EXPERT VIEW: What is the extent of the role played by genetic factors in periodontitis?
Figures and table: role of genetics in periodontitis
While genetic factors are known to play a role in periodontitis, a lot of research still needs to be done to understand the precise mechanisms involved. Indeed, the limited extent to which the genetic factors associated with periodontitis have been identified is “somewhat disappointing”, say Bruno G. Loos and Deon P.M. Chin, from the Academic Centre for Dentistry in Amsterdam. Here, they outline what is known today and discuss the most promising lines of inquiry.
Periodontitis is a complex chronic inflammatory disease, in which there are multiple causal components1 that play their aetiological roles simultaneously and interact with each other.
At least five domains of causal risk factors can be distinguished for periodontitis (see Fig. 1):
- Environmental factors (a dysbiotic subgingival bacterial biofilm);
- Genetic risk factors;
- Lifestyle factors such as smoking, poor diet, and stress;
- Systemic diseases, such as diabetes;
- Other factors, as yet unknown but most likely also including tooth-related, occlusal, and iatrogenic factors.
Within the domain of genetic risk factors for periodontitis, not only do certain genetic variations play a role, epigenetic changes in DNA are also involved.
For the last 20 years, the periodontal community has followed the classification of two distinct phenotypes of periodontitis: aggressive periodontitis (AgP) and chronic periodontitis (CP). AgP occurs most often at a younger age (up to 35 years old) and these cases involve more genetic risk factors than CP cases (see Fig. 2).
However, the phenotypes AgP and CP may not be as distinct as previously assumed and thus may not really be separate entities, because they do share genetic and other risk factors. It has been long recognised that cases of AgP can occur also in people aged over 35 and that cases of CP can occur in those below this age.
Nonetheless, almost all current studies on genetics use the defined disease entities: either AgP or CP. This has helped researchers to focus on well-described case-control studies, something that is much needed in the search for genetic risk factors.2
Genetic basis of periodontitis
On the basis of epidemiological studies of twins and families with a higher rate of AgP, it can be concluded that in the younger patients the genetic contribution may account for as much as 50% of causal factors, while in the older patients a genetic contribution of at most 25% has been estimated.3
As in other complex chronic diseases, it is important to realise that a multitude of genetic variations (probably more than a hundred) are involved, so periodontal disease is called polygenic. Taking this into account, it is somewhat disappointing that, in the case of periodontitis, the genetic factors associated with or contributing to the pathogenesis have been identified only to a very limited extent and have been poorly validated.
It is also possible that genetic variants associated with periodontitis in, for example, Caucasians may not be associated with other ethnic populations such as Asians, Brazilians, and Africans. While a considerable overlap of genetic variants between different ethnicities is expected, it is important to realise that there will also be population-specific risk gene variants.
The most common genetic variation between individuals is called a single nucleotide polymorphism (SNP). The frequency of a SNP is on average one per 300 nucleotides. Therefore, it is estimated that there are over 10 million SNPs in the human genome. These are annotated in the haplotype map (HapMap). There are different types of SNPs: noncoding, coding, and regulatory polymorphisms. In addition, there are other genetic variations such as variable number tandem repeats (VNTR), nucleotide insertions and nucleotide deletions.
Variants in 38 genes have been associated with periodontitis, identified by using either the candidate-gene approach or by genome-wide association studies (GWAS) (see Table).
Most often, the genetic loci, and the genetic polymorphisms that are positioned within these loci, have been chosen for candidate-gene studies of periodontitis based on their perceived participation in various adaptive and innate immune responses. They may also have previously been associated with other chronic inflammatory diseases, such as Crohn’s disease, rheumatoid arthritis, and cardiovascular disease. The overlap of the risk genes in chronic diseases is called pleiotropy.4
Within the candidate-gene studies, the allele frequencies of selected SNPs are compared between a group of periodontitis cases and periodontitis-healthy controls. Whether a genetic variant has a clinical effect and an effect on the phenotype depends on whether the SNP is located in the coding, non-coding, or regulatory region of the gene. Most genetic risk variants do not result in obvious phenotypic changes, while some may result in clear alterations to function or protein structure.
Many candidate-gene studies that have been performed in periodontitis have had varying and often contradictory results. Because of the absence of sufficient power and because of the absence of correction for multiple testing, false positive and negative results (type I and II errors) cannot be excluded.3 Findings of negative associations for one selected SNP cannot rule out a potential disease association of the gene in question.
Therefore, researchers today are more aware that it is necessary that each genetic study should assess the haplotype information – that is to say, multiple SNPs – as completely as possible. Genotyping a single variant simply provides no information on a possible disease association of the genetic locus when the outcome is negative.
Furthermore, the phenotype classification of periodontitis and control subjects has not been consistent across the various studies. On top of that, many studies have failed to take into account lifestyle factors, potential differences in allele carriership related to gender, or the presence of co-morbidities.
The genome-wide association study approach
A genome-wide association study (GWAS) is a powerful molecular technique to analyse hundreds of thousands – or even millions – of variations in genomic DNA simultaneously and to determine if any genetic locus is associated with a certain disease phenotype.4
GWAS has an open-ended approach, so no a priori candidate is investigated. It analyses SNPs covering the entire human genome. This approach will lead to the discovery of novel candidate genes that have not been known or previously hypothesised – which yields not only new genetic risk factors but also the genetic variants found in GWAS can point to hitherto unknown genes and proteins. This enables the investigation of possible roles in biological pathways, especially in diseases such as periodontitis in which the pathophysiology is not well understood.
The results of an initial GWAS need to be replicated (validated) in an independent case-control cohort with the candidate-gene approach. Until now five GWAS related to periodontitis have been performed.
Genetic variants associated with periodontitis
A total of 38 genes have been identified, in which one or several genetic variants have been associated with periodontitis, based on either the candidate-gene approach or GWAS (see Table).
Only original genetic studies in which at least 100 cases and at least 100 controls were enrolled were considered in this brief review; however, this low cut-off level may still yield false positive results (type I error).3
The table presents a global compilation, summarising the results from studies that have included different ethnicities. The genes which have variant alleles (minor alleles) associated with both AgP and CP, with AgP only, with CP only, or just with periodontitis (PD) are listed in the table in sequence of the number of independent studies available. A given gene with an SNP association with the disease in at least two independent studies provides greater certainty about the validity.
Genetic polymorphisms in four genes (IL6, PTGS2 [COX2], IL10, and DEFB1) are associated with both AgP and CP. The most studied genes are IL6 and PTGS2 – five independent studies found an association of minor alleles with both AgP and CP. Genetic variants in seven genes are associated today with AgP only, of which SNPs in CDKN2B-AS1 (ANRIL) seem to be the most robustly validated.
For CP patients, 22 genes have been reported to harbour genetic polymorphisms that have significantly different frequencies compared to controls. The gene CXCL8 (IL8) was found to be positively associated with CP in five independent studies, while each of the other 21 genes is suggested in only one or two independent reports.
Five genes are listed at the end of the table for which gene variants are reported in association with unspecified PD and only in single studies.
Overall, genetic polymorphisms associated with either only AgP, only CP, or both, are mostly located on chromosomes 1 and 6 – five in the first case, seven in the second. These chromosomes may be “hotspots” related to periodontitis.
Conclusions about genetic factors
Various conclusions can be drawn:
- Genetic factors play a role in the aetiology of periodontitis, and genetics contributes to one of at least five areas of casual factors.
- The contribution from genetics in younger individuals (most often AgP) is higher than in older individuals (most often CP).
- Environmental (a dysbiotic subgingival bacterial biofilm) and lifestyle factors play a more dominant role in the phenotype of the disease in older patients with CP.
- Researchers now hypothesise that epigenetic modifications of genomic DNA may also play a role in older people and as the result of inflammatory and infectious processes.
- Another DNA modification that can occur during life is leukocyte telomere lengthening attrition (LTA). It was found that CP patients have shorter telomere lengths than controls.5
In addition, it is interesting to realise that the initial colonisation of the teeth and the subgingival compartment in periodontal health and disease may also be affected by the genetic composition of the host.
Although periodontitis is considered to be a chronic inflammatory disease, the term “infectogenomics” has been proposed for the genetic-environmental interaction.6 In general, this term describes the influence of the genetic make-up on the acquisition, carriership, and possible outgrowth of microorganisms in a given ecological niche.
The current concept is that periodontitis can develop in a genetically susceptible subject, who has an aberrant host immune response and/or intolerance for (some) gram-negative bacteria. In this way, the hyperactive inflammatory process creates a favourable ecological niche in which proteolytic bacteria can thrive.
This would mean, in the case of periodontitis, that host genetic make-up also plays a role in the composition of the subgingival microbiota, thereby contributing to a dysbiotic biofilm. In this context, a recent study used GWAS to identify genetic signatures for certain “biotypes” of periodontitis patients, including colonisation with certain periodontal pathogens.7
Major challenges lie ahead to unravel further the genetic basis of periodontitis. In view of the proposed polygenic background, the identification so far of 38 genes is limited.
It should be noted that genetic studies need larger cohorts or case-control biobanks2,6 and, at present, there is only one biobank of this type in Europe8 – although European researchers are now joining forces with genetic researchers in the USA.
Another challenge is the phenotypic description and grouping of individuals. All studies to date have used AgP and CP as two distinct phenotypes. However, it may well transpire that this is the same disease, but with a different expression or progression rate, depending on each individual’s lifestyle, environmental factors, and comorbidities.
Another task that lies ahead is the development of a validated multicausal model or algorithm that could be applied clinically: a model where it would be possible to include various aetiological factors simultaneously, including a “fingerprint” of genetic variants, which would help patients and clinicians determine both risk of disease development and prognosis of treatment. The recent study by Offenbacher et al. (2016) has taken an important step towards this goal.7
1. Loos, B.G., Papantonopoulos, G., Jepsen, S. & Laine, M.L. (2015): ‘What is the contribution of genetics to periodontal risk?’ Dental Clinics of North America, 59, 761-780.
2. Schäfer, A.S., Jepsen, S. & Loos, B.G. (2011): ‘Guest editorial: Periodontal genetics – A decade of genetic association studies mandates better study designs.’ Journal of Clinical Periodontology 38, 103-117.
3. Schäfer, A.S., Van der Velden, U., Laine, M.L. & Loos, B.G. (2015): ‘Genetic susceptibility to periodontal disease: new insights and challenges’ in Lindhe., J. & Lang., N.P. (eds), Clinical Periodontology and Implant Dentistry, 6th edition, Chichester, UK, Wiley Blackwell, pp. 290-310.
4. Vaithilingam, R.D., Safii, S.H., Baharuddin, N.A., Ng, C.C., Cheong, S.C., Bartold, P.M., Schaefer, A.S. & Loos, B.G. (2014): ‘Moving into a new era of periodontal genetic studies: relevance of large case-control samples using severe phenotypes for genome-wide association studies,’ Journal of Periodontal Research, 49, 683-695.
5. Sanders, A.E., Divaris, K., Naorungroj, S., Heiss, G. & Risques, R.A. (2015): ‘Telomere length attrition and chronic periodontitis: an ARIC Study nested case-control study’, Journal of Clinical Periodontology, 42, 12-20.
6. Nibali, L., Di Iorio, A., Onabolu, O. & Lin, GH. (2016): ‘Periodontal infectogenomics: systematic review of associations between host genetic variants and subgingival microbial detection’, Journal of Clinical Periodontology 43, 889-900.
7. Offenbacher, S., Divaris, K., Barros, S. P., Moss, K.L., Marchesan, J.T., Morelli, T. & Laudes, M. (2016): ‘Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease’, Human Molecular Genetics, 25, 2113-2129.
8. Schaefer, A.S., Bochenek, G., Jochens, A., Ellinghaus, D., Dommisch, H., Guzeldemir-Akcakana, E., Graetz, C., Harks, I., Jockel-Schneider, Y., Weinspach, K., Meyle, J., Eickholz, P., Linden, G.J., Cine, N., Nohutcu, R., Weiss, E., Houri-Haddad, Y., Iraqi, F., Folwaczny, M., Noack, B., Strauch, K., Gieger, C., Waldenberger, M., Peters, A., Wijmenga, C., Yilmaz, E., Lieb, W., Rosenstiel, P., Doerfer, C., Bruckmann, C., Erdmann, J., König, I., Jepsen, S., Loos, B.G. & Schreiber, S. (2015): ‘Genetic evidence for PLASMINOGEN as a shared genetic risk factor of coronary artery disease and periodontitis’, Circulation: Cardiovascular Genetics. 8, 159-67.
Bruno G. Loos is professor and chair of the Department of Periodontology at the Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit Amsterdam, The Netherlands. He is also course director of the postgraduate programme in periodontology. He studies genetic aspects of periodontitis as well the systemic effects of periodontitis.
Deon P.M. Chin is a third-year bachelor student in Biomedical Sciences at the University of Amsterdam and is following her internship at the Academic Centre for Dentistry Amsterdam with Prof Loos as her supervisor. She is highly interested in studies into the genetic background of inflammatory diseases.
This article is partly based on the paper: Loos, B.G., Papantonopoulos, G., Jepsen, S., & Laine, M.L. (2015): What is the contribution of genetics to periodontal risk? Dental Clinics of North America, 59(4), 761-780.