Genetic Involvement in Dental Implant Failure: Association With Polymorphisms of Genes Modulating Inflammatory Responses and Bone Metabolism

Dental implants are widely used for the effective and predictable treatment of tooth loss. According to Albrektsson's and Karoussis's criteria, success rates of implants have reached 92.6% and 83.0%, respectively.¹  The 10-year survival rate of successful implants is over 93%.^1,2  Implant loss is a serious complication, categorized either as early or late loss. Early implant failure reflects only a failure in osseointegration,³  that is, loss within 6 months of implantation or before the implants are loaded.^4,5  The majority of failures are due to early loss and are associated with surgical trauma, infection, and inadequate bone quantity or quality. Late loss of osseointegrated implants is categorised as that occurring beyond 6 months post-implantation.^4,5  Late loss may result from mechanical damage to the implant or from biological causes leading to peri-implantitis and lack of support by surrounding bone.

Peri-implantitis and periodontitis are inflammatory and infectious diseases that result in the destruction of the tissue supporting the tooth or implant, leading to tooth/implant loss.⁶  Approximately 30% of patients with dental implants develop peri-implantitis.⁷  In addition to microbial infection, the host response plays an important role in the pathogenesis of periodontitis and peri-implantitis. Host response to microorganisms triggers the release of pro-inflammatory mediators. In physiological situations, the periodontal or peri-implant tissues in close contact with the dental biofilm have an active immune response and low-grade inflammation.⁶  Once the production of inflammatory mediators is dysregulated, the host cells release toxic products, resulting in tissue destruction around teeth and oral implants.^6,8  Interleukin-1 (IL-1), IL-6, IL-17, and tumor necrosis factor (TNF)-α are known as strong pro-inflammatory molecules.⁶  The implants have also been shown to stimulate macrophages to release pro-inflammatory cytokines, such as IL-1 and TNF-α, which mediate the inflammatory and osteolytic process of peri-implantitis as well as promote the matrix metalloproteinases-mediated degradation of extracellular matrix components. However, this phenomenon happens only in a minority of patients, suggesting an important role of host factors, particularly the immune response to the implants.⁹  An adequate immunologic response and an appropriate tissue repair mechanism are required for implant osseointegration. So, short term or low level of inflammation with moderate IL-1 and TNF-α release benefits dental implant osseointegration. Strong or long term IL-1 and TNF-α release-mediated inflammatory and osteolytic processes enhance the risk for severe peri-implantitis and implant failure.⁹  In addition to bacterial plaque and host immune response, prosthetic and surgical factors can also induce peri-implantitis,^10,11  suggesting that iatrogenic factors are involved in the pathogenesis of the peri-implantitis. Many iatrogenic factors, including excess cement remnants or/and incorrect finishing line, bio-corrosion, failed bone reconstruction, overloading, inappropriate restoration design, implant malpositioning, microleakage at the implant-abutment interface, abutment unscrewing, and implant crack or fracture, may be associated with peri-implantitis.^10–15 

Multiple factors—including implant material properties, surgical procedure, and host characteristics—affect implant success rate, and the precipitating cause of failure cannot always be identified. Early studies revealed the existence of clustering of implant failure, ^16–18  with multiple early losses occurring in a single individual, suggesting that genetic aspects and/or an immune response may be contributing factors.⁴  Inflammation has a critical effect on osseointegration and implant success. Inflammatory cytokine production induces peri-implantitis and stimulates bone resorption, resulting in implant failure. It has been reported that inflammatory mediators such as IL-1β, TNF-α, IL-8, and macrophage inflammatory protein-1α are significantly higher in the peri-implant crevicular fluid (PICF) of patients with peri-implantitis, implying that cytokines could be prognostic markers of implant failure.^7,19 

A single nucleotide polymorphism (SNP) is single nucleotide variation at a specific position of the genome. Each variation appears in some appreciable degree within a population. SNP may occur within coding and non-coding sequences of genes, or in the intergenic regions. Considering degeneracy of the genetic code, SNP within a coding sequence may change the amino acid sequence of the coding polypeptide (nonsynonymous SNP), or not affect the protein sequence (synonymous SNP). SNP outside protein-coding regions may still regulate gene expression through affecting the transcription factor binding, gene splicing, mRNA degradation, or the sequence of noncoding RNA. Therefore, SNP underlies differences in our susceptibility to disease. SNP of inflammatory cytokine genes may affect their expression levels or amino acid sequence and, consequently, the host inflammatory response. The groups of genes involved in the regulation of inflammatory responses and bone metabolism have been investigated and associated, to some extent, with peri-implantitis and implant loss (Table, Figure). Based on a PubMed search using the keywords dental (oral) implants, failure (loss), and genetics (polymorphisms), this review summarizes research and updates information on the association of polymorphisms of several relevant genes with dental implant failure.

Interleukins (IL) are a group of cytokines that play important roles in the immune response. IL-1 is a potent pro-inflammatory cytokine that maintains periodontal homeostasis and plays an essential role in pathogenesis of periodontitis.³⁹  The functional polymorphism in the IL-1 gene may be a genetic risk factor for implant failure. Studies of IL-1 polymorphism and dental implant failure initially involved the role of IL-1 in the development of periodontitis and peri-implantitis. An early study identified the IL-1 genotype as a strong indicator of susceptibility to severe periodontitis.⁴⁰  When IL-1A-889 C/T (rs1800587), IL-1A+4845 G/T (rs17561), and IL-1B+3954 C/T (rs1143634, formerly IL-1B+3953) polymorphisms were investigated, the discrepant results were achieved.^22,41–43  The available evidence was insufficient to confirm or refute their association with peri-implantiti.^44,45  Biochemical markers of the peri-implant immune response in PICF demonstrated that the influence of IL-1A-889 C/T and IL-1B+3954 C/T on the peri-implant crevicular immune response and peri-implantitis was limited.⁴⁶  The IL-1 receptor antagonist (IL-1RA) is an anti-inflammatory cytokine that binds to and blocks the IL-1 receptor and inhibits IL-1-mediated signals. Polymorphism of the IL-1RA encoding gene IL-1RN was genotyped and found that IL-1RN allele 2 was associated with peri-implantitis.⁴⁷  The frequency of the IL-1RN 2/2 genotype in chronic periodontitis patients and controls was reported to be 30% and 15%, respectively.⁴³  Data suggest that IL-1RN gene polymorphism is associated with peri-implantitis and chronic periodontitis, constituting a risk factor.^43,47 

A further question is whether IL-1 polymorphisms are associated with loss of bone surrounding the implant. Polymorphisms of IL-1A-889 C/T, IL-1B-511 C/T, and IL-1B+3954 C/T were detected and a significantly higher occurrence of marginal bone loss was observed in patients with the IL-1B-511 C/T 2/2 genotype, suggesting an association of this genotype with early marginal bone loss around endosseous implants.^48–50  Investigation of the association of IL-1 polymorphisms in IL-1A+4845 G/T and IL-1B+3954 C/T loci with peri-implant bone loss at osseointegrated dental implants revealed that smoking and IL-1 polymorphisms were associated with an increased risk for peri-implant bone loss in osseointegrated dental implants.⁵¹ 

In the past two decades, scientists have investigated the relationship between the IL-1 genotype and implant failure. An initial study found that IL-1 polymorphism did not increase the risk of implant failure, but smoking was a significant risk factor.²⁰  Further study found no association of four polymorphisms in the IL-1 gene cluster with early failure of osseointegrated implants.^21–23  When the effects of IL-1A-889 C/T, IL-1A+4845 G/T, and IL-1B+3954 C/T polymorphisms and smoking on the prognosis of osseointegrated implants were evaluated, the IL-1 genotype alone did not predict implant loss, but a significant synergistic effect was found between smoking and a specific IL-1 genotype, leading to significantly higher implant loss.^24,25 

The significance of IL-1 polymorphism in implant loss is a topic of debate. Polymorphisms of IL-1B+3954 C/T and IL-1RN (intron 2), both shown to alter coding protein expression, were investigated in subjects with implant loss, and genotype 2/2 of IL-1RN was significantly more frequent in individuals presenting multiple implant losses, suggesting a potential genetic basis for the clusterization phenomenon.²⁶  Polymorphisms of IL-1A-889 C/T and IL-1B+3954 C/T were significantly associated with the status of the dental implants.²⁷  When polymorphisms of IL-1A-889 C/T, IL-1B+3954 C/T, IL-1RN+2018 T/C (rs419598), and TNF-α-308 G/A (rs1800629) were genotyped in subjects with titanium implant failure, the minor alleles of the studied polymorphisms in the implant failure group were more frequent than in controls. The incidence of implant loss increased along with the increase in number of risk genotypes, demonstrating an additive effect.⁹  TNF-α and IL-1β secretion upon titanium stimulation was significantly higher in patients with implant loss.⁹  Data indicate that IL-1β/TNF-α release and number of risk genotypes are significantly and independently associated with titanium implant failure.⁹  The T allele of IL-1A-889 C/T and IL-1B+3954 C/T was significantly associated with early implant failure and the IL-1B+3954 C/T polymorphism is likely to impact osseointegration.³  A meta-analysis supported that the IL-1A-889 C/T and IL-1B+3954 C/T composite genotype and the T allele of IL-1B-511 C/T were associated with increased incidence of implant failure/loss.³⁹ 

In addition to IL-1, interleukins including IL-2, IL-4, IL-6, IL-10, and IL-17 have been investigated for their association with early implant failure. IL-2 and IL-6 are cytokines involved in T-cell activation and B-cell differentiation. Both have been implicated in stimulation of osteoclast activity and bone resorption.^52,53  Several studies have reported polymorphisms of IL-2-330 T/G (rs2069762),⁵⁴  IL-6-174 G/C (rs1800795),^55–57  IL-6-1363 G/T (rs2069827), and IL-6-1480C/G^57,58  to be associated with periodontitis, and G allele of polymorphism rs2069837 (A/G) located in intron 2 of IL-6, was shown to be a potential marker of protection against chronic periodontitis.⁵⁹  Polymorphism of IL-2-330 T/G and IL-6-174 G/C in promoter regions contributes to the transcription activity of these cytokines. In an early study, the allele and genotype distribution of IL-2-330 T/G and IL-6-174 G/C was not significantly associated with early failure of dental implants.²⁸  But the A Allele of IL-6 rs2069843 (A/G) and T allele of IL6+4272 C/T (rs2069849) were found to be associated with the loss of mini-implants for orthodontic anchorage.³⁰ 

IL-4 induces differentiation of naive helper T cells and stimulates proliferation of activated B and T cells. Initial study indicated that IL-4-590 C/T (rs2243250) was not associated with severe periodontitis.⁶⁰  When polymorphisms of IL-4-590 C/T, IL-4+33 C/T (rs2070874), and IL-4 70 bp variable number tandem repeat (VNTR) (rs79071878) were investigated, the alleles/genotypes of IL-4-590 C/T and IL-4 VNTR polymorphisms were not found associated with implant loss.²⁹  Although frequency of genotype IL-4+33 C/T was not significantly different between groups, the C allele was associated with dental implant loss.²⁹ 

IL-10 is an anti-inflammatory cytokine. Polymorphisms of IL-10-1082 A/G (rs1800896), IL-10-819 C/T (rs1800871), and IL-10-592 A/C (rs1800872) on the promoter region of the IL-10 gene have been reported to be associated with IL-10 production and autoimmune disease. When these three polymorphisms were analyzed, no allele, genotype, or haplotype was significantly associated with dental implant loss or chronic periodontitis.^4,31  A study further confirmed that IL-10-1082 A/G polymorphism was not associated with failure of dental implants.³²  However, polymorphism of IL-10-819 C/T and IL-10-592 A/C were associated with susceptibility to chronic periodontitis.⁶¹  When 23 candidate genes for periodontitis were evaluated, association of IL-10 rs61815643 with aggressive periodontitis was observed.⁶² 

IL-17 is a pro-inflammatory cytokine secreted by activated T cells.⁶³  The IL-17 concentration was higher in tissue adjacent to degraded bone, and increased IL-17 levels have been associated with chronic periodontitis.^64,65  IL-17 gene polymorphism was investigated in patients with chronic periodontitis, patients with peri-implantitis, and healthy individuals. The frequency of the CC genotype of IL-17 rs10484879 (A/C) in the peri-implantitis group was significantly higher than in healthy individuals and those with chronic periodontitis, suggesting that the CC genotype may contribute to the pathogenesis of peri-implantitis.⁶³ 

Tumor necrosis factor-α (TNF-α) is a pro-inflammatory mediator involved in the regulation of bone resorption.^66,67  Several studies suggested that the TNF-α-308 G/A polymorphism was not associated with peri-implantitis, peri-implant bone loss, or early implant failure.^31,37,68,69  In recent studies, the A allele in TNF-α-308 G/A increased the level of this cytokine and was associated with periodontitis.^70,71  The AG genotype of TNF-α-308 G/A was associated with a fivefold risk of peri-implantitis compared to other genotypes.⁷²  However, a meta-analysis concluded that TNF-α-308 G/A polymorphism was not significantly associated with the risk of peri-implant disease.⁷³ 

Receptor activator of nuclear factor kappa B ligand (RANKL)—also known as TNF-related activation-induced cytokine or osteoprotegerin (OPG) ligand—is a member of the TNF superfamily. The RANK-RANKL-OPG signaling pathway is involved in osteoclastogenesis, osteoclast activation, and regulation of bone resorption. Polymorphisms of RANK genes rs3018362 (A/G) and rs35211496 (C/T) were investigated in individuals with peri-implantitis, with chronic periodontitis, and periodontally healthy. The CC genotype of the rs35211496 RANK gene was significantly associated with peri-implantitis and was suggested as a genetic risk factor.⁷⁴  When the RANKL gene polymorphisms of rs9533156 (T/C) and RANKL+290 A/G (rs2277438) were analyzed, the CT genotype of rs9533156 was significantly associated with peri-implantitis.⁷⁵  RANKL-438 A/G polymorphism was not associated with the failure of dental implants.³² 

Matrix metalloproteinases (MMP) are a class of zinc-dependent proteolytic enzymes responsible for extracellular matrix metabolism that are possibly involved in the osseointegration process of dental implants.^76,77  Matrix metalloproteinases have been found in peri-implant sulcular fluid, playing a pathologic role in peri-implant bone loss.^78,79  The polymorphisms in MMP-1,^33,34  MMP-8,⁷⁵  and MMP-9³³ have been investigated. Polymorphisms of MMP-1-1607 G/GG (rs1799750) and MMP-1-519 A/G (rs1144393) in the promoter region of human MMP-1 have been shown to increase transcription activity.³⁴  Polymorphism of MMP-1-1607 G/GG was reported to be associated with severe chronic periodontitis.⁸⁰  The 2G allele and 2G/2G genotype in patients with severe periodontitis were significantly more frequent than in the healthy group.⁸⁰  The genetic association of MMPs with periodontitis risk has been well-reviewed.⁸¹ 

Polymorphism of MMP-1-1607 G/GG has been demonstrated to be associated with early implant failure.³³  The frequency of the G allele and the G/G genotype in the MMP-1-1607 G/GG were 62% and 34%, respectively, in patients with one or more early failed implants, compared with 75% and 62% in control group, indicating an association with early implant failure.³⁴  The MMP-1-519 A/G polymorphism was not significantly associated with implant loss.³⁴  When the MMP-8-799 C/T (rs11225395) polymorphism in the promoter region of the MMP-8 gene in nonsmoking patients was investigated, it was found that the T allele and the T/T genotype were associated with early loss of implants.³⁵  The MMP-9-1562 C/T (rs34016235) polymorphism in the MMP-9 promoter region was not associated with chronic periodontitis⁸²  or implant loss.³³ 

Bone morphogenetic proteins (BMP) represent a family of growth factors that facilitate osteogenesis. The BMP-4 genetic polymorphism was found to influence marginal bone loss around implants before implant loading.⁸³  When 13 polymorphic sites in BMP-4, FGF3, FGF10, and FGFR1 genes were analyzed, the TT genotype of BMP-4 rs2761884 (G/T) contributed to healthy peri-implant, while BMP-4 GAAA and GGGA haplotypes were associated with peri-implantitis.⁸⁴  Fibroblast growth factors (FGF) and their receptors (FGFR) are involved in the regulation of cell proliferation, differentiation, and migration. The TT+CT genotypes of FGF3 rs4631909 (C/T) were more frequent in healthy controls. The C allele frequency of the FGF3 rs4631909 (C/T) and FGF10 CCTG haplotype were positively associated with peri-implantitis.⁸⁴  The BMP-4 and FGF10 haplotypes showed a relationship with peri-implantitis. Bone morphogenetic protein/retinoic acid inducible neural-specific protein 3 (BRINP3) is involved in cell proliferation, migration, and death.⁸⁵  Polymorphisms of BRINP3 rs1935881 (A/G) and rs1342913 (A/G) have been associated with periodontitis⁸⁶  and peri-implantitis.⁸⁷ 

Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine involved in pathophysiological functions such as reduction of inflammation and promotion of wound healing. The polymorphisms of TGF-β1-509 C/T (rs1800469) and TGF-β1-800 G/A (rs1800468) in the promoter region increase its transcription activity. Polymorphism in TGF-β1-509 C/T is likely to be associated with severe periodontitis,⁸⁸  but the polymorphisms of TGF-β1-509 C/T and TGF-β1-800 G/A were not significantly associated with early implant failure.³⁶ 

Other genes that modulate inflammatory responses or bone metabolism have been investigated with respect to association with dental implant loss or peri-implantitis. Cluster of differentiation 14 (CD14) is involved in the immune response by acting as a co-receptor of Toll-like receptor 4 and MD-2 for the detection of bacterial lipopolysaccharide. Individuals with CC genotype of CD14-159 C/T (rs2569190) showed a fivefold risk for peri-implantitis and higher RANKL level and the RANKL/OPG ratio in peri-implant crevicular fluid.⁷²  Polymorphisms of Toll-like receptor 2⁸⁹ and Toll-like receptor 4⁹⁰ were not associated with periodontitis. Calcitonin receptor (CTR) is involved in maintenance of calcium homeostasis and bone metabolism. Individuals with the TC genotype for CTR were 20 times more likely to suffer early marginal bone loss in the mandible than patients with the CC genotype.⁹¹  Vitamin D receptor polymorphism (rs731236) was suggested as a marker for susceptibility to chronic periodontitis⁹²  but was not associated with dental implant loss.³⁸  A group of small noncoding RNAs, known as miRNAs, are involved in multiple physiopathological processes. miR-146a (rs2910146) and miR-499 (rs3746444) gene polymorphisms were related to increased risk of chronic periodontitis and peri-implantitis.⁹³  Several other genes, including PF4/PPBP/CXCL5,⁹⁴  SIGLEC5, DEFA1A3,⁹⁵  IFI16, AIM2,⁹⁶  FBXO38, AP3B2,⁹⁷  and IFIH1⁹⁸ have also been associated with periodontitis. The circadian rhythm system and cartilage extracellular matrix have been demonstrated to contribute to osseointegration via vitamin D regulation and influenced the success of dental implants.⁹⁹  Genes encoding BRAF,¹⁰⁰  lactotransferrin,¹⁰¹  and haptoglobin¹⁰²  have been investigated but not found to be associated with implant loss, peri-implantitis, or periodontitis.

Dental implant loss in some patients cannot be explained by clinical factors alone, ¹⁰³  and several phenomena imply the existence of genetic risk factors for implant failure.¹⁰⁴  Implant failure does not occur randomly among populations, but multiple implant failures may occur in a single individual, demonstrating a clusterization phenomenon.¹⁷  Recurrence of implant failure is common.¹⁰⁵  The possibility of a genetic predisposition for dental implant complications has attracted attention in the past two decades.¹⁰⁶  Currently available data appear to support the existence of genetic susceptibility, but this remains unresolved. Discrepancies in results maybe attribute to small sample sizes and the potential limitations of data gathered from specific geographic populations. Most importantly, studies are dependent on polymorphism analysis and lack experimental evidence. Further study, with larger sample sizes in various ethnicities, is necessary to determine the effect of genetic polymorphisms. In addition, since only genes involved in immune regulation and bone metabolism have been investigated thus far, a genome-wide screen or omics-study—such as genomics, transcriptomics, proteomics, and metabolomics—will be valuable to detect genuine susceptibility genes. Finally, and critically, it is necessary to develop an animal model to carry out experimental studies to elucidate the roles and mechanisms of genetic factors. The results will be helpful for the identification of proper candidates for dental implants in clinical practice.

Abbreviations

BMP

bone morphogenetic protein

BRINP3

bone morphogenetic protein/retinoic acid inducible neural-specific protein 3

CD14

cluster of differentiation 14

CTR

calcitonin receptor

FGF

fibroblast growth factor

FGFR

fibroblast growth factor receptor

IL

interleukin

IL-1RA

IL-1 receptor antagonist

MMP

matrix metalloproteinase

OPG

osteoprotegerin

PICF

peri-implant crevicular fluid

RANKL

receptor activator of nuclear factor kappa B ligand

SNP

single nucleotide polymorphism

TGF-β1

transforming growth factor-β1

TNF-α

tumor necrosis factor-α

VDR

vitamin D receptor

VNTR

variable number tandem repeat

This study was funded by Open Fund of Guangdong Key Laboratory of Pharmaceutical Functional Genes (No. 2014B030301028 and No. 2017B030314021).

No conflict of interest is declared.