## 4 Discussion  
This study aimed to verify if there is an association between the polymorphisms of the IL-1A, IL-1B, and IL-1 RN genes and peri-implantitis. It is a relevant topic since, if this association is confirmed, it is possible to identify patients who have this polymorphism and the physician's approach can be adjusted in order to prevent the onset of this disease, considered a public health problem. Genetic polymorphisms are constant and can be measured before disease onset, thus it could be of great benefit for treatment planning and prognosis in an early stage. Despite the fact that peri-implantitis etiology and pathology are complex, the identification of genetic biomarkers associated with peri-implantitis risk could be a valuable tool in daily clinical practice. They could be used for early identification of individuals predisposed to increased peri-implantitis risk, and this would help practitioners (after estimating dental implants prognosis) in individualizing their treatment plan. The future of disease diagnosis must involve not only identifying more susceptible patients but also identifying disease-associated biomarkers. Biomarkers are biological indicators with high prognostic and predictive value that can be related to the onset or development of a pathology. Frequently they must be able to predict the presence of a disease or its progression. A recent paper that has focused on five promising host derived biomarkers as candidate for early diagnosis of periodontitis, IL-1 \(\beta\) was one of them [36]. After a systematic search, which is described in the flowchart in Figure 1, eight articles were obtained for the present systematic review [21; 22; 23; 24; 25; 26; 34; 35]. Table 1 shows the general conclusions of each of the eight articles. Four of these articles concluded that individuals with the IL-1 gene polymorphisms had a higher risk for the development of peri-implantitis [21; 22; 24; 26]. These results are in agreement with  
Figure 8: Forest Plot of the cumulative meta-analysis for the IL-1B +3954 polymorphism. [PERSON] et al., 2006 [21]; [PERSON] et al., 2011 [23]; [PERSON] et al., 2019 [24]; [PERSON] et al., 2021 [26]. Figure 7: Log OR meta-regression for the IL-1B +3954 polymorphism as a function of the year of publication (\(p\)-value = 0.014, coefficient = 0.067). what is found in the systematic review of [PERSON] et al. [27]. In this systematic review, the authors observed that in two of the three studies which evaluated peri-implantitis in relation to IL-1 genotype, the findings indicate that IL-1 RN, IL-1A \(-\)899, IL-1B \(+\)3954 gene polymorphisms were correlated to increased peri-implant tissue infection and destruction [27]. In 2008, [PERSON] et al. carried out a systematic review [37] where two articles were included [38; 39], and they concluded that there is not enough evidence to support or refute an association between the IL-1 genotype status and peri-implantitis. It should be mentioned that the articles included in this review evaluated peri-implantitis based on bone loss [37; 38]. The number of studies in the literature evaluating this association is limited and some of these do not refer to confounding variables such as periodontal condition, ethnicity, and smoking status. These factors may explain the differences found between the different studies. The ethnicity of the populations included in the studies varies and there are studies that include patients who smoke and others who do not. On the other hand, the definition of peri-implantitis varies between studies, which makes comparisons between studies difficult. In our systematic review, we only included articles in which peri-implantitis was the evaluated outcome. From 2018, with the new Classification of Periodontal and Peri-implant Diseases and Conditions, it will be easier to standardize the definition of peri-implantitis between studies [6].