MMP1-1607 polymorphism increases the risk for periapical lesion development through the upregulation MMP-1 expression in association with pro-inflammatory milieu elements

Abstract

Increased matrix metalloproteinases (MMPs) activity is a hallmark of periapical granulomas. However, the factors underlying the MMPs expression modulation in healthy and diseased periapical tissues remains to be determined. Objective In this study, we evaluated the association between the MMP1-1607 polymorphism (rs1799750) and pro-inflammatory milieu elements with MMP-1 mRNA levels in vivo.Material and Methods MMP1-1607 SNP and the mRNA levels of MMP-1, TNF-a, IFN-g, IL-17A, IL-21, IL-10, IL-4, IL-9, and FOXp3 were determined via RealTimePCR in DNA/RNA samples from patients presenting periapical granulomas (N=111, for both genotyping and expression analysis) and control subjects (N=214 for genotyping and N=26 for expression analysis). The Shapiro-Wilk, Fisher, Pearson, Chi-square ordinal least squares regression tests were used for data analysis (p<0.05 was considered statistically significant).Results The MMP1-1607 1G/2G and 1G/2G+2G/2G genotypes were significantly more prevalent in the patients than in controls, comprising a risk factor for periapical lesions development. MMP-1 mRNA levels were higher in periapical lesions than in healthy periodontal ligament samples, as well as higher in active than in inactive lesions. The polymorphic allele 2G carriers presented a significantly higher MMP-1 mRNA expression when compared with the 1G/1G genotype group. The ordered logistic regression demonstrated a significant correlation between the genetic polymorphism and the expression levels of MMP-1. Additionally, the pro- and anti-inflammatory cytokines IL-17A, IFN-g, TNF-a, IL-21, IL-10, IL-9, and IL-4 were significant as complementary explanatory variables of MMP-1 expression.Conclusion The MMP1-1607 SNP was identified as a risk factor for periapical lesions development, possibly due to its association with increased MMP-1 mRNA levels in periapical lesions. The MMP-1 expression is also under the control of the inflammatory milieu elements, being the cytokines TNF-a, IL-21, IL-17A, and IFN-g associated with increased MMP-1 levels in periapical lesions, while IL-10, IL-9, or IL-4 presented an inverse association.

Potential role of TP63 in apical periodontitis development

“…, Trombone et al . ). For example, allelic and genotypic association was observed between IL1B SNP and subjects with deep caries and AP, therefore, this variation might play a role in the AP development in patients with deep caries (Dill et al .…”

“…In this context, polymorphisms in genes/proteins with known functions in pulpal/periapical disease (e.g. interleukins, matrix metalloproteinases, heat shock proteins) have recently been reported to have allele-specific effects on AP susceptibility (Morsani et al 2011, Menezes-Silva et al 2012, Amaya et al 2013, Dill et al 2015, Evrosimovska et al 2015, Maheshwari et al 2016, Trombone et al 2016. For example, allelic and genotypic association was observed between IL1B SNP and subjects with deep caries and AP, therefore, this variation might play a role in the AP development in patients with deep caries (Dill et al 2015).…”

“…Taken together, these observations suggest that TP63 may have a role in the development and pathogenesis of AP lesions, therefore making it a plausible gene for AP. In recent years, in addition to an infectious origin, the development of AP has been linked to the host immune response and studies have shown that individual genetic variation through the effects of single nucleotide polymorphisms (SNPs) might contribute to increased AP susceptibility and development (Morsani et al 2011, Menezes-Silva et al 2012, Amaya et al 2013, Dill et al 2015, Evrosimovska et al 2015, Maheshwari et al 2016, Trombone et al 2016.…”

TBX21-1993T/C polymorphism association with Th1 and Th17 response at periapex and with periapical lesions development risk

“…This study had institutional review board approval of University of São Paulo (process 2115‐2009). Patients and control subjects were selected as previously described . Patients presenting periapical lesions (characterized radiographically as rarefaction lesions with the disappearance of the periodontal ligament space and discontinuity of the lamina dura) were referred to endodontic surgery after conventional root canal treatment failure (presence of periradicular radiolucency that did not resolve or that increased in size with evidences of continuous bone resorption before acceptable endodontic treatment) .…”

“…The genotypic analysis comprised 188 patients ( N = 188, aged 19–60; 91 females and 97 males) from the periapical lesions group, 152 patients from the deep caries group ( N = 152, aged 22–56; 72 females and 80 males), and 283 subjects from the control group ( N = 283, aged 18–56; 138 females and 145 males). For the genotypic analysis, patients from periapical lesions and deep caries groups and control subjects’ epithelial buccal cells were sampled from inner cheek buccal mucosa scrapping after a mouthwash with 3% glucose for genotyping purposes . DNA was extracted from epithelial buccal cells with sequential phenol/chloroform solution as previously described and used for the allelic discrimination of TBX21‐1993T/C SNP (rs4794067) variants, performed with Taqman (Applied Biosystems, Warrington, UK) chemistry as previously described .…”