Dr. Rajesh Sethuraman, Dr. Tanvirjahan Babi
Professor and Head of Department,
Department of Prosthodontics and Crown & Bridge,
K M Shah Dental College and Hospital, Sumandeep Vidyapeeth Deemed to be University,
Citations : Sethuraman R, Babi T. Genetic Polymorphisms and Residual Ridge Resorption in Edentulous Jaws: An Overview. J Prosthodont Dent Mater 2021;2(1): 31-37.
Residual ridge resorption has been a chronic entity that has mauled prosthodontic rehabilitation by affecting support, stability and retention of complete dentures. Though innumerable researches have shown the interdependence or direct relationship of anatomical, systemic, nutritional and prosthetic factors to loss of residual ridge, genetic factors have been often neglected as a predisposing factor. Implant failures and periodontitis that manifest bone loss have often been linked to single nucleotide polymorphisms. Since bone resorption is a common feature observed in alveolar ridge loss, it can be hypothesised that a similar genetic mechanism is applicable for residual ridge resorption too. This overview is a summary of the various genotype polymorphism and their probable mechanisms in residual ridge resorption.
Human dentition is in a state of constant flux. The teeth, gingiva, oral mucosa and alveolar bone are in a state of constant change due to the interaction between physiologic and pathologic factors along with an interplay of prosthetic influences. Among the different components of the stomatognathic system, the alveolar bone is the most dynamic. Hence the loss of teeth and the resulting edentulism is much more than an absence of teeth but a complex biomechanical and biochemical process that continues for life. Whereas loss of teeth has been inevitable due to various consequences, loss of bone has been impossible to predict and arrest in spite of advances in prosthodontics. Alveolar ridges are columns of bone in the upper and lower jaw that circumferentially surround and hold the teeth. They are unique in structure and function as their main function is to retain teeth. Ironically when the teeth are lost, they cease to perform the function that they are intended to do and hence slowly start resorbing due to disuse or abuse.
Edentulism has been considered to be a physiological manifestation of an aging process. However, prosthodontics classifies it as a pathology. Atwood described residual ridge resorption as a “MAJOR ORAL DISEASE ENTITY”. It is expressed as loss of bone that begins once teeth are extracted and continues even after prosthetic rehabilitation. The innate properties of a complete denture viz. support, stability and retention, are dependent on the quality and quantity of the denture bearing mucosa and ridge.1 Ever since then residual ridge resorption (RRR) is a term that is used to designate the alveolar ridge changes post extraction of teeth, that are seen even after socket healing. Literature has been umpteen with research on factors that can lead to RRR and they have often concluded that anatomic, systemic, metabolic and prosthetic factors are the most predominant etiologies that predispose to RRR. Lateral cephalograms and panoramic radiographs studies on residual ridge resorption have constantly proven significant differences in the rate of RRR in edentulous jaws.1-6 The long-term prognosis for maintenance of the edentulous residual ridge has been totally based on opinion derived from empirical evidence. De Vans dictum though has always echoed the need to preserve than treat, preventive prosthodontics has often been a neglected area.
Genetics has often provided pertinent solutions to chronic conditions that can be diagnosed, prevented and treated even before they manifest. RRR being a chronic pathology can also have a genetic correlation. It was not until the Human Genome Project a joint venture by the National Institutes of Health and the Department of Energy from 1985 to 2003, along with international collaborations determined the complete DNA sequence of human chromosomes.7 During the course of completing human genomic sequences, it was observed that genome sequences of different individuals vary. This reference sequence of the genome provides a baseline information to study the nature of sequence variation, especially of Single Nucleotide Polymorphisms (SNP), in human populations. SNP typing can be a powerful tool for genetic analysis. It is inferred that this aid will help us to decipher the relationship between loci at specific sites in the genome with the individual characteristics of our patients. SNP mapping helps to study genes that are responsible for pathologies especially it can be useful for common chronic diseases like residual ridge resorption. It can help to quicken the identification and localisation of genes contributing to the severe form of RRR, unveil the mechanisms, and long-term prognosis of rate and forms of residual ridge resorption. In addition to this, SNP mapping can facilitate the use of advanced and novel treatment modalities to augment vertical bone in edentulous ridges.
The concept of SNP mapping can help identify if patients with poor ridge foundation share the same nucleotide patterns. Also, as the healing of extraction sites involve an interplay of events from formation of clot, ingrowth of capillaries into the socket, appearance of primitive mesenchymal cells that differentiate into osteoblasts which in turn lay trabecular bone, reappearance of haematopoietic tissue and lastly osteoclastic bone resorption. The ultimate result after this cascade of events is an edentulous ridge. As the edentulous residual ridge is formed from wound healing process, the SNPs in genes that are responsible for the healing of mucosal and bone tissue can be contributing factors that lead to normal or abnormal ridge forms and also its maintenance. Hence, clinical researches that can evaluate the correlation between SNP genotypes and resorption pattern of edentulous ridges shall be of great significance in predicting, preventing and planning treatments for completely edentulous patients.
The role of SNP gene mapping in periodontal bone loss and implant failures have been evaluated8, however it has not been researched much in relation to edentulous ridge resorption. An overview of the existing literature on the role of SNPs and RRR can help to understand the current status of genetic control of edentulous ridge resorption.
Single nucleotide polymorphisms (SNPs) genotype of FGFR1OP2/ wit3.0
In the early healing period, the extraction socket is filled with oral fibroblasts producing fibroblast growth factor receptor 1 oncogene partner 2/ wound inducible transcript 3.0 (FGFR1OP2/wit3.0).9,10 FGFR1OP2/wit3.0 which is a cytoskeleton molecule. This molecule polymerizes and positions along the collagen fibres that align along areas of stresses in bone. It has been postulated that an increase in this molecule accelerates the contraction of the collagen gel populated with fibroblast cells. Further heterozygous null mutation of FGFR1OP2/wit3.0 slows down the mobility rate of fibroblastic cells.11 Thus, it has been hypothesised that this molecule may partly control the augmented contraction of wounds of the oral cavity.12 Residual ridge resorption occurs when there is an excessive uncontrolled wound contraction.
In 2011 Suwanwela et al,13 studied the effect of haplotype SNPs of FGFROP2/ wit3.0 on residual alveolar ridges in long-term edentulous subjects. Twenty long-term fully edentulous subjects using conventional complete dentures participated in the study. Of these participants, 70% were Whites, 5% Hispanic, 20% were Asians (Continental Asians including Indians and Pacific Islanders). 5% of the participants did not report any ethnicity and could not be traced. Six SNPs rs1051513, rs859024, rs2046937, rs2129091, rs2279351 and rs840869 were evaluated as they were assumed as the tag-SNPs that may exhibit sensitivity for haplotype constructs. Results from this study showed that the polymorphism genotype of the FGFR1OP2/wit3.0 allele had a positive correlation to alveolar bone loss and hence may be a predictor for the qualitative and quantitative classification of edentulous bone loss. To be specific, SNPs rs840869 and rs859024 presented a closer link with the extremely resorbed edentulous lower jaw. Therefore, it can be concluded that patients having dominant minor allele of rs840869 and/or rs859024 may be at an increased risk of RRR.
In 2012, Kim JH et al,14 conducted a study on 134 Korean unrelated individuals presenting full or partial edentulism for minimum 2 years. Eight SNPs (rs2306852, rs2279351, ss518063498, rs78054962, ss518063493, ss518063913, ss518063476, rs840869) that were not in high linkage disequilibrium at r2 threshold of 0.80 in the FGFR1OP2 gene were selected for genotyping. The earlier study by Suwanwela et al showed that the dominant minor allele of SNPs rs840689 and rs859024 of FGFR1OP2/wit 3.0 may be associated with extremely atrophied lower jaws.13 However, the study by Kim et al did not show any correlation of the seven SNPs and atrophic changes of residual ridges. Only one participant showed correlation of dominant minor allele of ss518063493 with excessive atrophic changes in residual ridge. The non-significant correlation may be attributed to the variation in the ethnicity of the participants of both studies. Although this result cannot be proven statistically, it can be predicted that patients, carrying the ss518063493 dominant minor allele, have an extreme risk of edentulous lower ridge atrophy.
Single nucleotide polymorphisms (SNP) of the HIF-1α gene
The edentulous residual ridge takes its form due to the bone formation-resorption activity, inside and outside of extraction socket.15,16 Immediately after tooth extraction, osseous tissues bordering the alveolar socket become hypoxic. This is the most prominent event among the changes in osseous tissue caused due to reduced masticatory loading from the teeth conducted through the periodontal ligament. Hypoxia inducible factor (HIF-1), is a transcriptional complex. It has a significant contribution in maintaining oxygen homeostasis at systemic and cellular levels in mammals. HIF-1 is the major regulator of oxygen-regulated gene expression. HIF-1 effectors are involved in new blood vessel formation, tone of blood vessels, epithelial homeostasis, and extracellular matrix metabolism. These processes are extremely important for the healing of wound after teeth extraction.17-19 HIF-1α expression shows difference in skin and oral wound healing process. Lower expressions of HIF-1α is seen in oral mucosal wounds.20 Due to this particular phenomenon oral wound healing consequences may result in residual ridge resorption.
Paek et. al, in 2015,21 used the marker SNPs of HIF-1α to perform SNP association analysis in 202 unrelated Korean subjects with at least 2 years of edentulism and no systemic co-morbidities for bone. After the gene sequencing, a total of six tag SNPs were selected (ss526883730, rs11549465, rs11549467, rs4902080, rs2057482, ss526883733). Among the SNPs studied, rs11549467 was associated with the risk of RRR. rs11549467 and rs11549465, increase the transactivation capacity of HIF-1α increasing angiogenesis and fresh vessel formation. Thus, it can be interpreted that rs11549467 can produce disturbances in osseous formation and resorption resulting in residual ridge loss.
In 2019, Emam et.al,22 conducted a clinical study on 50 completely edentulous Egyptian subjects. The relation between RRR and SNP 1772 C>T in the HIF-1α gene was evaluated. The collected DNA sample had CC, CT and TT genotype. Statistical analysis suggested an association between SNP 1772C>T in HIF-1α gene and the severe inexplicable RRR type in the mandibles of Egyptian completely edentulous patients possessing TT genotype.
SNPs in cytokines and cytokine receptor gene
Cytokines are peptides and they work as immunomodulating agents. Cytokines are of different kinds ranging from interferons, interleukins, chemokines, lymphokines to tumor necrosis factor (TNF). Tumor necrosis factor-α (TNF-α) is a multifunctional cytokine of TNF ligand superfamily. It regulates various cellular proliferation, differentiation of cells, maintenance of a differentiated phenotype, and cell apoptosis.23,24 In the bone microenvironment TNF-α has multiple actions on bone cells25. TNF-α inhibits DNA and collagen synthesis and osteocalcin gene expression in osteoblasts, but then it stimulates the synthesis of proteolytic enzymes such as plasminogen activators and matrix metalloproteinases and of cytokines such as IL-8, IL-6, and monocyte macrophage colony-stimulating factor (MCSF) in these cells.26 TNF-α potently induces bone resorption.27 It has been reported that TNF-α promotes bone resorption in vitro and in vivo by activating mature osteoclasts or by stimulating proliferation and differentiation of osteoclasts precursors or indirectly via a primary effect on osteoblasts.
Al Sheikh HA et.al,28 in 2020 conducted a study on a Saudi population of 192 complete and partial edentulous patients. The SNPs, including TNFα (rs1800629), IL10 (rs1800872, rs1800896), IL1RN (rs419598), TNFRSF11B (rs11573847), TNFRSF11A (rs4485469), NOD2 (rs5743289), and MMP1 (rs1799750, rs554499, rs5854) were genotyped. rs1800896 (-1082T>C) in the promoter region of IL10 gene and a transversion mutation are mainly correlated with residual ridge resorption. In addition, rs5743289 in NOD2 (Nucleotide-binding oligomerization domain-2) gene exhibited its significant association with RRR. Hence, it can be inferred that SNPs of cytokines are related to atrophic changes in residual alveolar ridge.
SNP in Matrix Metalloproteinase
Matrix metalloproteinases-1 is one of the major proteinases of the Matrix Metalloproteinase family. It has a propensity to denature Type I collagen. Further, at neutral pH, other collagen types are also susceptible to MMP-1 degradation. Type I collagen is a major component of the extracellular matrix (ECM). As the body is rich in type I collagen, MMP-1 is crucial for altering of ECM.29 MMPs mainly regulate various cell behaviours such as angiogenesis, cell multiplication, apoptosis, changes in cell movement. Further it also has effects on the immune system and host defence. Diseases that destroy cartilages and bones, carcinogenesis and cardiac diseases, altered activity of MMPs is found.29,30 It has been hypothesized that SNPs of MMP-1 in bone remodelling genes can contribute to excessive residual ridge loss as well as maintenance.
In 2015, Sundar SS et.al32 designed a study evaluating relation of MMP-1 polymorphism and the loss of completely edentulous residual ridge. 33 South-Indian subjects were recruited into the study. 2G polymorphism, was seen in patients with history of implant failure and progressive periodontitis. These conditions are primarily manifested with excessive loss of bone. Previous researches have correlated 2G polymorphism and bone loss in patients with periodontitis. This means that genetic alterations can lead to increased destruction of extracellular matrix clubbed with presence of mRNA in more numbers in the inflamed gingiva.33 MMP-1 polymorphism results in increased levels of mRNA level in inflamed tissues. This further leads to increase multiplication and denaturing of collagenase in the stroma of the tissues leading to increased bone loss.34 Further GG polymorphism of MMP 1 gene at −1607 domain was related to improper osseointegration, early bone loss and ailing and failing implants.35,36 Thus it can be assumed that 2G SNP found in edentulous subjects can predict predisposition to residual ridge loss. Nevertheless, 2G SNP is an important indicator for bone loss.
The role of genetic polymorphism in residual ridge resorption has been limited to SNPs in cytokines, fibroblast growth factors, hypoxia inducible factor and matrix metalloproteinases. The results of genetic influence on periodontal disease and implant failures may be indirectly extended to residual ridge resorption. Further generalisability of the results of the established genetic correlations and ridge atrophy is that ethnic variances that influence genetic predilections. Though the studies have a good internal validity, they cannot be extrapolated to the Indian population due to difference in ethnicity. This calls for more well conducted genetic researches on residual ridge resorption in the Indian population. In addition, efforts on genetic diagnostic tests, genetic counselling, candidate gene approaches can provide more genotypic information that can provide additional genomic risk markers. Once strongly correlated, genetic factors can also be identified as a controlling factor in residual ridge resorption. These can be used as useful diagnostic and prognostic aids in the future to prevent and control ridge loss thus making prosthodontic rehabilitation more predictive and successful.
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