Role of Genetic Biomarker in Dental Implant Loss

ABSTRACT

Dental implants provide a predictable treatment option for partial and complete edentulism via the placement of a fixed permanent artificial root to support prosthetic dental crowns.
Despite the high survival rates, long-term dental implant failures are still reported, leading to implant removals and additional financial and health burdens. The understanding of the osseointegrated implant failure as a complex, multifactorial process; and the observed aggregation of repetitive failure in certain individuals raise intresting questions related to host susceptibility to dental implant failure. Genetic analysis applied to dental implants began in the late 1990s, and since then, increased interest in genetic susceptibility to the phenotype has been demonstrated by several studies. These studies, however have been based on and limited to candidate gene association analysis and were intended to find associations between specific alleles or genotypes of genetic markers and susceptibility to implant failure. The aim of this review is to provide a brief description of the current methodology for genetic analysis of complex traits, followed by a comprehensive review of the literature related to genetic susceptibility to dental implant failure and a discussion of different aspects of the applied methodology for effective screening, prevention and treatment.
Keywords: genetic factors, dental implants, bone quality, genetic polymorphism.

INTRODUCTION

With the increase of life expectancy worldwide general health needs has been increasing substantially in terms of psychological and physical perspective, including oral treatments, resulting in better life quality. Dental implants have been extensively used to replace missing teeth, accomplishing satisfactory aesthetics and function.1 The clinical success of dental implants is based on the principle of osseointegration2 which is defined as the anchorage of the implant surface in the surrounding bone. The mechanism of osseointegration of dental implants is very similar to primary bone healing. A significant reduction in the bone-implant contact may jeopardize the osseointegration process and lead to implant loss.3 Implant loss is considered a complex, multifactorial trait, investigated by several clinical follow-up and retrospective studies.4 In this context, knowledge of the genetic factors that influence osseointegration and the possible longevity of dental implants is pertinent for investigation in the field of implantology, in order to identify intrinsic risk factors.

A successful implant osseointegration is likely to depend on factors such as an appropriate tissue repair mechanism5 and adequate immune system response.6 This immune system works by regulating the balance of cytokines, chemokines and interleukins during inflammatory conditions. Different types of interleukins play an important role in bone remodeling by inducing bone resorption (e.g., IL-6), or stimulating bone formation (e.g., IL-10). While some cytokines act as an anti-inflammatory profile, such as IL-10, other molecules and cytokines such as IL-2 and IL-6 are involved with pro-inflammatory activity and bone loss.⁷

THE CHALLENGES OF IMPLANTOLOGY

Dental implant failure could include surgical complications, patient aesthetic concern or implant functional disability. A significant reduction in the boneimplant contact may jeopardize the osseointegration process and lead to implant loss. Implant loss is considered a complex, multifactorial trait, investigated by several clinical follow-up and retrospective studies.3 The process is divided into early and late events: early failure occurs before implant load, and late failure takes place after the implant has received occlusal load.8 Early failures have been related to smoking9, ageing, systemic disease.10 Late failures have been related to peri-implantitis11 and occlusal overload. The goal that should be achieved by modern implantology research is developing tools able to predict the patient biological response to treatment before implant surgery intervention.³

GENETIC POLYMORPHISM AND DENTAL IMPLANT FAILURES

Interindividual variability to different phenotypes is partially determined by the human genetic code.2 Specifically, variability is due to the existence of a large number of polymorphisms, gene sequence variations with minimum allele frequency higher than 1% in the population distributed evenly throughout the entire genome. A polymorphism can be said “functional” when it modulates gene expression and alternatively, can be defined as “silent” if no obvious predictable biological impact can be inferred.²

The most commonly studied functional polymorphisms for dental implant failure are variations of the interleukin-1 (IL-1) gene.2 However, polymorphisms in the promoters of IL-2 and IL-6 genes were also associated with an increase in the expression of both cytokines and with the development of chronic diseases such as periodontitis thus leading to implant failure.12 Interleukins are inflammatory mediators secreted by the immunogenic cells in response to an inflammatory procedure taking place after an implant surgical procedure. These cytokines have been considered to play a key role in the regulation of the inflammatory response, immunogenic host response and osseointegration.¹³

A. Polymorphism in Interleukin-1 (IL-1)-Related Genes

Interleukin-1 (IL-1) is considered a pro-inflammatory mediator with central importance in the initiation and maintenance of acute inflammatory responses.3 Besides acting as a mediator of local inflammation, IL-1 can also produce systemic effects. IL-1 is the term for two polypeptides: IL-1A and IL-B which are encoded by distinct genes but share approximately 50 % sequence homology. IL-1 has pro-inflammatory, bone resorbing properties and immunological properties. Today, IL-1 family is recognized to include 11 total members, which play particular roles in immune-inflammatory aspects of the host response. IL-1 is thus a “cytokine” and this term is used to connote that the sources and actions of IL-1 and related polypeptides include several different cell types.3 IL 1A and IL1B gene polymorphism causes increase in osteoclast activity and thus causing increase bone resorption and poor periodontal status. Thus, it is suggested that IL-1 participates in the pathogenesis of diseases involving bone tissue and can impair periodontal and peri-implant tissues. Searching for diagnostic markers to monitor implant health status, levels of interleukins have been measured in diseased implant site. Higher levels of IL-1B were found in diseased implant sites when compared with healthy one, suggesting that such inflammatory mediator is associated with implant failure.7 Higher levels of TNF-A also showed association with unfavorable clinical outcomes at 2 and 14 days after implant placement, being proposed that TNF-A gene expression may predict clinical complications.¹⁴

B. Polymorphism in Interleukin-2 (IL-2)-Related Genes

Interleukin-2 (IL-2) is a cytokine involved in the B-cell activation.It stimulates macrophages, natural killer cells, and T-cell proliferation, which mediate the cellular immune response; thus, it is regarded as a pro-inflammatory cytokine.15 Polymorphism of interleukin-2 has implicated in increased osteoclast activity, impairing periodontal and peri-implant tissues but it is not directly responsible for implant failure.¹⁶

C . Polymorphism in Interleukin-4 (IL-4)-Related Genes

IL-4 is a potent down regulator of macrophage function that inhibits the secretion of pro-inflammatory cytokines, such as IL-1, IL-6, and tumor necrosis factor (TNF). IL4 gene, which encodes the anti-inflammatory cytokine IL-4, is present on chromosome 5q31.1 and comprises 4exons in approximately10kb.Polymorphisms in the IL4 gene have been recently associated with susceptibility to chronic periodontitis and had shown an impact in the modulation of osseointegration in the brazilian population. For the first time, to our knowledge, the C allele of the +33 (C/T) (rs2070874) polymorphism in the IL4 gene was significantly associated with susceptibility to dental implant loss in the Brazilian population studied.¹⁷

D. Polymorphism in Interleukin-6 (IL-6)-Related Genes

Interleukins-6 (IL-6) plays a role in B-cell differentiation and T-cell proliferation. It also stimulates hematopoiesis and accelerates bone resorption. Polymorphism in IL-6 showed significant effect on periodontal disease but had no effect on early implant failure.¹²

E. Polymorphism in Matrix metaloproteinases (MMPs)

Matrix metalloproteinases (MMPs) represent the major class of enzymes responsible for ECM metabolism. They are metal-dependent proteolytic enzymes that contribute to the degradation and removal of collagen from damaged tissue. Previous studies have also shown that MMPs (e.g. collagenases, gelatinases ) are present in peri-implant sulcular fluid and may play a pathologic role in peri-implant bone loss. Matrix metalloproteinase-1 (MMP-1), also known as collagenase-1, is a key mediator of the degradation of collagen, which is abundant in connective tissue and bone matrix. An enhanced secretion of MMP-1 was verified in peri-implantitis fibroblasts compared to healthy and periodontitis sites. MMPs are likely to be involved in the dental implant osseointegration process.3 The most important MMPs involved are are MMP-1 and MMP-9. Polymorphisms in MMP1 were associated with implant failure, while no implant loss is seen for MMP-9 promoter region polymorphism.²

F. Polymorphism in genes involved in Bone metabolism

Bone is one of the classical target tissues for vitamin D action. Vitamin D regulates calcium homeostasis by influencing intestinal calcium absorption, renal calcium reabsorption, and bone calcium metabolism. Vitamin D is ingested or cutaneously produced upon exposure to ultraviolet B radiation in an inactive form. Activated mainly at the kidney, resulting in the active form called 1,25-dihydroxyvitamin D3. 1,25-(OH)2D3 is believed to exert most of its actions by binding to the vitamin D receptor (VDR). VDR also plays a complex role in the control of bone homeostasis and recruits coregulators, which may have activating or repressing effects. Polymorphisms in the VDR gene significantly alter expression and/or function of VDR, which may interfere in mineral bone density.3 Bone morphogenetic protein (BMP) family, as a member of the TGF-B superfamily, has a variety of functions in the development and reparation of bone tissue. The hallmark of the BMPs is their ability to induce bone formation by promoting osteoblast differentiation (BMP4 gene).3 A polymorphism in the bone morphogenetic protein-4 (BMP-4) gene was associated with marginal bone loss before second stage surgery (implant loading) associated with marginal bone loss around dental implants.²

FUTURE INSIGHTS IN GENETIC RESEARCH ASSOCIATED WITH DENTAL IMPLANTS

Although candidate gene, association analysis has been proved to be a promising tool for the dissection of the nature of genetic component controlling dental implant failure, the design is limited by the fact that just a small segment of the genome is analyzed. Moreover the sample sizes are often small; therefore, findings must be replicated in larger populations as a consequence, genetic susceptibility to osseointegrated implant failure remains
widely unknown.³

Despite these promising advances, the exact number, identity and role of regulatory factors that lead to a successful implant osseointegration and its maintenance are still largely unknown, which limits genetic analysis approaches based on functional candidate genes.3 Candidate gene approach is limited in providing a genome-wide perspective on interesting gene regions and gene-to-gene interactions.²

CONCLUSION

Genetic studies may shed new light not only upon the physiopathology of dental implant failure but also upon broader, related processes, such as bone healing. Despite the difficulties, the motivation to continue applying traditional and new approaches for genetic analysis towards a better understanding of dental implant physiology and failure mechanisms is clear. There are few studies that have attempted to relate the presence of certain polymorphisms with a higher risk of early implant failure and/or peri-implantitis. Based on available research and the current level of understanding regarding the relationship between poly-morphisms for early failure or peri-implantitis, a reliable and/or reproducible genetic biomarker of risk has not yet been identified that could be used in the general population or commercialized. However, many authors agree that this is a field that warrants deeper investigation. Given the positive results of some preliminary investigations, new studies are needed that employ larger sample sizes and stringent methodologies in order to minimize the lack of uniformity and bias.

REFERENCES