies of pit-and-fissure- and smooth-surface caries in permanent dentition
Few caries genes have been discovered and validated. Recent studies have suggested differential genetic factors for primary dentition caries and permanent dentition caries, as well as for pit-and-fissure– and smooth-surface caries. This study supports the notion that genes differentially affect cariogenesis across the surfaces of the permanent dentition.
J Dent Res. 2013;92(5):432-437.
Source: PubMed.gov
1840
Baltimore College of Dental Surgery, the first dental college, opens
1890s
W.D. Miller develops the chemoparasitic caries theory, which states that bacteria in the mouth produce acids that dissolve tooth structures when in the presence of fermentable carbohydrates
1948
National Institute of Dental Research (NIDR) is founded
1952
Biomedical researcher Norman Simmons isolates structurally pure DNA, paving the way for Watson and Crick to predict its structure
1973
Laboratory of Oral Medicine is established to conduct both clinical and laboratory research on the cause, prevention, and treatment of diseases of the soft tissue of the oral cavity
1984
NIDR inaugurates the Dentist Scientist Award Program designed to provide opportunities for dentists to develop into independent biomedical investigators in oral health research
2003
Human Genome Project completed
2011
National Institutes of Health establishes Genetic Testing Registry to aggregate information about available genetic tests for the public
2012
First genome-wide association study to identify genes affecting susceptibility to caries in adults conducted
