Overzealous immunological reactions are believed to cause abnormal tissue destruction leading to periodontitis. Inflammatory cytokines are involved in the initiation and continuation of such immune reactions. Interleukin-1 (IL-1) has been long recognized in periodontal tissues and its relevance to the development of periodontitis has been established (Page 1991). IL-1 receptor recognizes both IL-1 α and IL-1β, which are encoded by distinct genes but share approximately 50 % sequence homology. IL-1 receptor also binds to IL-1 receptor antagonists (IL-1RA, encoded by IL-1RN gene). Whereas IL-1α or IL-2β exerts downstream reactions after binding to IL-1 receptor, IL-1RA simply occupies the IL-1 receptor without any intracellular effects and thus is considered an inhibitor of IL-1 functions (Arend and Guthridge 2000). Among these IL-1-related molecules, it has been reported there is an increased level of IL-1β in gingival crevicular fluid associated with severe periodontitis (Chaudhari et al. 2011; Honig et al. 1989; Liu et al. 1996) and peri-implantitis (Curtis et al. 1997; Kao et al. 1995; Panagakos et al. 1996; Tsai et al. 1995).

Kornman et al. (1997) reported that the genotype exhibiting concurrent minor allele SNPs in IL-1α (−889) and IL-1β (3953) were found to be more prevalent in non-smoker patients with severe chronic periodontitis (Kornman et al. 1997). Initially, the assay for IL-1α (−889) SNP presented some technical difficulties. However, IL-1α (−889) SNP was later found within the same “haplotype” of IL-1α (4845) SNP. When we inherit the genetic information from our ancestors, a block of chromosome often containing multiple genes (called alleles) is transmitted as one piece. This piece of chromosomal fragment is called haplotype. In other words, the IL-1α (−889) SNP located before the beginning of the IL-1α coding sequence and IL-1α (4845) SNP located the end of IL-1α coding sequence should be transmitted together over many generations. Therefore, the presence of IL-1α (−889) SNP should be predicted by the test for IL-1α (4845) SNP, which provided a technically feasible assay. Currently, SNPs of IL-1α (−889) and IL-1α (4845) are interchangeably used. It was also found that due to early sequence irregularities, IL-1β (3953) SNP may be interchangeably described as IL-1β (3954).

A commercially available clinical test of IL-1 SNPs was developed to determine the SNP minor alleles of IL-1α (−889/4845) and IL-1β (3953/3954). PTS^® genetic susceptibility test is the only commercially available SNP test in dentistry and currently distributed by Interleukin Genetics, Inc. and by OralDNA Labs (limited to the US market). In this test, patients who carry the minor allele of both IL-1 SNP sites would be informed of a potentially increased susceptibility to severe chronic periodontitis. The availability of the PTS^® test may have contributed to the robust increase in genetic association studies for both periodontitis and implant failure (Table 4.1).

Feloutzis et al. (2003) investigated 180 patients, who received at least one ITI implant at the University of Berne (Feloutzis et al. 2003). In this study, 7 out of a total of 182 implants were lost during the loading period, all of which were placed in the maxilla of heavy smokers defined as 20 cigarettes per day for at least 20 years. For the remaining implants, the periapical radiographs taken during the multiple recall visits were used to measure the average loss of bone heights mesial and distal to the implant surface (the absolute bone loss, ABL). ABL as well as the bone loss per year was found to be significantly greater in the heavy smoker group; however, these peri-implant bone loss values were not associated with an IL-1 genotype based on the PTS^® test (Feloutzis et al. 2003). Contrary to the hypothesis, there was a general but insignificant trend that IL-1 genotype positive patients showed smaller bone loss values as well as less bleeding-on-probing sites. When the smoking habits and IL-1 genotypes were combined, non-smokers or former smokers carrying the positive IL-1 genotypes indicated significantly less peri-implant bone loss (ABL and the bone loss per year). The smokers with the positive and negative IL-1 genotypes showed similar bone loss values. Therefore, if patients do not smoke, the data from this study suggest that the positive IL-1 genotype by PTS^® test may indicate protection from the peri-implant bone loss.

Gruica et al. (2004) reported a follow-up study using the increased number of patients in the same institution (Gruica et al. 2004). This study included 180 patients and peri-implant biological complications were found associated with the longer number of years smoked (p  =  0.0101) and the greater number of implants placed (p  =  0.0075). On the contrary, IL-1 minor allele genotypes examined by PTS^® test failed to show any correlation with peri-implant biological complications. However, detailed examinations revealed that 12 patients in this study were current heavy smokers carrying the IL-1 minor allele genotypes and 6 patients in this group exhibited biological complications. Periapical radiographs taken at recall visits of 1 and 8 years and radiographic peri-implant bone loss values were determined during this period of 7 years. The statistical evaluation using a generalized estimating equation suggested a correlation between IL-1 minor allele genotypes and peri-implant bone loss.

The IL-1 genotypes have been repeatedly examined in patients who have experienced implant failure or peri-implantitis. However, the results from all authors failed to establish the statistically significant correlation between IL-1α (−889/4845) and IL-1β (3953/3954) dominant minor SNP alleles, with various biological complications associated with dental implants (Table 4.1) (Campos et al. 2005b; Jansson et al. 2005; Laine et al. 2006; Lin et al. 2007; Montes et al. 2009; Rogers et al. 2002; Shimpuku et al. 2003; Wilson and Nunn 1999). As such, the IL-1α (−889/4845) and IL-1β (3953/3954) SNP genotype alone may not explain the cause of implants failure (Bormann et al. 2010).

Several investigations examined different SNP genotypes associated with IL-1 genes such as IL-1β (−511) or IL-1RN (intron 2) and found suggestive or strong correlations with the loss of multiple implants or marginal bone loss (Dirschnabel et al. 2011; Laine et al. 2006; Lin et al. 2007; Montes et al. 2009; Shimpuku et al. 2003).

In a recent study, while statistical significance was not achieved, there was an increased trend of the prevalence of these SNP minor allele genotypes in patients experiencing peri-implantitis among the other evaluated implant-related biological complications (Vaz et al. 2011). Rogers et al. (2002) reported no significant correlation between the IL-1α (−889/4845) and IL-1β (3953/3954) SNP genotype and implant failure; however, severe adult chronic periodontitis was significantly associated with IL-1β (3953/3954) SNP, but not IL-1α (−889/4845) (Rogers et al. 2002).

The IL-1-related genes are located in close proximity within the approximately 300 Kb region chromosome 2q14 (Fig. 4.4a). The number of publications on the positive association of IL-1 genes with implant failure appeared to increase in the area between IL-1β (−511) and IL-RN (intron 2) (Fig. 4.4b). Incidentally, an analysis of this IL-1 cluster region comparing 40 generalized aggressive periodontitis patients and 96 periodontally healthy subjects similarly reported the elevated association between IL-1β (−511) and IL-RN (intron 2) (Fig. 4.4c) (Scapoli et al. 2005).

Melo et al. (2011) did not find any differences in the genotypic variations in IL-1β (3953/3954), IL-1β (−511) and IL-6 (−174) SNPs in peri-implantitis patients, and the same patient groups did not show the increase or decrease in the concentrations of IL-1b and IL-6 in the crevicular fluid sample obtained from healthy osseointegrated implants, peri-implantitis sites as well as healthy teeth (Melo et al. 2011). However, this study did not evaluate IL-1RN and IL-36RN.