What is Single Nucleotide Polymorphisms?
A single nucleotide polymorphism, or SNP (pronouned "snip"), is a change in a single nucleotide in the genome that causes variations in DNA sequences between members of the same species. In order for the variation to be considered as a “polymorphism,” it has to be “common” in the population. Otherwise, the variation is just a rare mutation. For example, a single-nucleotide change in the DNA sequence of a specific gene, such as from ACGCCAG to ACTCCCG, that occurs in greater than or equal to 1% of the population can be considered as a SNP. These variants are called alleles, representing alternative forms of DNA in a locus, or position on the chromosome. Sometimes short (1 to 3 base-pair-long) insertions and deletions in the DNA sequence, or indels, are considered SNPs as well.
Importance of studies of gene polymorphism towards the identification of susceptible groups or prognostic indicators of oral disease.
Caries Genetic Predisposition Analysis by Saliva Testing
Dental caries (also known as tooth decay) remains the most common chronic disease of childhood and adulthood.
In children, dental caries are five times more common than asthma and seven times more common than environmental allergies, with more than 40% of children exhibiting caries when they enter kindergarten. In 2005, it was estimated that dental health care costs were approximately $84 billion, of which 60% or about $50 billion were related to treatment of dental caries. Although overall caries prevalence has declined over the last 40 years, dental caries in the primary dentition and mean caries rates in children ages 2-11 has increased markedly over the past 12 years. Childhood caries is a serious public health issue because of associated health problems and because disparities in oral health have led to substantially higher average disease prevalence among children in poverty and in under-served racial and ethnic groups. These issues are of such concern that in 2005, the American Academy of Pediatrics made children's oral health one of their top areas of focus.
The etiology of dental caries has been studied for many years. Multiple factors contribute to a person's risk for caries, including: 1) environmental factors such as diet, oral hygiene, fluoride exposure and the level of colonization of cariogenic bacteria and 2) host factors such as salivary flow, salivary buffering capacity, position of teeth relative to each other, surface characteristics of tooth enamel and depth of occlusal fissures on posterior teeth. In spite of all that is known about this disease, there are still individuals who appear to be more susceptible to caries and those who are extremely resistant, regardless of the environmental risk factors to which they are exposed, implying that genetic factors also play an important role in caries etiology. This conclusion is supported by studies in both humans and animals, with the most compelling evidence coming from studies of twins reared apart in which investigators found significant resemblance within monozygotic (MZ) but not dizygotic (DZ) twin pairs for percentage of teeth and surfaces restored or carious and estimated the genetic contribution to caries as 40%. Other recent studies of twins reared together estimated the heritability for caries, adjusted for age and gender, as ranging from 45-64%.
Despite the strong evidence of a genetic component to risk for dental caries, there have been only a few studies of candidate genes in caries.
Regarding genes involved in caries development in children, it was hypothesized that genetic variation in taste pathway genes (TAS2R38, TAS1R2, GNAT3) may be associated with dental caries risk and/or protection. Studies have demonstrated the importance of dietary habits, nutritional status, and chemically determined taste sensitivity with respect to caries risk.
The results published from 2449 individuals tested by the Center for Oral Health Research in Appalachia (COHRA), a partnership between the University of Pittsburgh and West Virginia University, have identified two genes important in taste-sensing that are associated with dental caries risk and/or protection in the childhood; TAS2R38 and TAS1R2. Families were recruited by the Center for Oral Health Research in Appalachia (COHRA) for collection of biological samples, demographic data, and clinical assessment of oral health, including caries scores. Multiple single-nucleotide polymorphism (SNP) assays for each gene were performed and analyzed by transmission disequilibrium test (TDT) analysis (FBAT software) for three dentition groups: primary, mixed, and permanent. Statistically significant associations were seen in TAS2R38 and TAS1R2 for caries risk and/or protection. These results highlighted the importance of understanding the role of taste preferences in caries and the utility of a genetics approach that overcomes the methodological challenges of laboratory taste preference assessment and reported dietary habits. Ultimately, the characterization of genes involved in taste preference and their genetic association with caries will contribute to greater screening of susceptible individuals with primary and mixed dentition and inform intervention strategies.
For permanent dentition caries- risk assessment, a comprehensive genome wide search is the only approach that will allow us to identify those genetic regions likely to harbor genes increasing the risk for dental caries, and eventually to identify the etiologic genes and to explore the interaction of those genes with microbiological, dietary, fluoride, and behavioral factors that are known to be associated with caries risk and progression. A relevant genome-wide scan study of dental caries in adults, was published recently (BMC Oral Health 2012, 12:57). The overarching goal was to identify novel genetic factors that contribute to dental caries in permanent dentition in adults, through large-scale genome-wide association studies of well-characterized families and individuals at multiple sites in the U.S.
Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR, U01-DE018903). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.
Results from the GWAS analysis, could identify genes that demonstrated both the suggestive P-values and the biologically relevant functions for dental caries.
Taken advantage of the recent knowledge of the genetic components of caries development in primary and permanent dentition, we developed a molecular test to identify those individuals at risk. Briefly, DNA from the patient’s saliva is isolated and sequences in those regions where single nucleotides polymorphisms were identified in recent genome-wide scan studies, with a “protector” or “high risk” role for caries development. Those pool of genes are sequencing together, with semiconductor-sequencing technology on a microchip, and a report of genetic risk is generated upon the alleles detected in the hot regions.
Finally, the assessment of caries risk from DNA isolated from saliva enhances the implementation of targeted strategies, and thereby contribute to early dental caries prevention