Regular readers of this blog will know that I frequently write about eclectic topics of relevance to dentistry and healthcare, and this month is no exception. We are going right back to the basic building blocks of life, genetics. The saying goes “it’s all in your DNA”. But what about the oral cavity?
Dentistry has transformed continuously over the centuries with invention and innovation seeming to speed up as the years pass. Maybe that’s just my age. Whilst dentistry has historically relied predominantly on the patient history, visual examination, periodontal probing, radiographic investigation and other tests to help diagnose and treatment plan for the common diseases and conditions affecting the oral cavity, lots of devices, materials and techniques are developed each year to help patients and the clinical team to improve dental care. Genetics is one of the areas that has quietly and slowly advanced over many years and will become increasingly important.
Want to know more? Dental genetic testing is moving at pace from being both a worthwhile research tool and futuristic proposition for individual patients to having increasing potential for direct practical application in clinical care. A bit of background. The human genome is complex and contains 3.2 billion base pairs of information. That’s a lot of DNA, which is the molecule contained by almost every nucleated cell and codes for both the structure of the human body through proteins and functional RNA molecules. In turn, these control cellular activity but also code for the observable characteristics of humans, known as traits or phenotype. A fascinating fact is that over 100 genes have been identified as having a role in the development of teeth. So far, this will be revision to most people in dentistry. Moreover, the human genome also includes crucial information about the relationship between health and disease, metabolism of food and medication, tissue regenerative potential, disease susceptibility and so on. As the saying goes, make sure you choose your parents wisely.
It is nothing new for genetic investigations to be part of dentistry and with studies having recognised the familial traits, the understanding of craniofacial growth and development of craniofacial syndromes, linkages with common systemic conditions, and more recently, molecular diagnosis of common dental conditions, genetics and the identification of specific causative genes has consistently been important in dentistry over a long period. However, with the advent of genomics, a wider landscape has opened up to investigate genetic susceptibility to caries, periodontal diseases, craniofacial anomalies, heritability and patterns of hypodontia and other oral diseases, along with how patients will respond to treatment strategies. The backbone of this is genome-wide association studies and the increasing availability of genetic sequencing to individualise prevention, diagnosis and treatment strategies.
When you think about the prospect of genetic input to oral healthcare diagnosis and planning, it is easy to see that this is precision dentistry. In the same way as a carefully crafted bridge or delicately placed implant, input from genetics has the potential to allow the dental team to tailor oral healthcare to the individual based on their unique patient-specific biological profile. Being able to determine the disease susceptibility of a patient, undertake microbiome and multi-omics analysis on an individual patient, understand the response to drugs and materials through pharmacogenomics, as well as determine the genetic background to inherited craniofacial conditions, whilst being able to undertake a genetic screen for cancer genes and at the same time develop scope for regenerative dentistry would be big leaps forward for our profession.
Genomic, proteomic, transcriptomic, and metabolomic technologies are collectively known as “omics” and offer a patient-specific approach to understanding oral disease pathways. Moving beyond treating symptoms to identifying the biological drivers of disease will be essential in treating some of the dental diseases effectively. Current applications and research in dental genetics include analysing genetic variants associated with inherited disease and disease susceptibility, alongside profiling of the oral microbiome for periodontal disease risk. This is very logical and practical. And as we have known for many years, genetics has a significant part to play in the wider aspects of systemic disease susceptibility, and we should not forget the complex relationships of dental and systemic conditions. A key example is the deepening understanding of the inflammatory gene variants associated with periodontal disease such as interleukin-related genes including IL-1. These inflammatory pathways are also of interest in understanding the complex associations between periodontal inflammation and systemic conditions such as cardiovascular disease through the exaggerated inflammatory response. PAX9, MSX1, WNT10A and AXIN2 have all been identified as culprits in hypodontia. But mutations in the AXIN2 gene have also been linked between severe hypodontia and colorectal cancer, and perhaps we should consider referring patients with multiple missing teeth and a history of colorectal cancer for early poop screening and genetic testing.
The new name for genetic testing in periodontology is ‘precision periodontics’. It is an emerging field integrating genomic, microbiomic, proteomic, bioinformatic and environmental data to provide patient-centred tailored periodontal care. Indeed, there are many genetic testing kits on the market. Most cost around £100-£300 and use saliva which is a rich source of both human DNA and the genes of the oral microbiota. As I noted in a previous blog, there are 20 billion microorganisms in our mouths, and that is a massive amount of genetic material to test. Whilst the American Dental Association Guide to Salivary Testing is naturally cautious, I would expect their view might change as the technology develops. One aspect to consider with precision periodontics is that whilst these are potential adjunctive non-invasive diagnostic tests, they are inevitably a snapshot assessment. Most patients are unlikely to repeat such testing on a frequent basis. Although the patient’s inherited DNA sequence is largely stable, the bacteria, fungi, viruses, protozoa and so on in our mouths are in constant flux and point-of-care testing would offer clinical advantages for instant results and could become another longitudinal measurement of the response to periodontal interventions.
Pharmacogenomics is part of the drive towards personalised prescribing and has real potential to alter prescribing patterns. It is a growing field across the world and in the UK, the National Health Service has specific programmes targeting the potential for integration of pharmacogenetics as part of healthcare delivery Introduction to pharmacogenomics — Knowledge Hub. Considering that genetic variation can influence how our patients respond to different medications and drugs, it is logical that this should extend to dentistry. Analgesics, antimicrobials, dental sedation, anti-inflammatories, local anaesthetics, endodontic medicaments, even the humble toothpaste and so on are all used in oral healthcare. Patients do not always metabolise drugs and chemicals in an identical manner. There are major differences in enzyme activity such as CYP2D6 and CYP2C9 which influence drug effectiveness and indeed drug toxicity with reduced function of the latter dialling up ibuprofen exposure and the potential adverse effects. This highlights the fact that there is also a worry about slow metabolism of an active drug increasing overdose risk, whilst slow metabolism of a prodrug requiring metabolic activation could result in inadequate effects. Safety in dental sedation is paramount and with CYP3A4 and CYP3A5 being involved in the metabolism of midazolam, pharmacogenetic variability is also of concern and could be worthy of further investigation. Looking to the future, chairside pharmacogenomic testing prior to prescribing specific drugs in dentistry could become the accepted norm. After all, targeted HLA-B*58:01 testing is an established pharmacogenetic strategy prior to prescribing allopurinol for the reduction of uric acid levels in gout within higher-risk populations. Perhaps now is the time to start considering a speedy saliva test to reduce complications, drug reactions and other drug-related challenges, especially in patients with medical co-morbidities?
The early detection of oral cancer can be assisted with molecular genetic methods of identifying genetic mutations, disease biomarkers and the abnormal cellular precursors of malignant changes. With salivary testing being a suitable non-invasive test, there is promise in identifying HPV-related disease, tumour suppressor gene mutations, epigenetic changes and indeed other genetic mishaps at an early stage, noting that clinical examination and histopathological diagnosis remain crucial.
The heritability of the craniofacial complex is increasingly being explored. Moreover, the genetics of disease as well as health is gradually being revealed with ongoing research. As an orthodontist who has an interest in clefting and other structural disorders of the craniofacial complex, I have been following genetic developments over my career. Many candidate genes have been explored including MATN1, MYO1H, GHR, FGFR2 and a number of growth-related signalling pathways. Whilst we wait for conclusive evidence on the precise genes and their pathways, deepening our genetic understanding of facial growth anomalies, jaw relationship disturbances, eruption of teeth, skeletal discrepancies as well as hypodontia will help in the clinical care of patients who are managed by orthodontists, and cleft and craniofacial teams. Predicting growth potential in orthodontics, response to orthodontic treatment and orthodontic forces, relapse risk, susceptibility to root resorption, and treatment timing are all of considerable value in targeting treatment resources. In particular, a plethora of candidate genes and genetic pathways have been investigated for their potential role in this side-effect of orthodontics including IL1B, IL1RN, P2RX7, SPP1, CASP1, VDR and genes involved in the RANK/RANKL/OPG pathway. In addition, greater genetic understanding of other disorders including amelogenesis imperfecta (AMELX, ENAM, FAM83H, MMP20, KLK4, WDR72), dentinogenesis imperfecta (DSPP) and ectodermal dysplasia (EDA, EDAR, EDARADD, WNT10A) would allow multidisciplinary teams to coordinate comprehensive oral care.
One aspect for the future is regenerative dentistry through stem cells. With investigations ongoing involving gene editing and tissue engineering to help produce new oral tissue, reliance on long-term repair and replacement with artificial materials might reduce. CRISPR, and in particular CRISPR-Cas9, is one method being used to edit genes through targeted DNA changes. This is purely experimental in dentistry but offers promise for the correction of inherited dental disorders at the molecular level in the future.
At this point, you might be asking about how artificial intelligence (AI) fits in. AI analysis of large datasets of clinical, radiological, microbiological, salivary biomarker, risk factors and genetic information has the potential to take the predictive modelling to the next level and change some aspects of dentistry from repair to patient-specific prevention. There are of course challenges to be addressed arising from ethics, data security, training, cost and accessibility with clinical evidence also being key.
Is genetic testing likely to be mainstream in dentistry? Since developments have been stepwise over a long period of time, a big-bang approach is unlikely, but I can envisage this continuing to be a creeping development. As evidence accumulates along with genetic sequencing becoming cheaper and faster, I could imagine dentists asking patients “have you brought your genes with you today” as the patient enters the dental surgery. After all, it’s all in your DNA.
If you would like to contact me, please get in touch via dental@rcsed.ac.uk.