The Human Genome Project is credited with the arrival of the genomics era. The project was initiated in 1990 and achieved its primary goals by 2003. A multinational collaboration, the project’s initial goal was to identify each of the 3 billion DNA nucleotides of the human genetic material and to estimate the number of genes. Although this project has been completed, the core exploration has continued with an expanded focus that includes identifying the function of each gene and its protein product, dissecting the complexity of gene expression and its regulation, and defining the genomes of other organisms used as model systems to help decipher the workings of the human genome. Further, several other important “-omics” disciplines have emerged from the Human Genome Project, such as transcriptomics, proteomics, and metabolomics. Each is focused on understanding key aspects of how the information stored within an organism’s genome is converted into the complicated cellular machinery that sustains life.

Additional “-omics” disciplines, such as epigenomics, pharmacogenomics, nutritional genomics, and microbiomics, focus on how factors from the environment that an organism inhabits communicate with the genetic material to impact the ultimate biological outcome. The weblike complexity of higher organism functioning can be daunting to dissect but, fortunately, the blueprint for life is fundamentally the same among organisms so that many of the findings from research with less complex organisms can be extrapolated to human implications. An overview of the Human Genome Project can be found at the websites for the National Human Genome Research Institute (www.​genome.​gov) and the U.S. Department of Energy (genomics.​energy.​gov), which co-administered this global project.

The Human Genome Project brought to the forefront of healthcare an important fundamental biological principle: genes underlie function. There is a direct connection between the information in our genes and our ability to carry out the myriad activities that support life. This awareness alters our thinking about dysfunction (“disease”) because it’s now clear that there is a logical underpinning to disease, one that can be systematically dissected and targeted with appropriate therapeutic interventions. We do not “get” a disease; disease develops because our individual genetic makeup includes gene variants (also called “genetic variations”) that make us susceptible to disease through their ultimate influence on physiological function. The susceptibility may be strong or it may be too weak in itself to lead to significant dysfunction unless one or more environmental factors interacts with those variants. The chronic diseases that challenge healthcare today are the result of interactions between our genes and our environment. Each of us has all the genes that characterize the human species but with slight variations that convey genetic uniqueness to each of us. It’s these variations that determine an individual’s disease susceptibility and how s/he responds to particular environmental factors, such as food, medications, or environmental toxins. Defining the various factors involved and their interactions is expected to provide clinicians with the potential for more effectively managing existing disease and to be well positioned to prevent disease before it manifests.

Another important accomplishment of the Human Genome Project has been in the area of genetic technology. New technological advances have been developed, but even the original technologies have advanced to the point where analyzing the composition of the genetic material is considerably faster and cheaper than even a few years ago [1]. Ongoing development in genetic technologies is essential for genomics to achieve clinical utility. In order to predict a patient’s drug response or disease susceptibility, clinicians will need to know which gene variants are present within an individual’s genome. Significant progress is being made in developing fast, accurate, and inexpensive genetic testing and can be expected to continue so that test panels with clinical validity and utility will be readily available for widespread application in the near future. Expect testing to become increasingly simplified in administration but increasingly complex in clinical implications as knowledge expands and multiple gene–gene and gene-environmental factor interactions are discovered and associated with clinical outcomes. Systems biology and bioinformatics will be important behind-the-scenes fields supporting clinical application of the -omic technologies. Recent reviews address emerging technologies and disciplines and their importance to the development of genomics as clinically useful [2–4].

Oral health is of no exception when it comes to the important role of genes in function and is expected to benefit from the scientific foundation and resultant clinical applications of genomics [5–8]. Although the exploration of gene-based mechanisms in dental medicine is in its early stages, gene variants are being investigated for association with caries development, [9, 10] enamel formation, [11] and gingivitis and periodontitis [12–21]. A recent study in twins by Rintakoski and colleagues [22] includes a summary of the key research linking genes and oral disease. Among the clinical applications of genomics to oral health are pharmacogenomics and the prediction of patient response to medication; determining whether a patient is susceptible to being in a pro-inflammatory state, which promotes periodontal disease among other chronic diseases; predicting risk of caries formation; and nutritional genomics and its promise of matching diet and lifestyle choices to the underlying genotype of the individual in order to better manage existing chronic disease and prevent future disease.

Over the past decade, leaders in dental education have realized that genomics and molecular biology would need to be incorporated into dental practice and began to assess the preparation of dental professionals in these areas [23–26]. Behnke and Hassell [26] evaluated the genetics education requirements for admission into and graduation from dental schools and dental hygiene programs during 2003–2004. They found that none of the dental hygiene schools required a course in genetics for entry nor included one within the curriculum. Of the 54 dental schools, only one required a genetics course prior to entry and six had a formal, required course in genetics within the curriculum. In 2008, one of the three reports from the “New Models of Dental Education” study, funded by the Josiah Macy, Jr. Foundation, addressed genetics and its implications for clinical practice [5]. In this report, the panel considered the anticipated changes in dental practice and the knowledge, skills, and attitudes that would be required by dental professionals in an era of genetics and molecular biology. The report acknowledged the challenges of integrating these disciplines into the typically dense dental education curriculum and offered educational strategies for consideration. Despite the challenges, the fundamental role of genes in health and disease mandates the development of new knowledge and skills for dental professionals who can look forward to an expanded role in caring for the whole patient.

This chapter will provide the fundamentals of genomics, pharmacogenomics, and nutritional genomics and their anticipated applications to oral health and dental medicine.

Because the information encoded within our genes is directly linked to our functional outcomes, we now realize that it’s important to understand gene-protein-function connections at the molecular level. This section provides a brief overview of the key aspects of how the genes direct the operation of an organism and how information from the environment communicates with the genes. This overview provides the background for understanding the utility of genomic applications, particularly pharmacogenomics and nutritional genomics, to dental medicine.

Although the focus of this chapter is on molecular genomics, the impact of changes to chromosome structure should be noted because such changes can ultimately impact DNA and its translation into the proteins needed for function. Chromosomes can be thought of as a packaging mechanism by which the large amount of DNA is packed within the microscopic nucleus. A chromosome represents a linear sequence of DNA nucleotides, with each gene and each nucleotide within that gene having a specific “address” on a particular chromosome. Should the normal number of copies of a chromosome or a chromosomal region be increased or decreased, the amount of information available is altered, which can result in more or less of a protein being produced. For the most part, alterations in the amount of genetic material are not well accommodated and these conditions typically lead to serious dysfunction/disease and often death. Similarly, breakage can occur in one or more chromosomes so that material is lost or its location changed (the “sticky” ends of broken chromosomes can append to another chromosome or the broken section can invert and insert “backwards” into the same location). When transcription of this rearranged DNA occurs, the information is often nonsensical, critical proteins are not made, and function is impaired. Such changes in chromosome number or structure are referred to as “chromosomal abnormalities” and will be seen in dental practice because individuals with these aberrations often have oral problems that can range from tooth morphological abnormalities to cleft palate to chewing and swallowing problems. The review by Jafarzadeh on taurodontism may be of interest in that it is often seen with Klinefelter syndrome (more than one X-chromosome in males), the most common chromosomal abnormality in humans [28, 29].

Clearly changes in DNA or in its epigenomic “markings” are important to our ultimate functioning and to our health and disease susceptibilities. The terminology for such changes is in transition. In this section, the spectrum of biological outcomes resulting from changes in DNA sequence or epigenomics markings is explored. An attempt is made to convey understanding within the present context and to point out limitations to current terminology and how it’s likely to change as both knowledge and technology expand. A number of familiar disease states are used to illustrate how understanding of “genetic disease” is undergoing major revision as the molecular basis for disease is now being explored. The important point is that the extent to which function is influenced by changes to genes can that vary from severe to mild depending on the role of the gene and where within the gene the change occurs, which may affect expression of the gene or the structure of the protein if the gene is expressed. Further, for many genes, a change may have no effect on function unless the gene interacts with one or more environmental factors. This latter mechanism seems to occur commonly and to be associated with chronic diseases.

Historically, linking a change in DNA to a change in protein expression or function and ultimately to a disease was a major breakthrough in understanding the critical role of genes in health and disease. Such diseases were originally called “genetic diseases” and thought to be a distinct type of disease that occurred rarely but was typically severe in its impact, which manifested early in life. When such changes were in genes and proteins involved in metabolic reactions, the disease was called an “inborn error of metabolism.”

Traditionally the term “mutation” was used to describe a rare change in the DNA sequence, which typically resulted in a detectable disease condition. However, as technology improved, more subtle subclinical effects were detected. In addition to the severe forms of disease, milder forms could be traced to a change in the same gene and, ultimately, technological advances allowed detection of changes that led to increased susceptibility but not necessarily to overt disease. These types of mutations came to be called genetic “variations” and the genetic basis ascribed to “gene variants” in which the DNA nucleotide sequence had been altered. In many cases only when the variation interacted with specific environmental factors did disease arise. The term “single nucleotide polymorphism” (SNP, pronounced “snip”) referred to those variations in which a single nucleotide change occurred and the variation was frequent in the population (initially defined as occurring in >1% of a population). More recently, alterations that change the epigenetic signature of the DNA have expanded the lexicon. The lines between the mutations and genetic variations have begun to blur as technological advances have enabled the discovery that many diseases have a spectrum of symptoms, ranging from severe to mild, regardless of the specific type of change involved or whether it occurs rarely or frequently within a population. The key defining characteristic appears to be the impact of a genetic alteration on functional outcomes.

Cystic fibrosis, sickle cell disease, and the inborn error of metabolism phenylketonuria are classic examples of rare single gene disorders that cause disease and are considered to result from “mutations.” Historically, when cystic fibrosis was diagnosed, genetic analysis confirmed the presence of two copies of a mutation in the cystic fibrosis transmembrane conductance receptor gene (CFTR). Over 1900 mutations have now been identified in this one gene, some of which lead to severe symptoms and others to a mild condition [39]. The changes have occurred in the same gene in all cases, but the nucleotide involved and the impact on function is the determining factor as to the severity of the outcome. If one of these changes in the CFTR gene is found to be common within a population, it might now qualify as a “gene variant” rather than a mutation.

Sickle cell disease also offers a dramatic example of the effect of a change in a single nucleotide on function and health. The substitution of a T for an A in the HBB gene sequence that encodes the beta-globin subunit of hemoglobin leads to the neutrally charged amino acid valine replacing the negatively charged glutamic acid. The resultant conformational change to the peptide decreases its ability to bind oxygen. Those with two copies of this alteration exhibit a sickled shape to their red blood cells and the painful symptoms of sickle cell disease under conditions of low oxygen tension. Further, those with a single copy have an intermediate phenotype, sickle cell trait. Not only does the actual change and its impact on function define the phenotype but the number of copies of the change (gene dosage effect) is also an important determinant of the biological outcome. Molecular and clinical details of this disorder can be found in reviews by Frenette and Atweh [40] and, more recently, by Steinberg and Sebastiani [41].

The inborn errors of metabolism (IEM) in which the impact is nutritionally related are similar in concept to cystic fibrosis and sickle cell disease in that they occur rarely but yield a detrimental functional impact. The classic IEM example is phenylketonuria (PKU) in which a single nucleotide change within the PAH gene leads to the absence of phenylalanine hydroxylase. This change prevents the conversion of the amino acid phenylalanine to tyrosine and creates a life-threatening deficiency in tyrosine if it is not supplied in the diet. It also leads to an accumulation of phenylalanine and its metabolites, such as phenylpyruvate, which can be detrimental to the developing brain. An overview of PAH and its relationship to PKU from an historical and contemporary status is provided by Zurfluh et al. [42].

As knowledge of molecular nutrition and molecular genetics increases, multiple phenotypes for PKU and other IEM have been detected. The review by Gersting et al. [43] of known PAH mutations suggests that a variety of types of changes is represented, all impacting the ability to ultimately generate tyrosine from phenylalanine. The spectrum for phenylalanine tolerance varies from PKU, which requires a phenylalanine-restricted diet, to mild hyperphenylalaninemia that does not require dietary restriction. This phenotypic spectrum appears to mirror the impact of the various changes on function and is emerging as a common theme as knowledge of the molecular basis for disease expands.

An example of a mutation that would clearly be labeled a “gene variant” is the 677C > T change in the MTHFR gene. This gene codes for the enzyme methylenetetrahydrofolate reductase that converts folate into its 5-methytetrahydrolfolate active form, which in turn is involved in the conversion of homocysteine to methionine as well as supplying other metabolic reactions with methyl groups [44]. Insufficient 5-methyltetrahydrofolate can lead to elevated levels of homocysteine, which have been linked to increased risk of cardiovascular disease [45]. A cytosine-to-thymine change at nucleotide 677 of the DNA leads to an enzyme that is impaired in its ability to supply adequate levels of active folate. With this particular nucleotide change, the impairment is not sufficient in itself to cause dysfunction and a disease state typically does not manifest unless the individual consumes insufficient folate. Dietary folate insufficiency, however, is suspected by the World Health Organization of being a common global problem [46].

Virtually all of the chronic diseases that plaque modern society, such as heart disease, cancers, diabetes, inflammatory disorders, osteoporosis, and obesity, are caused by changes that can be classified as genetic variations. A change in a single nucleotide may occur along with other single nucleotide changes that alone are minor in functional impact but increase risk in the aggregate or may interact with one or more environmental factors to promote dysfunction and disease. Additionally, changes impact the epigenetic markings of DNA and chromatin and interfere with access to the expression of one or multiple genes. Most likely these changes will also be found to fall at both ends of the mutation versus variation spectrum and points in between.

It should be apparent that the clear distinction between mutation and variation is becoming murkier, not clearer, as knowledge expands. Even the classic disorders such as sickle cell and the IEM are now known to have a spectrum of phenotypes that can be correlated with particular genetic changes and their impact on function. Clarity will not likely be achieved until large numbers of genetic alterations have been studied within multiple genes and the environmental triggers have been identified. The key points here, though, are that a single nucleotide change can have devastating consequences to function or may be silent unless interaction with an environmental trigger occurs. Further, genetic disease appears not to be a type of disease but underlies essentially all disease, with the severity reflecting the impact of the genetic alteration on function. Similarly, the earlier thinking that classified people as “normal” or “abnormal” with respect to a disease is giving way to an understanding that each person is genetically unique. Ultimately clinicians will need to integrate this new shift in thinking into every aspect of patient care, which includes dental medicine. Genomics will be incorporated into diagnosing oral disease, predicting susceptibility to developing cavities, defining a patient’s drug-metabolizing capacity, and determining dietary requirements.

Genomics and its related -omic disciplines have the potential for fostering the development of personalized healthcare, in which the genetic makeup of each individual can guide health-related decision making. In order to realize this potential, there must be a way to analyze the DNA sequence and its epigenetic markings. The basic technology for genetic testing has been in use for decades and new refinements and enhancements are continually being added. What lags at this point is the research foundation for associating phenotype with genotype. That is, we are in the early stages of associating defined gene changes (mutations or variations or epigenetic markings) with specific disease states and with particular gene-environmental factor interactions that can convert susceptibility into disease or offer effective intervention approaches. The following section provides an overview of the ongoing importance of using family history and genetic analysis to detect disease susceptibility.

Genetic testing is increasingly being used in healthcare settings. The type of testing may be chromosomal analysis to detect changes in number or structure of the chromosomes or DNA analysis for detecting particular mutations, SNPs, epigenetic modifications, or changes in the number of copies of a gene.

Considerable research attention is being directed toward identifying SNPs associated with a variety of chronic diseases and developing genetic tests. Several tests are presently available for use by providers and consumers. This application of genetic testing is in its infancy but holds considerable promise. The technology used for this type of testing is sound as it is the same as that used for decades in research and clinical labs to test for inborn errors of metabolism and other single gene, rare disorders. The limitation at present is the paucity of research validating the associations between particular SNPs and susceptibility to disease and the associations between particular interventions and improved disease management or prevention. However, genetic testing is expected to be an increasingly fruitful approach as research continues to move forward, providing a much-needed mechanism for identifying disease susceptibility that often cannot be determined through family history. Further, through genetic testing, disease susceptibility can be detected prenatally and can be used to guide diet and lifestyle decisions early in life, with the goal of preventing disease from developing.

The fundamental relationship among genes, gene alterations, protein, and biological function at all levels predicts that gene-related principles will become increasingly integrated into healthcare, including oral healthcare [23–26]. A heightened awareness of the value of including the broad scope of genomics in the dental school curriculum has been apparent during the past decade [5, 26]. This section provides examples of how genomics, pharmacogenomics, and nutritional genomics are presently being applied clinically.